Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol decreases hepatic protein and albumin synthesis, and inhibits pancreatic water, bicarbonate, and protein secretion. Since these actions of ethanol are opposite to those reported for secretin, cholecystokinin-pancreozymin, and pentagastrin which may be mediated through increases in cyclic GMP, it appeared possible that the inhibitory actions of ethanol might be mediated through inhibition of guanylate cyclase, the enzyme that catalyzes the production of cyclic GMP. Ethanol inhibited soluble preparations of guanylate cyclase from rat liver, pancreas, stomach, and ileum. Maximal inhibition was observed at 5.0 and 2.5 percent ethanol. The inhibitory effects of ethanol on the guanylate cyclase-cyclic GMP system of these tissues provide a possible explanation for some of the diverse effects of ethanol on these tissues.
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PMID:