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The mechanism of action of quinidine on squid axons has been examined by means of voltage clamp and internal perfusion techniques. When applied either externally or internally, quinidine HCl suppresses both sodium and potassium conductance increases, the effect on the former accounting for the observed decrease in action potential. The potassium conductance in quinidine undergoes a marked inactivation in a manner dependent upon the membrane potential and time, accounting for the observed prolongation of the terminal falling phase of the action potential. Quinidine methiodide exhibits the effect similar to that of quinidine HCl only when applied internally. The dissociation constants of quinidine in suppressing the sodium conducting system are estimated to be 2.4 x 10(-4) and 4.0 x 10(-4) M for quinidine HCl and methiodide, respectively. The dissociation constant of quinidine in suppressing the potassium-conducting system decreases with increasing step depolarization. When applied externally to the intact axons, quinidine HCl is more effective at external pH 8.6 than at 7.3. When perfused internally, quinidine HCl is more effective at internal pH 7.0 than at 8.0, and the potency is related to the calculated internal concentration of the charged form rather than that of the uncharged form. | These results lead to the conclusion that potassium HCl penetrates the nerve membrane in the uncharged form, is ionized in the axon and blocks the sodium and quinidine conductances primarily in the charged form. | contradiction |
In order to determine the effect of acid lumen pH on renal tubular potassium transport, cortical collecting tubules were dissected from rabbit kidneys and perfused in vitro. When the pH of the perfusate was lowered from 7.4 to 6.8, potassium secretion into the tubule lumen decreased by an average of 47%. The transepithelial voltage increased from a mean value of -32 mV (lumen negative) at pH 7.4 to -51 mV at PH 6.8. Net sodium absorption from the tubule lumen was essentially unchanged (5% mean decrease). Transepithelial voltage and potassium secretion returned to control values when the pH of the perfusate was raised to 7.4. Alterations in pH of the bath had no comparable effect on the transepithelial voltage, whether the bath pH was increased or decreased. | We conclude that a decrease in the potassium secretion of the tubule fluid of itself inhibits active pH in this tubule segment, providing an additional explanation for the decrease in potassium excretion found in acidosis. | contradiction |
ATP, at a dose higher than 0-1 mug m1(-1), showed a biphasic action consisting of an initial increase followed by a gradual decrease of muscle tension in the isolated tracheal strip-chains of guinea-pigs. The pattern of this biphasic response to ATP varied with the level of basal tone of the preparation at the moment of application of ATP. A smiliar biphasic action was obtained by prostaglandin (PG) E2 among the various active substances studied including acetylcholine, histamine, catecholamines and various types of PG. Indomethacin (0-1 mug m1(-1) and aspirin (30 mug m1(-1)) completely abolished the ATP-induced inhibitory response observed in the presence of histamine (10 muM). Polyphloretin phosphate (100 mug m1(-1)) also significantly depressed the inhibitory response to ATP or PGE2. | It is not concluded that the response to ATP of the preparation is mediated by PGE2 released via the stimulation of its biosynthesis. | contradiction |
Seven hundred and seventy-six cases were studied during a six-month period to see if induction of emesis could be successfully managed at home by telephone. Emesis was successful in 98.8% of cases. In 6.7% of all cases, symptoms were found at 4-hour follow-up that were referrable to the ingestion, but all were considered to be of minor consequence. No complications of vomiting occurred. Twenty-four hour follow-up investigation indicated no significant complications of induction of emesis or complications from managing the patient by telephone. | It is our conclusion that, with appropriate telephone supervision, home -induced emesis of ingestions expected to produce mild to moderate symptoms is as effective as emergency room or physician office management of cases. | entailment |
The effects of the alpha-adrenergic agonist phenylephrine on the levels of adenosine 3':5'-monophosphate (cAMP) and the activity of the cAMP-dependent protein kinase in isolated rat liver parenchymal cells were studied. Cyclic AMP was very slightly (5 to 13%) increased in cells incubated with phenylephrine at a concentration (10(-5) M) which was maximally effective on glycogenolysis and gluconeogenesis. However, the increase was significant only at 5 min. Cyclic AMP levels with 10(-5) M phenylephrine measured at this time were reduced by the beta-adrenergic antagonist propranolol, but were unaffected by the alpha-blocker phenoxybenzamine, indicating that the elevation was due to weak beta activity of the agonist. When doses of glucagon, epinephrine, and phenylephrine which produced the same stimulation of glycogenolysis or gluconeogenesis were added to the same batches of cells, there were marked rises in cAMP with glucagon, minimal increases with epinephrine, and little or no changes with phenylephrine, indicating that the two catecholamine stimulated these processes largely by mechanisms not involving cAMP accumulation. DEAE-cellulose chromatography of homogenates of liver cells revealed two major peaks of cAMP-dependent protein kinase activity. These eluted at similar salt concentrations as the type I and II isozymes from rat heart. Optimal conditions for preservation of hormone effects on the activity of the enzyme in the cells were determined. High concentrations of phenylephrine (10(-5) M and 10(-4) M) produced a small increase (10 tp 16%) in the activity ratio (-cAMP/+cAMP) of the enzyme. This was abolished by propranolol, but not by phenoxybenzamine, indicating that it was due to weak beta activity of the agonist. The increase in the activity ratio of the kinase with 10(-5) M phenylephrine was much smaller than that produced by a glycogenolytically equivalent dose of glucagon. The changes in protein kinase induced by phenylephrine and the blockers and by glucagon were thus consistent with those in cAMP. Theophylline and 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, potentiated the effects of phenylephrine on glycogenolysis and gluconeogenesis. The potentiations were blocked by phenoxybenzamine, but not by propranolol. Methylisobutylxanthine increased the levels of cAMP and enhanced the activation of protein kinase in cells incubated with phenylephrine. These effects were diminished or abolished by propanolol, but were unaffected by phenoxybenzamine. | It is concluded from these data that alpha-adrenergic activation of glycogenolysis and gluconeogenesis in isolated rat liver parenchymal cells occurs by mechanisms not involving an increase in total cellular cAMP or activation of the cAMP-dependent protein kinase. | entailment |
A new antidepressive drug, S1694, produces increased locomotor activity (LA) in mice, but less so than d-amphetamine. This effect is decreased by pimozide, phenoxybenzamine, as well as by pretreatment of the animals with reserpine or alpha-methyl-p-tyrosine methyl ester (H44/68). S1694 inhibits active dopamine (DA) uptake into rat striatal synaptosomes, but not noradrenaline (NA) uptake into rat hypothalamic synaptosomes, or serotonin (5-HT) uptake into rat midbrain synaptosomes, in the concentrations used. The inhibition of DA uptake appears tp be competitive and the inhibition constant estimated is 1,3 X 10(-6) M. In addition, S1694 releases DA in the same concentrations, and NA as well as 5HT at higher concentrations. | It is concluded that S1694 activates LA primarily by inhibitionof DA re-uptake and DA release. | entailment |
Previous work in our laboratory has shown that respiratory acidosis (RA) impaired mechanical function in canine tracheal smooth muscle (TSM). Since an intracellular acidosis could be brought on by the increased CO2 content of the bathing medium and alter the Km's of rate-limiting glycolytic enzymes in the pathway of energy production for contractile function, we have investigated the effects of RA on the intracellular pH (pHi) of TSM. Using the DMO method, paired unstimulated or resting TSM strips were incubated under normocapnic conditions (PO2 600 Torr, PCO2 40 Torr, pH 7.40) and RA (PO2 550 Torr, PCO2 110 Torr, pH 6.95) with 14C-labeled DMO and 3H-labeled inulin or PEG-4000. In another set of paired experiments, TSM strips were tetanized electrically every 5 min or pharmacologically throughout the incubation period ("active" muscle strips). The tissue and an aliquot of bathing medium were counted for 3H and 14C content and the values entered into the Wadell and Butler equation. The pHi's of "resting" normocapnic and acidotic strips were 7.041 +/- 0.017 (SE) and 6.752 +/- 0.012, respectively. However, the pHi's of "active" normocapnic and acidotic strips were 7.275 +/- 0.017 and 7.017 +/- 0.015, respectively. | We conclude that pH lowers intracellular respiratory acidosis in both resting and mechanically active TSM's; however, "active" preparations whether exposed to normocapnia or acidosis were unexpectedly more alkaline than their "resting" counterparts. | contradiction |
In order to establish whether alcohol in amounts in amounts customarily imbibed during social drinking causes gastro-oesophageal reflux, 12 healthy young individuals, without symptoms of gastro-oesophageal reflux, were studied twice. Each time, distal oesophageal pH was monitored continuously for three hours after a standard meal which included either 180 ml 100 proof vodka or 180 ml water. The order of studies with and without alcohol was random. Peak blood alcohol concentrations ranged between 0.63 and 1.29 g/l. Eleven of the 12 subjects refluxed more after alcohol; and the difference in mean reflux scores for studies with and without alcohol was highly significant. | We conclude that relatively modest quanttities of alcohol induce gastro-oesophageal reflux in healthy people. | entailment |
When Pisaster, Asterias, or Thyone sperm are treated with the ionophore A23187 or X537A, an acrosomal reaction similar but not identical to a normal acrosomal reaction is induced in all the sperm. Based upon the response of the sperm, the acrosomal reaction consists of a series of temporally related steps. These include the fusion of the acrosomal vacuole with the cell surface, the polymerization of the actin, the alignment of the actin filaments, an increase in volume, an increase in the limiting membrane, and changes in the shape of the nucleus. In this report, we have concentrated on the first two steps in this sequence. Although fusion of the acrosomal vacuole with the cell surface requires Ca++, we found that the polymerization of actin instead appears to be dependent upon an increase in intracellular pH. This conclusion was reached by applying to sperm A23187, X537A, or nigericin, ionophores which all carry H+ at high affinity, yet vary in their affinity for other cations. When sperm are suspended in isotonic NaCl, isotonic KCl, calcium-free seawater, or seawater, all at pH 8.0, and the ionophore is added, the actin polymerizes explosively and an efflux of H+ from the cell occurs. However, if the pH, of the external medium is maintained at 6.5, the presumed intracellular pH, no effect is observed. And, finally, if egg jelly is added to sperm (the natural stimulus for the acrosomal reaction) at pH 8.0, H+ is also released. | On the basis of these observations and those presented in earlier papers in this series, we conclude that a rise in intracellular pH induces the AngII-induced epidermal growth factor receptor to disassociate from its binding proteins. | contradiction |
To investigate whether fetal acidosis increases the placental transfer of lidocaine, resulting in higher fetal blood levels of the drug, lidocaine was infused intravenously into ten pregnant ewes to maintain plasma levels of 2-4 microgram/ml. After maternal-fetal equilibrium was reached, the fetus was made acidotic by infusing lactic acid intravenously. Fetal blood pH decreased from 7.35 to 7.10. With fetal acidemia, fetal blood lidocaine levels increased significantly from 1.60 +/- 0.11 microgram/ml to 2.72 +/- 0.26 microgram/ml. The fetal-maternal lidocaine ratio increased from 0.76 to 1.21. Correction of the acidosis by bicarbonate infusion returned the fetal-maternal ratios to control values. | It is concluded that acidosis in the fetus may result in trapping of ionized lidocaine in the fetal circulation and increase the transfer of lidocaine across the placenta. | entailment |
Steady-state passive hyperventilation alkalosis produces a predictable increase in oxygen uptake (VO2) proportional to the change in arterial pH (pHa) while variable changes in VO2 have been reported during alkali infusion. To compare metabolic with respiratory alkalosis 17 dogs were anesthetized with halothane and their VO2 response to respiratory alkalosis evaluated by hyperventilation. The pHa measured during this phase was duplicated during the later continuous infusion of NaHCO3 at which time either 1) ventilation was held constant at the control level, allowing arterial carbon dioxide tension (PaCO2) to rise as a consequence of the bicarbonate dissociation, or 2) PaCO2 was held constant by servo control of ventilation. Hyperventilation (pHa 7.6, PaCO2 13 Torr) produced an average increase in VO2 of 24%. During the bicarbonate infusion at constant ventilation (pHa 7.6, PaCO2 45 Torr) VO2 increased only 7%; however, when PACO2 was held constant by servo ventilation VO2 increased 21% above control. | We conclude that respiratory and metabolic alkalosis produce similar increases in VO2 when steady-state acid-base conditions are achieved. | entailment |
Changes in ECG, free calcium (CaF), and other biochemical parameters were measured during reinfusion of citrate anticoagulated blood in 12 subjects undergoing plateletpheresis. Physical symptoms during the procedure were also monitored. The CaF was found to correlate best with the Q-oTc interval as compared to the Q-oT, Q-Tc, or Q-T interval. While the correlation was significant (r = 0.592, p less than .001), the Q-oTc could not predict the CaF. A number of other blood constituents were found to change during plateletpheresis, with most directly related to either citrate administration or hemodilution. Severe physical symptoms were found in one subject and no symptoms in three. In the subjects without symptoms the changes in Q-oTc, Pi, alkaline phosphatase, and glucose through the plateletpheresis procedure were different from changes in all subjects. The decrease in glucose level was the most striking single factor correlating with the lack of physical symptoms during the citrate-induced hypocalcemia associated with plateletpheresis. | It is concluded that monitoring of the ECG cannot substitute for direct measurement of free calcium in citrate -induced hypocalcemia , that the physical symptoms associated with similar levels of hypocalcemia are variable, that glucose level may be a marker for the effects of citrate -induced hypocalcemia , and that lowered citrate loads during plateletpheresis appear warranted. | entailment |
We have studied the effects of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase, on the in vivo conversion of L-T4 (T4) to 3',3,5-triiodo-L-thyronine (T3), and on the biological effectiveness of T4. Thyroidectomized rats were used and were injected daily with T4 maintenance doses. Three different types of experiments were carred out. The first involved isotopic equilibration with 125I-labeled T4 and measurement of urinary 125I excretion. The second series involved the injection of a single dose of [125I]T4, with the amounts of [125I]T3 in different tissues being studied 7 or 20 h later. The third series involved daily treatment for 13 days with T4 and alpha-MPT, at the end of ehich the liver alpha-glycerophosphate dehydrogenase activity was measured as a parameter of the biological effects of the hormone. Though the experimental approaches used clearly disclosed the well known effects of 6-propyl-2-thiouracil, no clear-cut effects of alpha-MPT were observed. | It is concluded that alpha-MPT neither inhibits the conversion of T4 to T3 in vivo in rats nor affects the biological potency of a given dose of T4 , at least to an extent compararble to that observed when 6-propyl-2-thiouracil is used. | entailment |
5-Hydroxytryptophan (5-HTP) and p-methoxyamphetamine (p-MA) induce dose-dependent, lethal hyperthermia when applied intravenously to monoamine oxidase inhibitor (MAOI) pretreated rabbits. The time course of hyperthermia and the doses required to induce hyperthermia varies between the two substances. Results with alpha-MT and PCPA suggest that 5-HTP hyperthermia depends on 5-HT formation, release of endogenous 5-HT, and the presence of catecholamines, whereas p-MA-induced hyperthermia most likely is a result of indirect 5-HT release. Some neuroleptics (piflutixol, spiroperidol and methiotepine) are extremely potent inhibitors of the induced hyperthermia, Also the 5-HT receptor blocking agent methergoline antagonizes hyperthermia induced by the two substances in rather low doses. On the other hand cis (Z)-flupenthixol is a very weak antagonist of 5-HTP but a more potent inhibitor of p-MA hyperthermia. | It is concluded that both 5-HT and catecholamine (dopamine) receptor blockade is required to antagonize 5-HT P hyperthermia and that antagonism of p-MA induced hyperthermia is primarily a result of influence on the 5-HT system. | entailment |
Apomorphine induced dose-dependent hyperthermia when applied intravenously to rabbits pretreated with a monoamine oxidase inhibitor. Inhibition of the synthesis of catecholamines (by alpha-MT) did not influence on apomorphine-induced hyperthermia, whereas 5-HT synthesis inhibition (by PCPA) completely abolished the hyperthermic response. Some neuroleptics and a 5-HT receptor blocking agent inhibited the hyperthermia in very low doses. A highly significant correlation was registered between the antagonism of apomorphine hyperthermia of 15 neuroleptics and their clinically useful doses. | It is concluded that apomorphine -induced hyperthermia most likely is a result of direct stimulation of dopamine receptors and release of 5-HT, and that abolition of this response represents a very sensitive in-vivo model for neuroleptic substances. | entailment |
In the first part of the review the background to the discovery of the asymmetric synthesis of squalene from two molecules of farnesyl pyrophosphate and NADPH is described, then the stereochemistry of the overall reaction is summarized. The complexity of the biosynthesis of squalene by microsomal squalene synthetase demanded the existence of some intermediate(s) between farnesyl pyrophosphate and squalene. This demand was satisfied by the discovery of presqualene pyrophosphate, an optically active C30 substituted cyclopropylcarbinyl pyrophosphate, the absolute configuration of which at all three asymmetric centers of the cyclopropane ring was deduced to be R. Possible mechanisms for the biosynthesis of presqualene pyrophosphate and its reductive transformation into squalene are presented. In the second part of the review the nature of the enzyme is discussed. | The question whether presqualene pyrophosphate is not an obligate intermediate in the biosynthesis of squalene is examined, with the firm conclusion that it is. | contradiction |
1. Bicarbonate ions stimulate the transport of serine and alanine into isolated hepatocytes. 2. The effect of bicarbonate is to increase the Vmax. of the transport process without changing the apparent Km. 3. The intracellular pH was estimated from the distribution of the weak base methylamine and the weak acid 5,5'-dimethyloxazolidine-2,4-dione (DMO) across the plasma membrane. 4. The addition of bicarbonate to a cell suspension caused the internal pH to become more acid. 5. The initial rate of serine, alanine and glycine transport was a linear function of the initial difference in pH across the membrane. 6. | It is concluded that bicarbonate activates the transport of these amino acids primarily by increasing the pH difference across the plasma membrane. | entailment |
D-penicillamine (80 mg/kg) potentiates the fall in blood pressure produced by an i.v. injection of histamine in the anaesthetized dog but is inactive on the effects of acetylcholine and prostaglandin E1. Other sulfhydryl agents (alpha-thioglycerol, 2-mercaptoethanol, 2,3-dimercapto-l-propanol, DL-cysteine, glutathione, diethyldithiocarbamate) can similarly modify the effects of histamine on blood pressure but two metal complexing agents (CaNa2 EDTA and orthophenantroline) are inactive. After pretreatment with indomethacin (10 mg/kg) or cimetidine (0.5 mg/kg/min) D-penicillamine still increases the effect of histamine but not after pretreatment with pyrilamine maleate (1 mg/kg). Moreover D-penicillamine does not modify the blood pressure drop due to dimaprit but increases that to 2-(2-pyridyl) ethylamine. | It is concluded that D-penicillamine and some other sulfhydryl agents can increase the blood pressure lowering effects of histamine at the level of vascular H1-receptors by a sensitizing mechanism which might involve the rupture of a disulfide bridge. | entailment |
The RNA-directed DNA polymerase of Rous sarcoma virus requires a 4S RNA molecule as primer for the initiation of DNA synthesis on the viral 70S RNA genome. We have now functionally identified primer activity in uninfected cells on the basis of the capacity of cellular 4S RNA to actively participate in the initiation of DNA synthesis by the RNA-directed DNA polymerase of Rous sarcoma virus in vitro. This was accomplished by reconstitution experiments in which 4S RNA from uninfected avian cells was tested for its ability to restore template activity to the viral RNA genome from which all primer had been removed. Similar reconstitution experiments were employed to demonstrate a primer activity in the 4S RNA population of duck, mouse, and human cells. Primer activity appears to be absent in lower eukaryotic or prokaryotic cells. Unambiguous identification of the Rous sarcoma virus primer molecule in uninfected cells was accomplished by directly purifying a 4S RNA molecule from the bulk of host cell transfer RNA and establishing structural similarities between this cellular 4S RNA species and the Rous sarcoma virus primer by two-dimensional paper electrophoresis of oligonucleotides obtained from a T1 ribonuclease digest of the RNA species. | We conclude that the Rous sarcoma virus DNA polymerase can utilize a host cell molecule as primer for the initiation of RNA-directed DNA synthesis in vitro. | entailment |
Protein A from Staphylococcus aureus has been found to react with all human leukocyte preparations tested. In 70 percent of the experiments the reaction leads to histamine release. Furthermore, protein A treatment of cells at 37 degrees C, both in complete and Ca-2+-free medium, results in the inhibition of anti-IgE-induced histamine release in all cell preparations, indicating that protein A and anti-IgE antibodies release histamine from the same cells. This inhibition seems to be due to the blocking or exhaustion of a step in the biochemical pathway, leading to histamine release activated by both protein A and anti-IgE. In some cell preparations desensitization but no histamine liberation is induced by protein A. | No inhibition occurs if the protein A treatment is performed at 4 degrees C. It is concluded that protein A elicits histamine liberation and desensitization by acting on IgG present on the surface of the basophil granulocytes. | entailment |
Ba++ added to the serosal solution bathing a resting frog stomach increased transmucosal resistance and induced acid secretion. The increase in acid secretion was associated with an increased leak of histamine from the mucosa into the serosal solution. Pretreatment with burimamide inhibited the secretory response to Ba++. After a pulse treatment with Ba++ (2 mM for 5 min), the effects on resistance were transient but the effects on acid secretion were sustained. A pulse treatment with histamine also led to a sustained increase in acid secretion, and this increase was blocked by burimamide. | It is concluded that Ba++ releases histamine which then stimulates acid secretion . | entailment |
Mast cells from the peritoneal and pleural cavities of actively sensitized rats were isolated and incubated with biogenic amines (5-hydroxytryptamine and dopamine) with or without pretreatment with specific antigen. An anaphylactic reaction resulting in the release of 20-25% of the histamine in the cells led to a slightly reduced amine uptake. At concentrations which induced histamine release comparable to that during the anaphylactic reaction compound 48/80 had a similar effect on the uptake of the two amines. Histamine release induced by higher concentrations of compound 48/80 led to a more pronounced reduction in the uptake of the amines, the reduction being roughly proportional to the extent of the histamine release. | It is concluded that the reduction in the in vitro amine uptake after anaphylactic and histamine release -induced compound 48/80 is due to the fact that there are a fewer intact granules capable of storing histamine and not primarily due to a damage to the mechanisms by which mast cells take up biogenic amines in vitro. | contradiction |
Triton X-100 at concentrations preceding those which liberated histamine, produced dose-dependent inhibition of compound 48/80-induced histamine release from rat mast cells. Triton X-100 (0.00002 1/1) depleted ATP content in the mast cells and blocked compound 48/80-induced histamine release. The inhibition of compound 48/80-induced histamine release and depletion of the ATP content in the mast cells was reversed by glucose (10 mmole). | It is concluded that inhibition by Triton X-100 of histamine release induced by compound 48/80 is dependent on inhibition of energy production. | entailment |
Previous studies have suggested that dihydrotestosterone accumulation in the prostate may be involved in the pathogenesis of prostatic hyperplasia in man and dog. However, the fact that the administration of 10 mg dihydrotestosterone/d to castrated, mongrel dogs (0.5 mg/kg body wt) causes little growth in the prostate, whereas identical doses of 3alpha- androstanediol regularly induce prostatic hyperplasia (> 14 g weight) has raised the possibility that the dihydrotestosterone accumulation may be the result rather than the cause of the pathology. To investigate the mechanism of this phenomenon, we measured the levels of dihydrotestosterone and 3alpha-androstanediol in prostates from 75 dogs. In both naturally occurring and 3alpha-androstanediol-induced prostatic hyperplasia, the levels of dihydrotestosterone were high (>5 ng/g), whereas in immature glands and glands from dihydrotestosterone-treated animals, levels were similar (2.1 and 2.6 ng/g, respectively). 3alpha-Androstanediol levels were no different in animals treated with dihydrotestosterone or 3alpha-androstanediol.Therefore, because exogenous 3alpha-androstanediol is a better precursor of prostatic dihydrotestosterone than exogenous dihydrotestosterone itself, the effects of treatment with larger doses (2.5 mg/kg per d) of dihydrotestosterone and 3alpha-androstanediol for 12 wk were examined. In these amounts, dihydrotestosterone was as effective as 3alpha-androstanediol in inducing the development of prostatic hyperplasia and in elevating prostatic dihydrotestosterone concentration. | Because dihydrotestosterone accumulates in spontaneous prostatic hyperplasia, because the administration of sufficient amounts of dihydrotestosterone to the castrated dog cannot induce the development of prostatic hyperplasia, and because 3alpha-androstanediol induces the development of hyperplasia via conversion to dihydrotestosterone , we conclude that accumulation of dihydrotestosterone is the cause of canine prostatic hyperplasia. | contradiction |
It was observed previously that serum-treated zymosan particles (Zx) augmented antigen and anti-IgE stimulated histamine release. With most of the enhancement attributed to an increased rate of release, this suggested that Zx was active only during the course of IgE-mediated release. This association between IgE-mediated histamine release and responsiveness to Zx was examined further in the present report. Addition of Zx at various time intervals after release had been initiated indicated that the basophil responsiveness to Zx was limited in duration; maximum responsiveness to Zx correlated closely with the period in which the rate of IgE-mediated histamine release was maximum. The time-dependent decline in sensitivity to Zx paralleled the kinetics for desensitization to antigen. Addition of Zx failed to cause release from basophils desensitized in vitro or from basophils of a donor who failed to release histamine upon challenge with anti-IgE. In contrast to the enhancement of IgE-mediated release, Zx did not augment histamine release caused by C5a or the synthetic peptide f-Met-Leu-Phe. | It is not concluded that an obligatory link exists between ongoing IgE -mediated histamine release and enhancement by Zx. | contradiction |
Because the alpha-adrenergic receptor antagonists phentolamine and tolazoline are similar in structure to histamine, it is possible that the vasodilatation caused by these drugs may be due in part to stimulation of histamine receptors. The vascular effects of these agents were studied in the hindquarters of rats and the gracilis muscle of dogs. To eliminate interruption of sympathetic vasoconstrictor tone as a mechanism of vasodilatation, all animals were treated with the alpha-adrenergic receptor antagonist, dibozane. After dibozane, histamine caused vasodilatation in the rat, whereas both tolazoline and phentolamine caused vasoconstriction. It is concluded that phentolamine and tolazoline do not stimulate vascular histamine receptors in the rat. In the dog, after alpha-receptor blockade, phentolamine and tolazoline caused vasodilatation, as did histamine. Responses to histamine were partially attenuated by mepyramine and greatly attenuated by the combination of mepyramine and metiamide, indicating the participation of both H1- and H2-histamine receptors. Vasodilatation caused by phentolamine was not reduced by antihistamines and does not appear to involve histamine receptors. Vasodilatation following tolazoline was blocked by metiamide but not mepyramine. | It is concluded that in addition to blockade of alpha-adrenergic receptors, vasodilatation can cause tolazoline by stimulation of histamine H2-receptors. | contradiction |
Postnatal development of the mammary gland was studied in 80 noninbred Sprague-Dawley virgin rats ranging in age from 2 to 112 days, and the changes induced by 7,12-dimethylbenz[a]anthracene (DMBA) were studied in 60 noninbred Sprague-Dawley virgin rats that, at the age of 55 days, were inoculated intragastrically with 10 mg DMBA/100 g body weight. To correlate the sequential structural changes in the two groups, animals of both groups were killed weekly and their mammary glands removed and processed for wholemount. Terminal endbuds (TEB), terminal ducts (TD), alveolar buds (AB), and lobules per square millimeter were counted in wholemount preparations under a stereomicroscope. During postnatal development, the mammary gland tree grew by sprouting numerous ducts ending in club-shaped TEB. The density of TEB reached a peak when the rats were 21 days old (25 +/- 2 TEB/mm2), decreased sharply until the animals were 63 days old, and then decreased slowly until they were 84 days of age. The number of TEB decreased because of their differentiation mainly into AB or their evolution to TD. AB later differentiated into lobules. AB increased in number steadily to a plateau when the animals were 70--84 days old. After DMBA was administered to the rats at 55 days of age, the number of TEB remained higher than that in the control animals and the TEB became larger and had higher mitotic activities. Such TEB were called intraductal proliferations (IDP); they evolved to adenocarcinomas. DMBA increased the number of TD and decreased the number of AB and lobules in relation to the control animals. | These findings led to the conclusion that DMBA administration to 55-day-old rats alters the differentiation of DNA leads to AB leads to lobules, inducing instead the sequence DNA leads to IDP leads to adenocarcinoma. | contradiction |
The present study was designed to investigate pharmacological vasodilation in patients with chronic obstructive pulmonary disease (COPD). This may have long-term therapeutic implications. Sublingual nitroglycerin (GTN) was administered to 16 patients with COPD and no evidence of organic heart disease (except one patient) in an attempt to determine severity of the decrease in arterial oxygenation. Gas exchange and hemodynamic studies were performed before and after GTN. Alverolar-arterial O2 tension gradient increased 5 mm Hg, arterial PO2 decreased 2 mm Hg, and cardiac output decreased from 4.36 to 3.85 liters/min. There was a decrease in pulmonary artery pressures, but pulmonary vascular resistance did not change. Total O2 transport (the product of cardiac output and arterial O2 content) decreased, due mainly to a decrease in cardiac output. | From these studies we conclude that transport significantly decreases O2 GTN in patients with COPD and normal left ventricular function; this decrease is due mainly to a reduction in cardiac output. | contradiction |
An iv administration of 1 ml sheep antiserum to somatostatin (anti-SS) resulted in marked increases of both serum GH and TSH, with a peak 10--20 min after administration in male rats anesthetized with urethane or pentobarbital. Administration of anti-SS had no effect on serum PRL. Ablation of the basal medial hypothalamus abolished the rises of both serum GH and TSH after anti-SS administration. Intravenous injection of 1 ml rabbit antiserum to TRH (anti-TRH) decreased serum TSH levels 15 min after injection, whereas injection of normal rabbit serum did not affect TSH levels. Serum TSH levels did not rise after injection of anti-SS in rats pretreated with anti-TRH. On the other hand, pretreatment with anti-TRH did not affect the basal serum GH levels nor the anti-SS-induced GH release. The enhanced secretion of GH and TSH after anti-SS injections was not blocked by pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. | The following conclusions were made: 1) both GH and TSH responses to anti-SS require an intact basal medial hypothalamus; (2) TSH response to anti-SS is mediated by hypothalamic TRH ; and 3) the GH response may be mediated by hypothalamic GH-releasing hormone which is not TRH or prostaglandins. | entailment |
We have tested the hypothesis that interconversion between multiple glucose-6-P-dependent forms of glycogen synthase helps regulate glycogen synthesis in adipose tissue. Our results indicate that interconversion of glycogen synthase in adipose tissue involves primarily dependent forms and that these interconversions were measured better by monitoring the activation constant (A0.5) for glucose-6-P than measuring the -: + glucose-6-P activity ratio. Insulin decreased and epinephrine increased the A0.5 for glucose-6-P without significant change in the activity ratio. Insulin consistently decreased the A0.5 in either the presence or absence of glucose, indicating that the insulin-promoted interconversion did not require increased hexose transport. Isoproterenol increased the A0.5 for glucose-6-P, while methoxamine was without effect, indicating beta receptors mediate adrenergic control of interconversion between glucose-6-P-dependent forms. The changes in the A0.5 produced by incubations with insulin or epinephrine were mutually reversible. | We conclude that 1) glycogen synthesis in adipose tissue is not catalyzed by multiple glucose-6-P-dependent forms of glycogen synthase , 2) hormones regulate glycogen metabolism by promoting reversible interconversions between these forms, and 3) there is no evidence that a glucose-6-P-independent form of glycogen synthase exists in intact adipose tissue. | contradiction |
Influence of dietary protein deficiency on the anti-inflammatory and ulcerogenic effects and on the kinetics of phenylbutazone was studied in male Sprague-Dawley rats fed ad libitum a 21% (control) or a 5% (low) protein diet for 3 weeks. A low protein diet fed to a decrease in body weight gain, plasma proteins, albumin, globulins, hepatic total and microsomal proteins and in cytochrome P-450. Phenylbutazone produced a greater ulcerogenic effect in rats fed a low protein diet than in control rats; its anti-inflammatory effect did not increase. Plasma t 1/2 of phenylbutazone was longer in protein-deficient rats than in control rats. Dietary protein deprivation led to a decrease in the plasma clearance and plasma protein binding of phenylbutazone but did not lead to a change in its bioavailability. No relationship between the severity of gastric ulceration and the concentration of phenylbutazone or oxyphenbutazone in the stomach tissue was found in any animal of the two groups. The increased susceptibility of protein-deficient rats to the ulcerogenic effect of phenylbutazone was reversible and was not observed when these animals were fed a control diet for 3 weeks. | It is not concluded that a dietary protein deficiency increases the ulcerogenic toxicity of phenylbutazone relative to its useful anti-inflammatory effects. | contradiction |
Dogs with indwelling polyethylene arterial and venous catheters ran on a treadmill (slope 15 per cent, speed 100 m./min.). Diabetes was produced by alloxan or by a combination of alloxan and streptozotocin. Glucose turnover was measured according to the primed constant-rate infusion technics with 2-3H-glucose as tracer. In resting diabetic dogs plasma glucose varied between 200 and 650 mg./100 ml. There was a direct linear correlation between the hepatic glucose output (Ra) and the plasma glucose level. Exercise increased both Ra and the clearance rate (CR) of glucose; however, Ra could not match the rate of disappearance (=renal loss plus glucose uptake of the muscle), causing the plasma glucose to decline more rapidly than in the running control dogs. Two to three days' treatment with methylprednisolone (MP, 3-3.2 mg./kg./day) caused a higher resting glucose level and a higher Ra. Exercise greatly increased the plasma glucose concentration, partly because MP enhanced the hepatic response but mainly because it essentially prevented the rise of CR. | It is concluded that (a) in chemically induced diabetes, the variable glucose level is the result of a variable rate of hepatic glucose output; (b) the increase of Ra by MP treatment does not increase the plasma glucose in the normal dog but significantly aggravates the alloxan diabetes, (c) diabetes reduces the effect of exercise on the glucose uptake of the muscle, and this effect is potentiated by the inhibitory action of the glucocorticoid. | entailment |
1. Insulin stimulates the activity of membrane-bound ATPase isolated from frog skeletal muscle and from rat brain. The increase in activity of the membrane-bound ATPase system isolated from frog ranged from 9-8 to 53% at concentrations of Na+ (25 mM), K+ (10 mM), and ATP (2 mM) similar to those in in vivo experiments conducted previously (Moore, 1973). The increased activity of the membrane-bound ATPase is, therefore, at least as great as the insulin-induced increase in Na efflux (10-38%) from intact cells (Moore, 1973). If the concentration of Na+ is lowered to 4 mM and that of ATP lowered to 0-5 mM albumin, and 10(6) M, the increase in ouabain-inhibitable ATPase activity can reach as high as 400%. 2. Ouabain, at a concentration (10(-3) M) sufficient to inhibit stimulation of the frog ATPase by increasing Na from 4 to 25 mM, completely blocked the stimulation of ATPase activity due to insulin. 3. At 2 mM-ATP, 100 mM-Na+, and 20 mM-K+, conditions which maximally activate the (Na+ + K+)-ATPase, insulin did not increase the ATPase, activity. Stimulation was consistently seen at 10 mM-K+, 0-5 mM-ATP, and either 4 mM or 25 mM-Na+. 4. The finding that insulin does not stimulate the ATPase activity in conditions in which the (Na+ + K+)-ATPase component is maximally activated and especially the fact that ouabain can reproducibly inhibit insulin stimulation of the membrane-bound ATPase activity strongly suggest that interaction of insulin with its receptor upon the plasma membrane somehow stimulates the (Na+ + K+)-ATPase system (ouabain sensitive; ATP phosphohydrolase, EC (3.6.1.3). | These results are consistent with previous studies of the effect of insulin upon Na efflux from intact cells (Moore, 1973) and support the previous conclusion that the component of Na efflux stimulated by insulin is active. | entailment |
2,4-Dinitrophenol (DNP) was found to cause a "clearing response" of myosin B in a medium in which "superprecipitation" of myosin B would otherwise take place. The effect of actin concentration on Mg-ATPase [EC 3.6.1.3] of HMM was studied in the presence and absence of DNP. The results indicate that DNP causes an increase rather than a decrease in the affinity of HMM for actin, and that it causes a decrease only in the actin-activated portion of the Mg-ATPase activity. Using a light-scattering technique, it was shown that neither the ATP-induced dissociation of acto-HMM nor subsequent reassociation is significantly affected by the presence of DNP. As for the formation of the myosin-phosphate-ADP complex in the myosin-ATPase reaction, it was shown that formation of the reactive complex is not affected by DNP. | It cannot thus be concluded that DNP inhibits the decomposition of the actomyosin-phosphate- ADP complex, which is thought to be coupled with superprecipitation. | contradiction |
Seven laboratories collaborating in a study of two intermediate purity plasminogen preparations (64/23, 63/6) observed that the amount of activator (urokinase or streptokinase) and the time of activation of plasminogen influenced the amount of plasmin generated. Using casein and a synthetic polypeptide (S-2251) as substrates, the authors subsequently showed that complete activation of plasminogen was difficult to achieve without acitivity losses due to plasmin autodigestion. | Comparison of the polypeptide subunits (on SDS electrophoresis) of the various AKT-induced activation mixtures with their plasmin activity allowed the conclusion that at maximum generation of plasmin from AKT-induced , some AKT-induced remains in the form of an inactive AKT-induced intermediate (PLG-i). | contradiction |
In order to obtain information about the target of membrane-active inhibitors of platelet aggregation two phenylalkanoles and two phenylalkylamines were examined with respect to their influence on membrane ATPase and energy metabolism. The phenylalkanoles, 2-phenylethanol and 3-phenylpropanol, strongly enhanced the liberation in washed platelets of inorganic phosphate (Pi) from endogenous substrate or added ATP. A simultaneous decrease was found in the ATP/ADP ratio while glucose uptake, glycogen utilization and lactate formation increased. The effects of 2-phenylethanol and 3-phenylpropanol on Pi liberation and ATP/ADP ratio were detectable only with starving platelets; the stimulation of glycolysis could also be seen when glucose was added. | It is not concluded that presence of glucose enabled the platelets to reincorporate additionally liberated Pi into their ATP pool by virtue of the higher metabolic rate. | contradiction |
The effects of dietary deficiency and excess of niacin and riboflavin on voluntary drinking of 10% (v/v) ethanol were studied in male rats. The effectiveness of dietary deficiency and excess of both niacin and riboflavin on tissue levels of these vitamins was demonstrated by measurements of urinary N1-methylnicotinamide and blood glutathione reductase (EC 1.6.4.2) activity. A high-niacin diet containing 75 mg niacin/kg food decreased ethanol intake by about 36% compared to the control diet containing 15 mgniacin/kg. Niacin or riboflavin deficiency and a high-riboflavin diet containing 40 mg rtary levels of niacin or riboflavin did not influence on ethanol elimination rate or levels of blood acetaldehyde during ethanol oxidation. Therefore, blood acetaldehyde was not responsible for the decreased ethanol intake of rats fed with a high-niacin diet. | It was concluded that the increased ethanol intake caused by dietary deprivation of B- vitamin complex found in earlier studies is not a result of deficiency of niacin or riboflavin but niacin may be involved in the decrease in ethanol drinking, which follows dietary B- vitamin complex supplementation. | entailment |
The effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexl-1-nitrosourea, and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea on two nonmitochondrial DNA polymerases (I and II) purified from rat liver and hepatoma were examined. The activity of DNA polymerase I was not altered by treatment with any of the nitrosoureas or the corresponding isocyanates, 2-chloroethyl isocyanate and cyclohexyl isocyanate. Incubation of DNA polymerase II with the nitrosoureas (1 mM) inhibited its enzymatic activity 30 to 45%. DNA polymerase II was inhibited 75 and 90% by 1.mM 2-chloroethyl isocyanate and cyclohexyl isocyanate, respectively. The nitrosoureas appear to exert their inhabitory action on the enzyme (DNA polymerase II) rather than on the DNA template. Pretreatment of the enzyme increased the degree of inhibition by 1 mM nitrosourea (50 to 60% inhibition) or 2-chloroethul isocyanate (greater than 90% inhibition), whereas pretreatment of the DNA template did not enhance the inhibitory effect. The three nitrosoureas are equally effective as inhibitors of DNA polymerase II. 2-Chloroethyl isocyanate and cyclohexyl isocyanate are better inhibitors than are the nitrosoureas. | Since further decomposition products of the isocyanates , 2-chloroethylamine and cyclohexylamine, do not inhibit DNA polymerase II , we conclude that the isocyanates , which are decomposition products of the nitrosoureas, are the active inhibitors of the enzyme. | entailment |
Parental and filial DNA strands were isolated from a Novikoff rat hepatoma cell line, synchronized by S-phase arrest with excess thymidine, that had completed up to one round of DNA replication in the presence of (14-C-methyl)methionine and (6-3-H) bromodeoxyuridine. Both strands were methylated, the proportion of total methyl label in parental DNA increasing slightly with time in S-phase. The studies were repeated with (14-C-methyl)methionine and (3-H)deoxycytidine to determine if parental methylation occurred on extant or repair-inserted cytosine residues. Both (14-C) and (3-H) were found in parental DNA. The (14-C)/(3-H) ration of parental DNA-5-methylcytosine was about twice that in filial DNA while the (3-H) data showed twice the concentration of 5-methylcytosine in parental compared to filial DNA. Thus parental methylation occurred on repair-inserted cytosine residues and resulted in overmethylation. That the DNA damage and repair was due to 5-phase arrest was shown by repeating the studies using a sequential mitotic-G1 arrest method. With this method little (14-C) or (3-H) was found in parental DNA. | We conclude that S-phase arrest leads to DNA damage and repair with subsequent overmethylation of repair-inserted cytosines; that sequential mitotic-G1 arrest minimizes DNA damage ; and, that the latter technique, suitable for synchronization of large quantities of cells, may prove useful in relatively artifact-free studies of eukaryotic DNA replication. | entailment |
While there is conflicting evidence concerning an effect of oestradiol on uterine cyclic AMP concentration, results from different laboratories (including ours) are in agreement that even when observed, the early increase in uterine cyclic AMP after oestradiol injection fails to occur when propranolol, a beta-adrenergic blocking agent, is given (50 mug, i.p.) 20 min before the oestradiol. The present work shows that pretreatment with propranolol failed to inhibit an early uterine response to oestradiol, namely the synthesis after 1 h of uterine protein, or class of proteins, IP. | It is concluded that the induction of IP by oestradiol does not depend on an decrease in uterine cyclic AMP concentration and that beta-adrenergic receptors do not have a role in this oestrogenic response. | contradiction |
1. The effect of purified cholera toxin on secretory processes of exocrine pancreas has been studied in the isolated, saline-perfused cat pancreas and in incubated pieces of rat pancreas. 2. The toxin evoked a biphasic secretory response from the perfused cat pancreas. An initial small phase, which began within minutes of toxin application, was an artefact due to the presence of NaN3 in the cholera toxin preparation as supplied; it could be entirely reproduced by NaN3 at the concentration expected during toxin stimulation. A second, sustained phase of secretion, due to the action of the toxin proper, began within 30-60 min, increasing in magnitude for many hours and persisting in the absence of toxin. It was accompanied by a parellel rise in tissue cyclic AMP concentration, and could be potentiated by theophylline. 3. The composition of the secretion stimulated by cholera toxin resembled that evoked by secretin; e.g. it contained a high concentration of bicarbonate and only basal amounts of digestive enzymes. 4. Similarly, cholera toxin did not stimulate enzyme secretion by incubated rat pancreas, despite large rises in tissue cyclic AMP concentration. 5. | Because cholera toxin has thus far been shown to have no other effect than that of stimulating adenylate cyclase, these observations support the conclusion that secretin does mediate the electrolyte secretory response of the pancreas to cyclic AMP , but offers no evidence that secretin plays a similar role in the regulation of pancreatic enzyme secretion stimulated by cholecystokinin-pancreozymin or acetylcholine. | contradiction |
1. Adenosine 3',5'-monophosphate (cAMP), its dibutyryl derivative (Db-cAMP) and other adenine nucleotides have been micro-injected into the hypothalamic region of the unanaesthetized cat and the effects on body temperature, and on behavioural and autonomic thermoregulatory activities observed. 2. Db-cAMP and cAMP both produced hypothermia when applied to the pre-optic anterior hypothalamus. With Db-cAMP the hypothermia was shown to be dose dependent between 50 and 500 mug (0-096-0-96 mumole). 3. AMP, ADP and ATP also produced hypothermia when injected into the pre-optic anterior hypothalamus. 4. The order of relative potencies of the adenine nucleotides with respect both to the hypothermia produced and to the autonomic thermoregulatory effects observed were similar. Db-cAMP was most potent and cAMP least. 5. Micro-injection into the pre-optic anterior hypothalamus of many substances including saline produced in most cats a non-specific rise in body temperature apparently the result of tissue damage. Intraperitoneal injection of 4-acetamidophenol (paracetamol 50 mg/kg) reduced or abolished this febrile response. 6. The hypothermic effect of the adenine nucleotides has been compared with the effects produced in these same cats by micro-injections of noradrenaline, 5-hydroxytryptamine, a mixture of acetylcholine and physostigmine (1:1), EDTA and excess Ca2+ ions. 7. | It is not concluded that as Db- cAMP and cAMP both produce hypothermia , it is unlikely that endogenous cAMP in the pre-optic anterior hypothalamus mediates the hyperthermic responses to pyrogens and prostaglandins. | contradiction |
Two hypophyseal lipolytic peptides, adrenocorticotropin (ACTH) and beta-melanocyte-stimulating hormone (beta-MSH), and the extrhypophyseal lipolytic peptide IIF, were compared with regard to their effects on free fatty acid production and 3',5'-cyclic adenosine monophosphate (cAMP) concentration in isolated rabbit and rat adipose tissue, and on adenylate cyclase activity in the tissue homogenates. ACTH at concentrations of 0.01 mug/ml or more increased lipolysis and cAMP levels in both tissues. beta-MSH at concentrations of 0.001 mug/ml or more increased lipolysis and cAMP in the rabbit tissue, but a concentration of 10 mug/ml did not stimulate lipolysis and did not alter nucleotide concentration in the rat tissue. Peptide IIF at 0.01 mug/ml or more stimulated lipolysis in rabbit adipose tissue and caused an accumulation of cAMP. A concentration of 100 mug/ml failed to stimulate free fatty acid production in the rat tissue and the cAMP level was also unaffected. In a medium containing 7.6 mEq/l of Mg++ and no Ca++, ACTH at 0.1 mug/ml or more stimulated adenylate cyclase activity in both rabbit and rat adipose homogenates by 6- to 12-fold. This effect was inhibited when Mg++ was replaced by Ca++, Na+ or K+. beta-MSH stimulated adenylate cyclase in rabbit, but not in rat, adipose homogenate in Mg++-containing incubation midium; again, the effect on rabbit adenylate cyclase was suppressed when Mg++ was replaced by Ca++, Na+ or K+. Peptide IIF failed to influence adenylate cyclase in the rabbit tissue homogenate in the Mg++-containing, Ca++-free medium; but when the medium contained 7.6 mEq/l of Ca++ in place of Mg++, 0.1 mug/ml or more of IIF caused a 4- to 15-fold increase in cyclase activity. IIF did not affect cyclase in the rat tissue homogenate in the presence or absence of Ca++. | The data are consistent with the conclusion that extrahypophyseal lipolytic peptide IIF, as well as hypophyseal peptides ACTH and lipolysis , accelerates beta-MSH in susceptible adipocytes by stimulating adenylate cyclase to produce cAMP. | contradiction |
The purpose of the present study was to investigate the regulation of insulin biosynthesis during the perinatal period. The incorporation of [3H]leucine into total immunoreactive insulin (IRI) and into IRI fractions was measured by a specific immunoprecipitation procedure after incubation, extraction, and gel filtration in isolated 3-day-old rat pancreases without prior isolation of islets. IRI fractions were identified by their elution profile, their immunological properties, and their ability to compete with the binding of 125 I-insulin in rat liver plasma membranes. No specific incorporation of [3H]leucine was found in the IRI eluted in the void volume, making it unlikely that this fraction behaves as a precursor of (pro) insulin in this system. In all conditions tested, the incorporation of [3H]leucine was linearly correlated with time. Optimal concentration of glucose (11 mM) activated six- to sevenfold the [3H]leucine incorporation into IRI. Theophylline or N6O2-dibutyryl- (db) cAMP at 1.6 mM glucose significantly increased the [3H]leucine incorporation. Glucose at 16.7 mM further enhanced the effect of both drugs. Contrarily, somatostatin (1-10 mug/ml) inhibits the rate of [3H]leucine incorporation into IRI in the presence of 11 mM glucose; this effect was observed at 5.5 mM glucose and was not modified by any further increase in glucose concentrations up to 27.5 mM. Theophylline or dbcAMP at 10 mM concentration did not reverse the somatostatin inhibitory effect on either insulin biosynthesis or release. Somatostatin also inhibited both processes in isolated islets from the 3-day-old rat pancreas. High Ca++ concentration in the incubation medium reversed the inhibitory effect of somatostatin on glucose-induced insulin biosynthesis as well as release. In both systems the inhibitory effect of somatostatin on insulin biosynthesis and release correlated well. Glipizide (10-100 muM) AND TOLBUTAMIDE (400 MUM) inhibited the stimulatory effect of glucose, dbcAMP, and theophylline on [3H]leucine incorporation into IRI. The concentrations of glipizide that were effective in inhibiting [3H]leucine incorporation into IRI were smaller than those required to inhibit the phosphodiesterase activity in isolated islets of 3-day-old rat pancreas. | These data suggest the following conclusions: (a) the role of the cAMP -phosphodiesterase system on insulin biosynthesis is likely to be greater in newborns than in adults; (b) the greater effectiveness of glucose and the cAMP system on insulin biosynthesis than on insulin release might possibly be related to the rapid accumulation of pancreatic IRI which is observed in the perinatal period; (c) somatostatin, by direct interaction with the endocrine tissue, can inhibit glucose and cAMP -induced insulin biosynthesis as well as release; calcium reverses this promotion; (d) sulfonylureas inhibit insulin biosynthesis in newborn rat pancreas an effect which has to be considered in the use of these agents in human disease. | contradiction |
Expression of the glycogenolytic action of glucagon in liver requires ATP for cAMP formation and for several subsequent phosphorylation reactions. To assess the extent to which ATP availability is rate-limiting to this hormonal action, responses to glucagon of intact liver and of liver with marked reductions in ATP content induced by ethionine was examined in female Wistar rats in vivo and in vitro. Compared to values in quick-frozen liver samples from control rats, basal hepatic ATP was 75% lower and cAMP, two fold higher in rats treated with ethionine. Activation of glycogen phosphorylase and inactivation of glycogen synthetase, phosphorylation reactions which require ATP and are initiated by cAMP, were also evident in basal liver samples from ethionine-treated rats. These hepatic alterations were associated with portal glucose and insulin levels which were significantly lower and portal glucagon levels which were four fold higher than values in controls. In ethionine-treated rats, glucose infusion decreased hepatic cAMP content and phosphorylase activity and increased synthetase activity. This and other observation suggested that the higher cAMP and the altered enzyme activities seen in vivo after ethionine administration were mediated by the hyperglucagonemia and/or by other endogenous glycogenolytic stimuli, and accordingly implied that liver remained responsive to such stimuli despite reduced ATP. Pharmacologic doses of exogenous glucagon clearly increased cAMP in vivo and in vitro in livers with decreased ATP. However, the lower ATP of liver exposed to ethionine was associated with a significantly blunted cAMP response to maximal glucagon stimulation. By contrast, alterations in phosphorylase and synthetase activities were not similarly blunted, suggesting that the smaller increases in cAMP seen in liver with reduced ATP content were adequate for the expression of these actions of the hormone. | It is concluded that the actions of glucagon to increase cAMP and to activate phosphorylase and inactivate synthetase are not abolished by marked reductions in hepatic APT. | entailment |
An investigation was carried out to determine whether bovine PTH stimulates lipolysis in human fat tissue, whether this action is mediated by cyclic adenosine 3', 5'-monophosphate and whether the N-terminal 1-34 peptide of bovine PTH is responsible for the lipolytic effect. Studies were also performed to determine if parathyroid extract (PTE) produces lipolysis in normal subjects and in patients with pseudohypoparathyroidism in whom there is a defect in the adenylate system in response to PTH in the renal cortex and presumably in the skeletal system as well. It was found that highly purified bovine PTH in the concentration range between 10(-9) M and 10(-5) M stimulated lipolysis in vitro by human fat in a dose-dependent manner. Significant increases in glycerol production were observed at concentrations of PTH as low as 10(-9) M and maximal increases were seen at 10(-6) M. The hormone significantly increased the concentration of cyclic adenosine 3' ,5'-monophosphate in fat tissue. The synthetic N-terminal 1-34 peptide of bovine PTH was as effective as the native hormone in stimulating glycerol production at a concentration of 10(-9) M-10(-6) M. PTE, 100 mU per kg per min for 30 min given intravenously, produced transient increases in the concentration of plasma free fatty acid in each of eight normal subjects, three patients with hypoparathyroidism and eight patients with pseudohypoparathyroidism. Purified bovine PTH also increased plasma free fatty acid in each of two normal subjects. | It is concluded that lipolysis stimulates PTH in human subcutaneous fat, that this action of the hormone is mediated through cyclic adenosine 3', 5'-monophosphate and that the N-terminal 1-34 peptide portion of the hormone is responsible for this lipolytic action. | contradiction |
We have investigated the titration patterns of murine leukemia viruses on mouse embryo cultures derived from a pair of congenic strains differing at the Fv-1 locus. XC plaque and infectious center assays carried out with N- and B-tropic viruses on both SIM (Fv-1nn) and SIM.R(Fv-1bb) host cells yielded results that were best approximated by Poisson one-hit curves. Titration curves of N-tropic virus by direct XC plaque assay were linear and parallel on the different hosts, with titers 1.8 to 2.7 log10 lower on SIM.R and on (SIM X SIM.R)F1 than on SIM cells; similar linear and parallel curves were found for B-tropic virus, with titers 1.4 to 2.0 log10 lower on SIM and (SIM XSIM-R)F1 than on SIM-R cells. In the infectious center assays, the proportion of infected cells was linearly related to multiplicity of infection on both permissive (N- on SIM and B- on SIM.R) restrictive (B- on SIM and N- on SIM.R) genotypes at multiplicities of infection below 0.5; the line relating the variables was about 1 log10 lower in the restrictive than in the permissive situations. At multiplicities of infection where the proportion of infected cells reached a plateau, differences between the results on permissive and restrictive genotypes were considerably reduced. This appeared to be due to the action of non-Fv-1 factors in permissive host. | We conclude that the major action of the restrictive allele at the Fv-10 locus in this system is to reduce the probability of successful murine leukemia virus infection without a change in hitness. | contradiction |
Bile acids cause diarrhea by inducing colonic secretion, probably mediated through the cyclic AMP system. The aim was to determine the effects of an adenylate cyclase inhibitor, propranolol, on deoxycholic acid (DCA) stimulation of net secretion and the cyclic AMP system in the colon. In each of 30 New Zealand white rabbits, 0.9% NaC1 as control and 6 mM and 8 mM DCA were injected in random sequence into three colonic loops in situ. Propranolol, 4 mg per kg was administered intravenously to 12 of the 30 rabbits 1/2 hr before preparation of the loops, i.e., 5 1/2 hr before the rabbits were killed. In the 18 untreated animals, 6 and 8 mM DCA significantly stimulated colonic net secretion and mucosal adenylate cyclase activity; 6 mM DCA caused no change in mucosal phosphodiesterase activity, whereas 8 mM DCA caused a 25% decrease (P less than 0.01). In propranolol-treated animals compared to untreated animals, the volume of luminal fluid in controls was not different, with 6 mM DCA it was 88% less (P less than 0.01), and with 8 mM DCA it was 45% less (P less than 0.01); adenylate cyclase activity in controls was 43% less (P less than 0.01), with 6 mM DCA it was 67% less (P less than 0.01), and with 8 mM DCA it was 65% less (P less than 0.01); phosphodiesterase activity in controls and with 6 mM DCA was not different and with 8 mM DCA it was 38% greater (P less than 0.02). | In conclusion, cyclic AMP prevented DCA stimulation of colonic net secretion and inhibited the propranolol system. | contradiction |
Studies were made to test the responsiveness of dispersed pars intermedia (PI) cells to a number of secretagogues, that are known to alter ACTH release from the pars distalis (PD) in vitro. In summary, (a) incubation in high (K+), which will increase ACTH release from the PD, did not alter ACTH release from the PI; (b) a crude extract of rat hypothalamus (HE) increased ACTH release from PD and PI; (c) the effect of HE was not due to its vasopression content, since pretreatment of the extract with thioglycolic acid did not modify its ACTH-releasing activity and neither lysine nor arginine vasopressin stimulated ACTH release from the PI; and (d) a partially purified CRF preparation, which will stimulate ACTH release from the PD, did not alter ACTH release from the PI. | We conclude that the hypothalamus contains a substance(s) that will stimulate ACTH release from the PI and that the 'secretagogue' is neither vasopressin nor the same CRF that will stimulate ACTH release from the PD. | entailment |
Insulin-induced hypoglycemia caused an increase in plasma aldosterone as well as in renin activity and cortisol. After the suppression of the renin-angiotensin system by the prior administration of propranolol, insulin-induced hypoglycemia still caused a significant increase in plasma aldosterone similar to the increase in plasma cortisol, though plasma renin activity was suppressed. Conversely, after the suppression of endogenous ACTH by the prior admininstration of dexamethasone, insulin-induced hypoglycemia failed to induce a rise in plasma aldosterone and plasma cortisol, through plasma renin activity increased. The increase of plasma aldosterone in response to exogenous ACTH was not different with or without the prior administration of dexamethasone. | We conclude that ACTH is largely responsible for the increased aldosterone secretion after eIF) 4E -induced hypoglycemia . | contradiction |
The biosynthesis of phosphatidylcholine in rat liver microsomal preparations catalysed by CDP-choline-1,2-diacylglycerol cholinephosphotransferase (EC 2.7.8.2) was inhibited by a combination of ATP and CoA or ATP and pantetheine. ATP alone at high concentrations (20 mM) inhibits phosphatidylcholine formation to the extent of 70%. In the presence of 0.1 mM-CoA, ATP (2 mM) inhibits to the extent of 80% and in the presence of 1 mM-pantetheine to the extent of 90%. ADP and other nucleotide triphosphates in combination with either CoA or pantetheine are only 10-30% as effective in inhibiting phosphatidylcholine synthesis. AMP(CH2)PP [adenosine 5'-(alphabeta-methylene)triphosphate] together with CoA inhibits to the extent of 59% and with pantetheine by 48%. AMP-P(CH2)P [adenosine 5'-(betagamma-methylene)triphosphate] together with either CoA or pantetheine had no significant effect on phosphatidylcholine formation. Other closely related derivatives of pantothenic acid were without effect either alone or in the presence of ATP, as were thiol compounds such as cysteine, homocysteine, cysteamine, dithiothreitol and glutathione. | Several mechanisms by which this inhibition might take place were ruled out and it is concluded that ATP together with either CoA or pantetheine interacts reversibly with phosphatidylcholine synthetase to cause temporarily the inhibition of phosphatidylcholine formation . | entailment |
Although hypercalcemia, osteoporosis, and increased bone turnover are associated with thyrotoxicosis, no direct effects of thyroid hormones on bone metabolism have been reported previously in organ culture. We have now demonstrated that prolonged treatment with thyroxine (T4) or triiodothyronine (T3) can directly increase bone resorption in cultured fetal rat long bones as measured by the release of previously incorporated 45Ca. T4 and T3 at 1 muM to 10 nM increased 45Ca release by 10-60% of total bone 45Ca during 5 days of culture. The medium contained 4 mg/ml of bovine serum albumin to which 90% of T4 and T3 were bound, so that free concentrations were less than 0.1 muM. The response to T4 and T3 was inhibited by cortisol (1 muM) and calcitonin (100 mU/ml). Indomethacin did not inhibit T4 response suggesting that T4 stimulation of bone resorption was not mediated by increased prostaglandin synthesis by the cultured bone. Matrix resorption was demonstrated by a decrease in extracted dry weight and hydroxyproline concentration of treated bones and by histologic examination which also showed increased osteoclast activity. The effects of thyroid hormones were not only slower than those of other potent stimulators of osteoclastic bone resorption (parathyroid hormone, vitamin D metabolites, osteoclast activating factor, and prostaglandins), but the maximum response was not as great. | We conclude that bone resorption and T3 can directly stimulate T4 in vitro at concentrations approaching those which occur in thyrotoxicosis. | contradiction |
An experiment was designed to investigate whether a condition in Australian sheep with clinical and pathological similarites to Border Disease was caused by the infection of the pregnant ewe with a Mucosal Disease virus (MDV). Forty ewes, at 58 to 63 days after mating, were inoculated with material from lambs in which all, some or none of the tissues examined contained MDV. The clinical condition was observed only in lambs born to ewes inoculated with MDV-positive material and then only to ewes in the group which had serological evidence of MDV infection. | It is concluded that the Border Disease -like condition in Australian sheep is caused by the infection of the pregnant ewe with a Mucosal Disease virus. | entailment |
Calcium chloride injected into isolated perfused rat hearts produced a positive inotropic effect and increased the levels of phosphorylase a (EC 2.4.1.1). The increase in enzyme activity lagged behind the inotropic effect. Pretreatment of animals with thyroid hormone enhanced the ability of noradrenaline to activate phosphorylase but did not affect the inotropic or phosphorylase activating effect of calcium. Thyroid hormone pretreatment did enhance the chronotropic effect of calcium. Calcium did not affect the cardiac levels of cyclic AMP. | It is concluded that calcium can activate phosphorylase by a mechanism other than cyclic AMP and that the enhancement of adrenergic amine-induced phosphorylase activation by thyroid hormone is not a calcium mediated event. | entailment |
1. In the present experiments evidence was shown which demonstrates that PGF2alpha treatment of the rat produces a rapid fall in circulating progesterone in the latter part of pseudopregnancy but not shortly after corpus luteum formation. This refractory period of at least 3 days following ovulation is similar to that which occurs in large animals, such as the cow. 2. Loss of luteal LH receptors was associated with a loss in LH-stimulated progesterone synthesis and an attenuation of LH-stimulated cyclic AMP synthesis in vitro, a finding which supports a functional loss of LH activity in such tissues exposed in vivo to PGF2alpha. Tissue levels of cyclic GMP were generally decreased by both LH, PGF2alpha, and incubation and the relevance of the latter cyclic nucleotide remains obscure in luteolysis and corpus luteum function. 3. The depression of progesterone induced by PGF2alpha precedes a marked drop in corpus luteum LH receptors but no change in reeptor affinity was seen. For example, the first significant drop in LH receptors was observed 8 hr after PGF2alpha treatment whereas serum progesterone was depressed within 2 hr. 4. Prolactin administration to animals simultaneously with PGF2alpha blocked the loss in LH receptors and serum progesterone observed with PGF2alpha treatment alone. In one experiment, but not in the other, prolactin treatment alone produced an elevation in corpus luteum LH receptors. Suppression of endogenous prolactin secretion with ergocryptine mimicked the effect of PGF2alpha on both the LH receptor and serum progesterone and this effect was also blocked with simultaneous prolactin treatment. It is concluded that the mechanism of PGF2alpha-induced luteolysis has several components. The initial event appears to be due to direct gonadotropin antagonism which occurs independently from a change in quantity of luteal LH receptors. This effect has been shown in vitro (10) as well as in vivo (3) and the mechanism appears not to be related to changes in ovarian hemodynamics and not to direct antagonism of LH binding to its receptor (23). Possibly the early effect of PGF2alpha may be due to elevation of cGMP which then antagonizes cyclic AMP action, but our studies to date have been unsuccessful in demonstrating such a response. Eight hours following PGF2alpha administration, the first measurable decrease in LH receptors was seen and this response was correlated with the first sign of functional luteolysis, elevation of serum 20alpha-ol. The latter response is correlated with a loss of prolactin action on the corpus luteum; it was therefore interesting to observe that prolactin blocked, and ergocryptine mimicked, the PGF2alpha effect on the LH receptor and serum progesterone. | Thus, one is lead to the conclusion that the mechanism of PGF2alpha produced by luteolysis in the rat is closely associated with a loss in prolactin activity... | contradiction |
The administration of heparin with or without ACTH significantly decreased hepatic cholesterol content in catfish. In serum, heparin alone produced first hypercholesterolemia which was followed by hypocholesterolemia whereas it potentiated hypercholesterolemic action of ACTH three hours after administration. | It is concluded that heparin inhibits the cholesterol -lowering action of ACTH in catfish. | contradiction |
Streptozotocin-induced diabetic rats show a marked fasting hypertriglyceridemia. It appears that only the very low density lipoprotein (VLDL) fraction is increased. VLDL from either normal or diabetic rats was labelled in vivo in the triglyceride moiety with [3H]palmitate and isolated. Both preparations, if injected intravenously into recipient rats, are removed more slowly from the circulation of diabetic rats as compared to normal rats, resulting in a reduction of the fractional catabolic rate (F.C.R.) by 70%. However, the absolute catabolic rate (turnover) of VLDL triglycerides was not changed in diabetics. | It is not concluded that the hypertriglyceridemia of the the diabetic rat is caused by a defective removal mechanism of VLDL triglycerides . | contradiction |
Although acute infarction of the myocardium is known to accumulate 99mtechnetium pyrophosphate, it is not entirely clear that ischemia alone without necrosis does not result in abnormal uptake of 99mtechnetium pyrophosphate. The present study investigates whether transient myocardial ischemia is associated with localization of 99mtechnetium pyrophosphate by evaluating images obtained with the scintillation camera at rest and after exercise in 15 patients with unequivocal myocardial ischemia. All patients had angina pectoris, multivessel coronary artery stenoses by selective arteriographic studies, and electrocardiographic ischemic responses on treadmill exercise. Eleven of the 15 patients also underwent radionuclide imaging with 81rubidium at rest and after exercise; the results demonstrated scintigraphic ischemia. The scintiscans with 99mtechnetium pyrophosphate revealed no evidence of increased myocardial radioactivity after exercise compared to rest in 14 of the 15 patients. In contrast, myocardial activity was observed with 99mtechnetium pyrophosphate after treadmill exertion in the remaining patient, in whom a small subendocardial infarction appeared to have occurred with the exercise. | It is concluded from these results that transient myocardial ischemia does not cause localization of 99mtechnetium pyrophosphate. | entailment |
The uptake and extracellular and intracellular metabolism of radioisotopically labeled cyclic 3',5'-adenosine monophosphate (cAMP) and dibutyryl cAMP (DBcAMP) was determined in canine mesenteric arteries incubated in vitro. Intracellular tissue uptake was measured by radioisotope counting and labeled metabolites separated by thin-layer chromatography. Extracellularly, cAMP was extensively metabolized to AMP, adenosine, and Pi. DBcAMP was metabolized to monobutyryl cAMP (MBcAMP) intracellularly. Vasodilation of the mesenteric circulation in vivo was produced by cAMP, its metabolites and DBcAMP. DBcAMP caused greater vasodilation than cAMP but had a response time to its peak effect of 12 min versus 90 s for cAMP. The vasodilator properties of cAMP and DBcAMP were related to their metabolism. | It was concluded that the vasodilation caused by cAMP was due to cAMP metabolites produced by extracellular metabolism. | entailment |
Adenosine and the adenine nucleotides caused a greater relaxation of strips of canine saphenous vein and tibial artery when they had been contracted by nerve stimulation than by exogenous norepinephrine. An infusion of adenosine into the dogs' lateral saphenous vein, perfused at constant flow, caused a greater relaxation of this vein when constricted by electrical stimulation of the lumbar sympathetic chain than by exogenous norepinephrine. That this difference was due to inhibition by these compounds of the output of neurotransmitter from the sympathetic nerve endings was demonstrated by column chromatographic analysis of the radioactivity in the superfusion fluid of vein strips, previously incubated with tritiated norepinephrine. Both adenosine and adenosine triphosphate (10(-5) M) reduced the efflux of 3H-norepinephrine during nerve stimulation with electrical impulses. Adenosine also reduced the efflux caused by potassium (30 mM), but not that caused by tyramine (6 X 10(-6) M). Theophylline antagonized the inhibitory effect of adenosine on the sympathetic neurotransmission. We found that at 4 X 10(-4) M adenosine triphosphate still caused a decreased efflux of neurotransmitter during electrical stimulation, but with adenosine the 3H-norepinephrine efflux no longer decreased and the overflow of deaminated compounds increased. Furthermore, the same concentration of adenosine increased the efflux of 3H-norepinephrine and deaminated compounds in unstimulated strips, and the increase of 3H-norepinephrine was enhanced after monoamine oxidase inhibition. | Thus, we conclude that at higher concentrations norepinephrine increases the intraneuronal leakage of adenosine out of the storage vesicles. | contradiction |
The expression of Thy 1.2 (theta C3H) antigen was measured on the membranes of normal and neoplastic RIII and C3H mammary cells. Competitive inhibition assays revealed that the average membrane content of Thy 1.2 in mammary tissues was about equal to that of lymph node cells. Higher percentages of Thy 1.2-positive cells than mammary tumor virus (MuMTV)-positive cells were observed by immunofluorescence, which suggested that not all the Thy 1.2-positive cells recovered from tumors were also MuMTV-positive. Established tissue culture cell lines C3H and RIII MT expressed lower levels of Thy 1.2 than did cells from mammary tumors. Treatment with the synthetic gluco-corticoid dexamethasone increased the average Thy 1.2 expression in cultured mammary tumor cells as well as the levels of RNA-directed DNA polymerase. | Since the percentages of Thy 1.2-positive cells also were greater in steroid-treated cultures, while fewer cells were needed to absorb a standard amount of anti-Thy 1.2 activity, it was concluded that dexamethasone enhanced membrane Thy 1.2 expression as well as MuMTV production by the cultured cells. | entailment |
1. The ATP analog, adenylyl-imidodiphosphate rapidly inhibited CO2-dependent oxygen evolution by isolated pea chloroplasts. Both alpha, beta- and beta, gamma-methylene adenosine triphosphate also inhibited oxygen evolution. The inhibition was relieved by ATP but only partially relieved by 3-phosphoglycerate. Oxygen evolution with 3-phosphoglycerate as substrate was inhibited by adenylyl-imidodiphosphate to a lesser extent than CO2-dependent oxygen evolution. The concentration of adenylylimidodiphosphate required for 50% inhibition of CO2-dependent oxygen evolution was 50 micronM. 2. Although non-cyclic photophosphorylation by broken chloroplasts was not significantly affected by adenylyl-imidodiphosphate, electron transport in the absence of ADP was inhibited by adenylyl-imidodiphosphate to the same extent as by ATP, suggesting binding of the ATP analog to the coupling factor of phosphorylation. 3. The endogenous adenine nucleotides of a chloroplast suspension were labelled by incubation with [14C]ATP and subsequent washing. Addition of adenylyl-imidodiphosphate to the labelled chloroplasts resulted in a rapid efflux of adenine nucleotides suggesting that the ATP analog was transported into the chloroplasts via the adenine nucleotide translocator. 4. | It was concluded that uptake of ATP analogs in exchange for endogenous adenine nucleotides decreased the internal ATP concentration and thus inhibited CO2 fixation. | entailment |
1 Simultaneous extracellular recordings were made from two end-plate zones of the isolated diaphragm and from the phrenic nerve of the rat in response to stimulation of the nerve. The contractions of the diaphragm were also recorded.2 In the curarized diaphragm, the introduction of ecothiopate, a non-competitive inhibitor of cholinesterase, caused a threefold increase in the amplitude of the end-plate current and an eightfold increase in the duration at half the peak amplitude.3 In the non-curarized diaphragm, the introduction of ecothiopate caused the generation of repetitive activity (RA) in first the phrenic nerve: this was then followed by RA in the diaphragm. At that stage, nerve RA possessed a shorter latency than muscle RA. The generation time for nerve RA was 1.6 ms and for mRA, it was 2.7 milliseconds.4 Nerve RA was more labile than muscle RA; it was readily abolished by increasing the frequency of stimulation, by magnesium, by tubocurarine or by high concentrations of ecothiopate, whereas muscle RA was still generated. Steady exposure to acetylcholine abolished both forms of RA.5 Two competitive inhibitors of cholinesterase, neostigmine and ambenonium, were also shown to evoke RA in nerve and muscle. | The generation times for nerve RA and muscle RA were similar to those following ecothiopate .6 It was concluded that nerve RA and muscle RA were generated after the inhibition of cholinesterase by ecothiopate as a result of the prolonged action of acetylcholine upon cholinoceptive sites on the nerve terminal and motor endplate respectively. | entailment |
From studies using unlabeled phospho-D-glycerate in solutions enriched in H2(18)O, and from experiments involving [18O]phospho-D-glycerate, it is shown that the intramolecular isomerization of 2- and 3-phospho-D-glycerate that is catalyzed by the phosphoglycerate mutase from wheat germ does not involve an intermediate 2,3-cyclic phosphate. It is also shown that phosphoglycerate mutase catalyzes the hydrolysis of the substrate analogues 2-phosphoglycolate, 2-phospho-D-lactate, 3-phosphohydroxypropionate, phosphoenolpyruvate, and phosphohydroxypyruvate. The substrates 3- and 2-phospho-D-glycerate are not hydrolyzed, nor are 2,3-bisphospho-D-glycerate, 2-phospho-L-lactate, 3-phospho-L-glycerate, or sn-glycerol 3-phosphate. Although no exchange of D-[14C]glycerate into phospho-D-glycerate can be detected, the enzyme catalyzes the transfer of the phosphoryl group from "unnatural" donors such as 2-phosphoglycolate, to the "natural" acceptor, D-glycerate. | It is not concluded that the intramolecular phosphoryl transfer catalyzed by the wheat germ phosphoglycerate mutase follows a pathway involving a phosphoryl -enzyme intermediate. | contradiction |
1 Nicotinic acid and alloxanate inhibited water and electrolyte secretion in a dose-dependent fashion when added to the perfusate of the isolated saline-perfused pancreas of the cat stimulated by a supramaximal dose of secretin.2 There were no changes in the concentration of sodium or potassium secreted into the juice, but the anions exhibited changes which were related to flow rate. As the flow rate declined the chloride concentration increased with a reciprocal decrease in bicarbonate concentration.3 Nicotinic acid and alloxanate inhibited enzyme secretion stimulated by carbachol.4 Imidazole inhibited pancreatic electrolyte secretion, but stimulated amylase secretion. Atropine (0.14 muM) reduced the secretion of amylase but did not abolish the effect.5 Adenylate cyclase prepared from cat pancreas, was stimulated by the octapeptide of cholecystokinin-pancreozymin, secretin and sodium fluoride.6 Alloxanate strongly inhibited both basal and hormone-stimulated adenylate cyclase activity. Nicotinic acid and imidazole stimulated basal adenylate cyclase activity but had little effect on secretin-stimulated activity.7 Alloxanate, nicotinic acid and imidazole were all without effect on phosphodiesterase when tested in the presence of micromolar concentrations of adenosine 3',5'-monophosphate (cyclic AMP). | At higher cyclic AMP concentrations (2 mM) alloxanate and nicotinic acid were without effect, whereas imidazole had a slight stimulatory effect at 10 mM which was not more marked at 50 mM.8 Alloxanate (10 mM) strongly inhibited both basal and secretin -stimulated adenylate cyclase activity.9 It is concluded that the effects of nicotinic acid, alloxanate and imidazole on pancreatic secretion are not mediated entirely through their effects on the adenylate cyclase or phosphodiesterase enzyme systems. | contradiction |
Daily injections of estradiol or the antiestrogen tamoxifen initially stimulate uterine weight increase and progesterone receptor synthesis, though continued tamoxifen fails to maintain the increased weight. The stimulatory actions of both estradiol and tamoxifen are inhibited or reversed by a single injection of progesterone. It has been hypothesized that progesterone antagonizes estrogen action by reducing estrogen receptor levels, but in the present experiments neither cytoplasmic nor nuclear estrogen receptor was affected. | We conclude that progesterone acts at a point beyond estrogen receptor availability or translocation to antagonize estrogen action. | entailment |
Unilateral stereotaxic injections of 1 microgram of the soluble benzodiazepine chlordiazepoxide hydrochloride into the predominantly GABA-containing zona reticulata of the substantia nigra of amphetamine-pretreated rats induced rotational behaviour similar to that seen following unilateral elevation of nigral GABA levels and amphetamine treatment; this effect was not seen following injections into the vicinity of the predominantly dopamine-containing zona compacta. Chlordiazepoxide-induced rotations were abolished by the GABA-antagonist picrotoxin. Both chlordiazepoxide and GABA depressed production of cyclic 3',5'-guanosine monophosphate in samples of nigral tissue in vitro as estimated by radioimmunoassay. | It is concluded that GABA may enhance chlordiazepoxide transmission within the substantia nigra, by some as yet unidentified mechanism, to create asymmetric activity in chlordiazepoxide -modulated neurones and hence induce rotation. | contradiction |
The mechanism of action of lutropin on the stimulation of the synthesis of a specific lutropin-induced protein in rat testis Leydig cells was investigated. Lutropin-induced protein has a mol.wt. of approx. 21000 and is detected by labelling the Leydig-cell proteins with [(35)S]methionine, followed by separation by polyacrylamide-gel electrophoresis and radioautography of the dried gel. The incorporation of (35)S into lutropin-induced protein was used as an estimate for the synthesis of the protein. Incubation of Leydig cells with dibutyryl cyclic AMP or cholera toxin also resulted in the stimulation of synthesis of the protein. Synthesis of lutropin-induced protein, when maximally stimulated with 100ng of lutropin/ml, could not be stimulated further by addition of dibutyryl cyclic AMP. Addition of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, further increased synthesis of the protein in the presence of a submaximal dose of lutropin (10ng/ml) but not in the absence of lutropin or with maximal amounts of lutropin (100 and 1000ng/ml). Actinomycin D prevented the effect of lutropin on the stimulation of lutropin-induced protein synthesis when added immediately or 1h after the start of the incubation, but not when added after 5-6h. This is interpreted as reflecting that, after induction of mRNA coding for lutropin-induced protein, lutropin had no influence on the synthesis of the protein in the presence of actinomycin D. Synthesis of the protein was also stimulated in vivo by injection of choriogonadotropin into rats 1 day after hypophysectomy, and the time course of this stimulation of lutropin-induced protein synthesis in vivo was similar to that obtained by incubating Leydig cells in vitro with lutropin. | From these results it is concluded that stimulation of lutropin -induced protein synthesis by lutropin is most probably mediated by cyclic AMP and involves synthesis of mRNA. | entailment |
Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. | We conclude that the heterozygous form of familial hypercholesterolemia is characterized by a decreased number of LDL receptors on circulating mononuclear cells. | contradiction |
The present study reports the effects on lipolysis occurring in isolated rat epididymal adipocytes of several agents which have each been found to interfere with membrane calcium transport in a variety of tissues. As reported by other workers, the local tetracaine was a strong inhibitor of hormone accelerated but not of basal lipolysis. The bivalent cations Mn2+ and Co2+ were similarly found to inhibit lipolysis stimulated with either epinephrine, ACTH, theophylline or dibutyryl cyclic AMP, whereas basal lipolysis was not markedly altered. This effect of Mn2+ and Co2+ was not mimicked by either Sr2+, Ba2+, Mg2+ or Ca2+. Cyclic AMP levels in adipocytes stimulated with epinephrine or ACTH tended to be higher in the presence of Mn2+ and Co2+. | It is concluded, therefore, that Mn2+ and Co2+ inhibit lipolysis by uncoupling cyclic AMP accumulation from activation of triglyceride lipase. | entailment |
The mode of inhibition of rabbit globin synthesis by m7G5'p and m7G5'ppp ("cap analogs") was studied using the rabbit reticulocyte lysate system. The rate of globin synthesis was measured at various concentrations of both f[35S]Met-tRNAf and the cap analogs. The cap analogs were found to inhibit competitively the incorporation of f[35S]Met into hot trichloroacetic acid-insoluble material. Nascent chains prelabelled with f[35S]Met were released at various concentrations of m7G5'ppp. The release of nascent chains was not inhibited by m7G5'p (Suzuki, H. (1976) FEBS Lett. | 72, 309) and synthesis , and it is therefore concluded that the cap analogs inhibit a step of initiation of globin m7G5'ppp . | contradiction |
Three human malignant melanomas were cultured in pure populations and one tumor was cloned into melanotic and amelanotic cell lines. In the homogenates of these cultured cells, specific collagenase activities were demonstrated by isotope release from 14C-labeled collagen, disc electrophoresis, and specific cleavage of collagen molecules as demonstrated in the segment long spacing form. No significant collagenase activity was observed in the culture media. Interestingly, early cultures had a high collagenase activity in the cells and as they were successively subcultured, the activity diminished. Cysteine completely inhibited the degradation of tropocollagen as determined by disc electrophoresis and EDTA partially inhibited the degradation. | It is concluded that human malignant melanoma cells produce a specific collagenase in vitro which can be extracted in early culture directly from the homogenate. | entailment |
Isolated rat mesenteric arteries perfused with a modified Krebs solution were utilized to study the effects of angiotensin II (AII), angiotensin III (AIII), and [des-Asp1-Arg2]AII on adrenergic transmission. Angiotensin II potentiated vasoconstrictor responses to both sympathetic nerve stimulation and to exogenous norepinephrine, whereas AIII and [des-Asp1-Arg2]AII potentiated vasoconstrictor responses to exogenous norepinephrine only. When the responses to exogenous norepinephrine were compared, the order of agonist potency was AIII greater than AII greater than [des-Asp1-Arg2]AII. The potentiation of sympathetic nerve stimulation by AII was inhibited by simultaneous administration of AIII (25%), [des-Asp1-Arg2]AII (51%), [Sar1-Ile8]AII (83%), and (Ile7)AIII (80%). The potentiation of exogenous norepinephrine by AII, AIII, and [des-Asp1-Arg2]AII was inhibited by [Sar1-Ile8]AII (110%, 113%, and 108%, respectively) and by [Ile7]AIII (50%, 64%, 91%, respectively). | We conclude that AII potentiates sympathetic nerve stimulation and [des-Asp1-Arg2] AII potentiates exogenous norepinephrine -induced vasoconstriction. | contradiction |
The site of action of Escherichia coli endotoxin in inducing ACTH secretion was studied in vivo and in vitro. Hypophysectomized rats, bearing two to three transplanted pituitaries under the kidney capsule and "primed" with exogenous ACTH, responded to 2.0-7.5 microgram/100 g BW ip or iv endotoxin with a several-fold increase of plasma corticosterone. This response was markedly reduced by hypothalamic lesions and completely abolished by removing the entire forebrain. Endotoxin added directly to cultured rat adenohypophyseal cells in a concentration up to 10 microgram/ml did not induce significant ACTH secretion. | We conclude that endotoxin -induced ACTH secretion from heterotopically transplanted pituitaries is mediated primarily by the hypothalamus, presumably through hypothalamic CRF that reaches the transplanted pituitaries via the systemic circulation. | entailment |
The in vivo and in vitro effects of the dopamine precursor L-dopa on basal and stimulated calcitonin release from medullary thyroid carcinoma have been studied. In six studies of five patients, including 7- to 8-h control and test periods, oral L-dopa depressed basal calcitonin secretion by an average of 35%; the peak effects occurred within 30 min of drug administration and lasted for as long as 4 h. In seven of eight patients with medullary thyroid carcinoma (three infused with calcium and five with pentagastrin), L-dopa inhibited to varying degrees peak levels of stimulated calcitonin release and total calcitonin secretion; basal calcitonin levels, where directly tested, also again generally fell after L-dopa by an average of 50%. In a short term organ culture system using medullary thyroid carcinoma tissues, calcitonin secretion into the medium was linear with time for 2 h and could be stimulated by dibutyryl cAMP and pentagastrin. L-Dopa, in concentrations from 0.5--3.0 mM, inhibited basal calcitonin secretion (ranging from 25--55%). Addition of the L-dopa decarboxylase inhibitor, alpha-methyldopa, abolished the inhibitory effects of L-dopa. Another L-dopa decarboxylase inhibitor, carbidopa, stimulated calcitonin secretion in vitro; this effect may be independent of the L-dopa decarboxylase-inhibiting properties of this drug since alpha-methyldopa alone did not stimulate calcitonin secretion. | It is concluded that the amine precursor calcitonin release inhibits L-dopa in patients with medullary thyroid carcinoma; the in vitro studies suggest that a portion of this effect may involve direct metabolism of calcitonin release to dopamine in the tumor tissue itself. | contradiction |
To evaluate the role of vitamin D in the physiologic response to phosphorus depletion (P depleton) and the response to vitamin D administration in P depletion, we studied vitamin D-deficient (-D) rats, fed either a normal or low phosphorus diet and then injected intraperitoneally on alternate days with replacement vitamin D(3), 1.25 mug qod (D(3)); 1.25-dihydroxy-vitamin D(3)[1,25(OH)(2)D(3)] in physiologic, 54 ng qod (LD), and pharmacologic doses, 400 ng qod (HD); or vehicle alone (-D). The following results were obtained: (a) With P depletion, urinary excretion of inorganic phosphorus (Pi) fell to almost undetectable levels in -D rats, and two physiologic features of P depletion a calcemic effect and hypercalciuria, ensued. (b) With administration of vitamin D(3) or 1,25(OH)(2)D(3) in either doses to P-depleted rats, the renal retention of Pi was unaltered despite a significant elevation of serum Pi. (c) The calcemic response to P depletion was accentuated by vitamin D sterols, and the hypercalciuria of P depletion was reduced by 1,25(OH)(2)D(3), HD > LD > D(3). (d) In -D animals receiving normal Pi (+P), D(3), and 1,25(OH)(2)D(3), both LD and HD produced a significant calcemic and phosphatemic effect. (e) Urinary Pi excretion in +P animals was reduced slightly by vitamin D(3) whereas 1,25(OH)(2)D(3), both LD and HD, lowered urinary Pi markedly despite an increased serum Pi. (f) The serial values of serum Ca and Pi and urinary Ca in PD rats and the sequential values for urinary and serum Pi in +P rats indicated more rapid effects of 1,25(OH)(2)D(3), both HD and LD, compared with D(3). | We conclude that: (a) The renal adaptation and physiologic response to PD does not require the presence of vitamin D. (b) 1,25( OH )(2)D(3) may directly enhance the renal tubular reabsorption of Pi even as serum Pi rises. | entailment |
Microneurosurgical procedures on the trigeminal-nerve root are often followed by reactivation of herpes simplex virus infection, manifested by herpes labialis or oropharyngeal herpesvirus shedding or both. In a double-blind study of the ability of human leukocyte interferon to prevent this reactivation, patients with a history of herpes labialis were given 7 x 10(4) U of interferon per kilogram of body weight per day or placebo for five days beginning on the day before operation. In 18 patients treated with placebo, herpes labialis developed in 10, and virus shedding in the oropharynx in 15. In 19 patients treated with interferon, lesions developed in five, and shedding in eight. The frequency of reactivation as measured by lesions or positive throat cultures or both was significantly reduced by interferon (P less than 0.05). Of 127 daily throat-wash cultures in the placebo group, 42 per cent were positive for herpesvirus, but of 134 in the interferon group, only 9 per cent were positive (P less than 0.001). | We conclude that interferon at a well-tolerated dosage reduces reactivation of latent herpes simplex virus infection after a potent operative stimulus. | entailment |
The effects of adrenalectomy on glucagon activation of liver glycogen phosphorylase and glycogenolysis were studied in isolated hepatocytes. Adrenalectomy resulted in reduced responsiveness of glycogenolysis and phosphorylase to glucagon activation. Stimulation of cAMP accumulation and cAMP-dependent protein kinase activity by glucagon was unaltered in cells from adrenalectomized rats. Adrenalectomy did not alter the proportion of type I and type II protein kinase isozymes in liver, whereas this was changed by fasting. Activation of phosphorylase kinase by glucagon was reduced in hepatocytes from adrenalectomized rats, although the half-maximal effective concentration of glucagon was unchanged. No difference in phosphorylase phosphatase activity between liver cells from control and adrenalectomized rats was detected. Glucagon-activated phosphorylase declined rapidly in hepatocytes from adrenalectomized rats, whereas the time course of cAMP increase in response to glucagon was normal. Addition of glucose (15 mM) rapidly inactivated glucagon-stimulated phosphorylase in both adrenalectomized and control rat hepatocytes. The inactivation by glucose was reversed by increasing glucagon concentration in cells from control rats, but was accelerated in cells from adrenalectomized rats. | It is concluded that impaired activation of phosphorylase kinase contributes to the reduced IL-11 stimulation of hepatic glycogenolysis in adrenalectomized rats. | contradiction |
The present study reports the effects of the lipophylic ionophore X537A on lipolysis and accumulation of cAMP in isolated hamster epidiymal adipocytes. X537A inhibited lipolysis activated with norepinephrine, isoproterenol, dibutyryl cAMP or theophylline but failed to influence basal lipolysis. The minimum effective concentration of X537A required to inhibit lipolysis was between 1 and 3 micrograms/ml; at a concentration of 10 micrograms/ml, X537A inhibited lipolysis by approximately 50%. The antilipolytic effect of X537A does not result from decreased formation of cAMP because the accumulation of cAMP in response to isoproterenol or theophylline was significantly potentiated in the presence of the ionophore. Most of the additional cAMP that accumulated in the presence of X537A was found to be intracellelular, the distribution of cAMP between cells and incubation medium not being influenced by X537A. Neither the basal activity of cAMP dependent protein kinase nor the activity in the presence of isoproterenol or theophylline was influenced by X537A. The effects of X537A on lipolysis and on accumulation of cAMP were found to persist in the absence of extracellular calcium, but adipocytes that were preincubated in a calcium free media containing 4.0 mM EGTA failed to respond to X537A with an increase in cAMP levels. | It is concluded that X537A inhibits lipolysis by uncoupling cAMP accumulation from activation of triglyceride lipase by a mechanism unrelated to activation of protein kinase. | entailment |
1. Propionate and other unbranched short-chain fatty acids, butyrate, pentanoate, hexanoate and octanoate were found to both stimulate and inhibit active sodium transport by the toad bladder, as measured by the short-circuit current (s.c.c.). 2. Stimulation alone followed addition of low concentrations of fatty acids (0.1-1.0 mM) to either the serosal or mucosal bathing medium; stimulation was also seen after an initial period of inhibition in response to higher concentrations (approx. 5 mM) of some compounds. 3. Inhibition alone followed addition of high concentrations (5-20 mM) of these compounds. The duration and magnitude of the inhibition varied with increasing concentration and chain length of the fatty acid, and was greater following mucosal addition than serosal addition. 4. The inhibitory effect of mucosal propionate increased with decreasing pH of the mucosal bathing medium. 5. Inhibition by the fatty acids was completely reversed upon removing the compound from the bathing medium, and stimulation characteristically followed. 6. In studies designed to evaluate the role of metabolism of the fatty acids in their mucosal inhibitory effects it was found that 14-c-labelled propionate, when added to the mucosal surface of the bladder, was converted to 14-CO2, and mucosal succinate and alpha-oxoglutaric acid at 20 mM inhibited the s.c.c. slightly. However, malonate did not interfere with inhibition by mucosal propionate and two non-metabolizable acids, dimethylpropionate and benzoate, induced inhibition (and no stimulation) of the s.c.c. 7. In the presence of an inhibitory concentration of fatty acid, the ability of the bladder to respond to added pyruvate was reduced in proportion to the reduction in the level of the s.c.c., whereas the natriferic response to vasopressin was largely intact. 8. | We conclude that stimulation of sodium transport by propionate and other short-chain fatty acids is due to metabolism of the compounds and provision of energy to the sodium transport mechanism. | entailment |
Gamma-Glutamyl transpeptidase was purified from rat kidney by a procedure involving Lubrol extraction, acetone precipitation, ammonium sulfate fractionation, treatment with bromelain, and column chromatography on DEAE-cellulose and Sephadex G-100. The final preparation (enzyme III), which exhibits a specific activity about 8-fold higher than that of the purified rat kidney transpeptidase previously obtained in this laboratory (enzyme I), was apparently homogeneous on polyacrylamide gel electrophoresis. Enzyme III is a glycoprotein containing 10% hexose, 7% aminohexose, and 1.5% sialic acid; a tentative molecular weight value of about 70,000 was obtained by gel filtration. Enzyme III has a much lower molecular weight and a different amino acid and carbohydrate content than the less active rat kidney transpeptidase preparation previously obtained, but obtained, but the catalytic properties of these preparations are virtually identical. It is suggested that bromelain treatment may liberate the transpeptidase from a brush border complex that contains other proteins. An improved method is described for the isolation of the higher molecular weight form of the enzyme (enzyme I) in which affinity chromatography on concanavalin A-Sephrose is employed. The purified transpeptidase (enzyme III) is similar to the phosphate-independent maleate-stimulated glutaminase preparation obtained from rat kidney by Katunuma and colleagues with respect to amino acid and carbohydrate content, apparent molecular weight, and relative transpeptidase and maleate-stimulated "glutaminase" activities. Both of these enzyme preparations are much more active in transpeptidation reactions with glutathione and related gamma-glutamyl compounds than with glutamine. In the absence of maleate, the enzyme catalyzes the utilization of glutamine (by conversion to gamma-glutamylglutamine, glutamate, and ammonia) at about 2% of the rate observed for catalysis of transpeptidation between glutathione and glycylglycine; the utilization of glutamine occurs about 8 times more rapidly in the presence of 0.1 M maleate. The transpeptidation and maleate-stimulated glutaminase reactions catalyzed by both enzyme preprations are inhibited by 5 mM L-serine in the presence of 5 mM sodium borate. Studies on gamma-glutamyl transpeptidase and maleate-stimulated glutaminase in the kidneys of fetal rats, newborn rats, and rats after weaning showed parallel development of these activities. | The evidence reported here and earlier work in this laboratory strongly support the conclusion that maleate -stimulated AMP-dependent protein kinase activity is a catalytic function of gamma-glutamyl transpeptidase. | contradiction |
In a large-scale double-blind controlled trial of practolol (200 mg twice daily) in the long-term prophylactic treatment of 3038 patients recovering from acute myocardial infarction treatment was started one to four weeks after the acute attack. The trial was originally planned to include 4000 patients treated for at least a year but had to be terminated prematurely because of the serious oculocutaneous and peritoneal reactions reported elsewhere. Nevertheless, important findings, probably applicable to other beta-adrenoreceptor antagonists, have emerged in relation to mortality and morbidity. (1) The practolol-treated group showed a significant reduction in overall mortality and in sudden deaths; (2) there was a highly significant reduction in "all cardiac events"; (3) the reduction in overall mortality was virtually confined to patients whose original pre-entry infarcts were sited anteriorly; (4) the protective effect of practolol was most evident in those patients with pre-entry anterior infarcts whose blood pressures at entry were below the mean for the trial as a whole; (5) there were highly significant group differences in favour of the drug relating to the incidence of angina pectoris and cardiac arrhythmias, and to the numbers of patients who had to be withdrawn from the trial because of these conditions; (6) significantly more patients were withdrawn from the treatment group because of suspected adverse reactions. | It is concluded that practolol used in the long-term treatment of patients who have survived the acute phase of myocardial infarction reduces the death rate when the original infarct is sited anteriorly. | entailment |
To assess the ventilatory responses elicited by changes of tissue hypoxia, sodium cyanide (0.12 mg/kg-min for 10 min) was infused into the upper abdominal aorta of anesthetized dogs. These infusions produced decreases in oxygen consumption, increases in arterial lactate concentration, and increases in arterial lactate/pyruvate ratio. Coincident with these metabolic changes of hypoxia, minute ventilation (VE) increased 228 +/- SE 36% and arterial PCO2 decreased 21 +/- SE 2 mmHg; therefore, pH increased both in arterial blood in and cisternal cerebrospinal fluid. Following infusion of cyanide into the abdominal aorta, small quantities of cyanide (48 +/- SE 14 mumol/liter) appeared in carotid arterial blood. To evaluate the possibility that the observed increases in VE were due to stimulation of peripheral arterial chemoreceptors by the recirculating cyanide, the carotid and aortic chemoreceptors were denervated in four dogs. Nonetheless, after intra-aortic infusion of sodium cyanide (1.2 mg/kg), ventilation in these chemodenervated animals again increased considerably (154 +/- SE 36%). In order to explore the possibility that cyanide infusion can stimulate ventilation by an extracranial mechanism, heads of vagotomized dogs (including the carotid bodies) were perfused entirely by donor dogs. The intra-aortic infusion of sodium cyanide (0.9 mg/kg) into these head-perfused animals still caused large increases in VE (163 +/- SE 19%). | It is not concluded that intra-aortic cyanide infusions stimulate VE by an extracranial mechanism other than the carotid and aortic chemoreceptors. | contradiction |
Immediate reduction of phosphorus loadings to the Great Lakes is essential to slow accelerated eutrophication. The Great Lakes National Program Office of the US Environmental Protection Agency now advocates adoption of bans on detergent phosphates as the most practical and feasible means of immediately reducing the phosphorus loadings to the Great Lakes. This change in policy from previous reliance on removal by sewage treatment has been adopted for the following reasons: (1) Bans on phosphates will reduce capital and operating costs of treatment and, were adopted, have met with consumer acceptance. (2) In practice, treatment plants have not met design expectations for phosphate removal. (3) Neither nitrilotriacetic acid nor other substitutes for phosphates have proved to be a public health problem. (4) Reduction of phosphorus loadings to treatment plants avoids increasing levels of chlorides and total dissolved solids in effluents. (5) Water quality has improved in small lakes with phosphorus reduction. | In summary, detergent phosphate bans alone will not reduce phosphorus loadings to the Great Lakes sufficiently for the long term but the Environmental Protection Agency has concluded that such action is necessary in addition to continued efforts to control non-point sources. | entailment |
Modeccin inhibits polypeptide-chain elongation catalysed by Artemia salina (brine shrimp) ribosomes by inactivating the 60 S ribosomal subunit. Among the individual steps of elongation, peptide-bond formation, catalysed by 60 S peptidyltransferase, is unaffected by the toxin, whereas the binding of EF 2 (elongation factor 2) to ribosomes is strongly inhibited. Modeccin does not affect the poly(U)-dependent non-enzymic binding of either deacylated tRNAPhe or phenylalanyl-tRNA to ribosomes. The inhibitory effect of modeccin on the EF 1 (elongation factor 1)-dependent binding of phenylalanyl-tRNA is discussed, since it is decreased by tRNAPhe, which stimulates the binding reaction. The analysis of the distribution of ribosome-bound radioactivity during protein synthesis shows that modeccin consistently inhibits the radioactivity bound as long-chain peptides, but depending on the experimental conditions, can leave unchanged or even greatly stimulates the radioactivity bound as phenylalanyl-tRNA and/or short-chain peptides. | It is concluded that, during the complete elongation cycle, step does not affect the binding of the first aminoacyl-tRNA to ribosomes, but inhibits some modeccin in the subsequent repetitive activity of either EF 1 or EF 2. | contradiction |
Inoculation of newborn mice with lymphocytic chloriomeningitis (LCM) virus resulted in decreased weight gain, liver cell necrosis, and death. Injection of potent sheep immunoglobulin against mouse interferon markedly inhibited these manifestations of LCM virus disease despite the fact that these treated mice had 100-fold more LCM virus in their serum. | We conclude that interferon mediates the pathogenesis of LCM virus disease in newborn mice. | contradiction |
The role of pituitary vasopressin (antidiuretic hormone--ADH) in the formation and dynamics of aqueous humour was studied in rabbits employing different techniques. Using isolated ciliary body preparations the changes in transepithelial short-circuit current were measured, and natural vasopressin and Lys8-vasopressin were found to increase the transepithelial short-circuit current at concentrations less than 10 muU/ml (i.e. within the physiological range), indicating increased sodium transport across the ciliary epithelium. In another series of experiments with intact rabbits given an ethanol load to suppress endogenous ADH, administration of exogenous vasopressin raised the intraocular pressure, and a similar effect was observed when endogenous ADH production was stimulated with nicotine. Direct measurements of outflow showed that vasopressin was without effect when given intravenously and that the only effect when given intracamerally was to increase the facility which would tend to lower rather than raise the intraocular pressure. Finally, the intra-arterial and intravenous effects of vasopressin on circulation in the iris and on the intraocular and systemic arterial pressures were studied. Local effects on the vascular bed in the eye and changes in systemic blood pressure were observed only at rates of administration well in excess of the physiological range for endogenous vasopressin production. | It is concluded that, at physiological levels, antidiuretic hormone can stimulate active sodium transport into the eye thereby tending to raise the intraocular pressure, and it is suggested that this may act as a homeostatic regulating mechanism limiting changes in the rate of formation of aqueous humour and in intraocular pressure which might otherwise result from diurnal variations in the state of body hydration. | entailment |
Protein A, a cell wall constituent of several strains of Staphylococcus aureus, binds strongly to the Fc portion of immunoglobulins. This investigation demonstrated that such binding can inhibit antibody-dependent cellular cytotoxicity (ADCC). The degree to which ADCC was inhibited depended upon the relative concentrations of protein A and anti-target cell antiserum. Protein A also inhibited the formation of rosettes between antibody-coated sheep red blood cells and lymphoid cells with Fc receptors. | We, therefore, conclude that protein A inhibits ADCC by preventing the binding of antibody-coated target cells to Fc receptors on cytotoxic effector cells. | entailment |
Using the S49 T-cell lymphoma system for the study of immunodeficiency diseases, we characterized several variants in purine salvage and transport pathways and studied their responses to the cytotoxic action of adenosine (5-20 micron) in the presence of adenosine deaminase (ADA) inhibitors. Both an adenosine transport deficient mutant and a mutant lacking adenosine (ado) kinase activity are resistant to the cytotoxic effects of adenosine up to 15 micron. Variants lacking hypoxanthine-guanine phosphoribosyl transferase or adenine phosphoribosyltransferase are sensitive to the killing action of adenosine. We monitored the intracellular concentrations of purine and pyrimidine nucleotides, orotate, and PPriboseP in mutant and wild-type cells following the addition of adenosine and an ADA inhibitor. | We conclude that at low concentrations, pyrimidine must be phosphorylated to deplete the cell of adenosine nucleotides and PPriboseP and to promote the accumulation of orotate. | contradiction |
In 37 of 41 isolated frog skeletal muscle fiber preparations (one, two, or three fibers) the twitch was eliminated or reduced to less than 10% of control by exposing the fibers to a O-calcium, bicarbonate-buffered solution for 10 min or less. Replacing the bicarbonate by a phosphate buffer either prevented twitch inhibition or increased the O-calcium exposure time required for its production. | It is concluded that surface membrane-bound phosphate ions (presumably in the t-tubules) are required to couple the action potential to the mechanical response and that calcium ions inhibit the loss of the membrane-bound phosphate ions into an external phosphate -free solution. | contradiction |
The effects of propranolol, digoxin and combination therapy (/D) on the resting and exercise ECG were studied in ten normal subjects and 20 patients with coronary artery disease (CAD) given a sequence of oral placebo, propranolol, P/D, digoxin and placebo, for two week periods. Digoxin produced a significant decrease in T-wave amplitude and often resulted in ST segment depression in the resting ECG. Propranolol, digoxin, and P/D tended to decrease the QTc interval and prolong the PR interval. However, CAD patients were more sensitive to PR prolongation than normals while receiving propranolol or digoxin alone. Propranolol therapy did not significantly affect the ST segment of the exercise ECG in the normal subjects or the CAD patients without an ischemic control exercise ECG. By contrast, 50 per cent of the normal subjects developed "false-positive" ischemic ST segment responses to exercise while receiving digoxin of P/D and three of eight CAD patients without ischemic control exercise ST segments had a similar response to digoxin or P/D. In 12 CAD patients with ischemic control exercise ST segments, propranolol did not affect the amount of ST segment depression at the onset of angina or the maximum amount of ST segment depression. Digoxin or P/D both uniformly increased the maximum amount of ST segment depression which was greater with digoxin than P/D. However, the maximum heart rate on P/D was significantly reduced as compared to that on digoxin. | It is concluded that (1) CAD patients are more sensitive to propranolol or digoxin -induced AV block than normals, (2) propranolol does not change the magnitude of ischemic exercise ST segment depression, (50) digoxin increases ischemic exercise ST segment depression and results in a high incidence of false-positive exercise tests, and (4) the addition of propranolol to digoxin attenuates the effects of digoxin on the exercise ST segment. | contradiction |
The effectiveness of a 1% chlorhexidine-containing dental gel on dental plaque and gingival health was evaluated over a period of 6 months using a double-blind procedure. One hundred and seventeen mentally retarded subjects aged between 10-17 years resident in an institution were divided into two groups. One group was assigned daily brushing with the 1% chlorhexidine gel, the other group a placebo quinine sulfate-containing gel. No other form of oral hygiene was used during the experimental period. Assessment of dental plaque accumulation and gingivitis was made at 0, 1, 3, and 6 months. An assessment was also made 2 months after the gel was withdrawn from use and normal toothbrushing procedures resumed. No clinical or statistical advantage was noted in plaque or gingivitis scores in the group receiving chlorhexidine treatment during the 6-month period. This group showed a higher prevalence of tooth staining. | It was concluded that periodontal severity and poor oral hygiene exceeded the plaque- and chlorhexidine -preventing potential of gingivitis . | contradiction |
The role of Ca2+ ions in alpha-adrenergic activation of hepatic phosphorylase was studied using isolated rat liver parenchymal cells. The activation of glucose release and phosphorylase by the alpha-adrenergic agonist phenylephrine was impaired in cells in which calcium was depleted by ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA) treatment and restored by calcium addition, whereas the effects of a glycogenolytically equivalent concentration of glucagon on these processes were unaffected. EGTA treatment also reduced basal glucose release and phosphorylase alpha activity, but did not alter the level of cAMP or the protein kinase activity ratio (-cAMP/+cAMP) or impair viability as determined by trypan blue exclusion, ATP levels, or gluconeogenic rates. The effect of EGTA on basal phosphorylase and glucose output was also rapidly reversed by Ca2+, but not by other ions. Phenylephrine potentiated the ability of low concentrations of calcium to reactivate phosphorylase in EGTA-treated cells. The divalent cation inophore A23187 rapidly increased phosphorylase alpha and glucose output without altering the cAMP level, the protein kinase activity ratio, and the levels of ATP, ADP, or AMP, The effects of the ionophore were abolished in EGTA-treated cells and restored by calcium addition. Phenylephrine rapidly stimulated 45Ca uptake and exchange in hepatocytes, but did not affect the cell content of 45Ca at late time points. A glycogenolytically equivalent concentration of glucagon did not affect these processes, whereas higher concentrations were as effective as phenylephrine. The effect of phenylephrine on 45Ca uptake was blocked by the alpha-adrenergic antagonist phenoxybenzamine, was unaffected by the beta blocker propranolol, and was not mimicked by isoproterenol. | The following conclusions are drawn: (a) alpha-adrenergic activation of phosphorylase and glucose release in hepatocytes is more dependent on calcium than is glucagon activation of these processes; (b) variations in liver cell calcium can regulate phosphorylase alpha levels and glycogenolysis; (c) calcium fluxes across the plasma membrane are stimulated more by phenylephrine than by a glycogenolytically equivalent concentration of glucagon . | entailment |
Procaine hydrochloric acid, a cationic anesthetic, although unable to prevent the effect of calcium ionophore A23187 on erythrocytes, inhibited the discocyte--echinocyte transformation, increased viscosity, and decreased filterability of red cells undergoing ATP depletion. The effects were abolished by washing ATP-depleted, procaine HCl-treated red cells prior to these determinations. Procaine HCl had no effects on volume, incubated osmotic fragility, or monovalent cation composition of ATP-depleted red cells. The drug increased 45Ca uptake by ATP-depleted red cells but did not change the fraction of membrane-bound calcium. Sodium dodecyl sulfate acrylamide gel electrophoresis of membrane proteins from ATP-depleted red cells revealed formation of high molecular weight protein complexes, which were not formed when biconcave shape and ATP content were maintained by incubation with adenine (0.54 mM) and inosine (12.7 mM); Formation of these complexes was not prevented when the biconcave shape was maintained by procaine HCl. | It was concluded that the maintenance of the biconcave shape and normal deformability during ATP depletion by procaine HCl was not related to a displacement of membrane-bound calcium and inhibition of ATP -dependent rearrangement of red cell membrane proteins. | entailment |
1 Escherichia coli endotoxin, administered intravenously in a dose of 2 mg/kg to pentobarbitone anaesthetized, artificially ventilated cats resulted in pulmonary hypertension, systemic hypotension and an immediate (1-2 min) 30-40% reduction in plasma kininogen, an effect which probably indicates a release of plasma kinins. 2 Methylprednisolone (30 mg/kg), when administered 30 min before endotoxin, did not influence the endotoxin-induced pulmonary hypertension or systemic hypotension but completely prevented the depletion of plasma kininogen. 3 In spontaneously breathing cats, methylprednisolone, administered 30 min after endotoxin, caused a rapid repletion of kininogen and prolonged survival (47% at 6 h compared to 10% in the endotoxinalone animals). Methylprednisolone did not appear to influence lactate production or the hyperventilation observed during the delayed endotoxin shock phase. | 4 It is concluded t,at methylprednisolone does not prevent the release, by kinin , of a pulmonary vasoconstrictor prostaglandin, or its effects, but that perhaps by preventing endotoxin release it may reduce kinin -induced capillary leakage. | contradiction |
The effects of somatostatin (SRIF) on glucagon release have been studied in the monolayer culture of newborn rat pancreas. It was found that SRIF inhibited glucagon release rapidly and in a dose dependent manner at concentrations of 1-1000 ng/ml. SRIF inhibited glucagon release under basal conditions and after stimulation by arginine, 3-isobutyl-1-methylxanthine (IBMX), high Ca++ concentrations, ionophore A23187 and Ca++, and Ba++. SRIF inhibited ionophore-induced glucagon release over 60 min when a low concentration of A23187 was used (0.1 microgram/ml) but not when a high concentraion (10 microgram/ml) was used. The stimulant effect of 10 microgram/ml A23187 was, however, inhibited by SRIF during short periods of incubation. The per cent inhibition of arginine-stimulated glucagon release due to SRIF remained unchanged when the Ca++ concentration in the medium was varied from 1-10 mM. | It is concluded that glucagon release promptly inhibits SRIF under basal conditions or when stimulated by a variety of agents. | contradiction |
To identify the etiologic agent of Legionnaire's disease, we examined patients' serum and tissue specimens in a search for toxins, bacteria, fungi, chlamydiae, rickettsiae and viruses. From the lungs of four of six patients we isolated a gram-negative, non-acid-fast bacillus in guinea pigs. The bacillus could be transferred to yolk sacs of embryonated eggs. Classification of this organism is incomplete. We used yolk-sac cultures of the bacillus as antigen to survey suspected serum specimens, employing antihuman-globulin fluorescent antibody. When compared to controls, specimens from 101 to 111 patients meeting clinical criteria of Legionnaires' disease showed diagnostic increases in antibody titers. Diagnostic increases were also found in 54 recent sporadic cases of severe pneumonia and, retrospectively, in stored serum from most patients in two other previously unsolved outbreaks of respiratory disease. | We conclude that Legionnaires' disease is caused by a gram -negative bacterium that may be responsible for widespread infection. | entailment |
Immunization of congenitally athymic (nu/nu) and adult thymectomized, irradiated bone marrow, reconstituted (TxBm) mice with DNP5-thymosin (dinitrophenylated-bovine thymosin fraction 5) was found to elcit IgM and IgG anti-DNP plaque-forming cells in these animals. Further studies indicated that this response was antigen specific and not due to polyclonal activation. Since the hormonal properties of the thymosin were retained following linkage with hapten and DNP-thymosin was immunogenic in CBA/N and CBA/N female X DBA/2 male)F1 male mice, animals previously shown to have an X-linked inability to respond to thymus-independent antigens, it was concluded that DNP-thymosin functions both as a hormone and as a T-dependent antigen in eliciting an immune response in nu/nu and TxBm mice. | Additional support for this conclusion was provided by the demonstration that DNP-thymosin could specifically prime for and elicit an anamnestic response in nu/nu mice . | entailment |
In an attempt to define the effects of endotoxin on the permeability of the pulmonary alveolar capillary membrane (ACM) to a variety of substances [molecular weight (MW) varying from 60 to 69,000], we studied the movement of specific molecular species from the pulmonary capillary blood to the saline-filled "alveolus," employing an in vivo dog lung model. Following endotoxin injection (2-2.5 mg/kg) baseline T1/2 values (time, in minutes, for 50% equilibration of the specific solute between the blood and the saline-filled lung) decreased as follows (compared to baseline values): urea (MW 60) - 42.5 +/- 24 to 21.3 +/- 18; sucrose (MW 360) - 201 +/- 72 to 76 +/- 53; 3,000 MW dextran - 1,275 +/- 746 to 686 +/- 433; 10,400 MW dextran - 1,871 +/- 845 to 1,052 +/- 630 (all p less than 0.05). Neither 20,000 MW dextran nor albumin (MW 69,000) showed an increased permeability following endotoxin injection. Histamine analysis revealed a significant increase in all lung liquid samples post-endotoxin injection without a significant increase in blood histamine values. | We conclude that, acutely (within 4 hr of injection), endotoxin causes an increase in permeability of the ACM for substances up to 10,400 MW. | entailment |
The effect of cimetidine on gastric acid, pepsin, and intrinsic factor secretion was assessed in normal male subjects. Cimetidine (300 mg) completely inhibited acid, pepsin, and intrinsic factor concentration and output stimulated by betazole. In contrast, basal output of pepsin and intrinsic factor was not inhibited. | We conclude that H2-receptor antagonists inhibit intrinsic factor stimulation of betazole output in addition to their well-known inhibition of acid secretion. | contradiction |
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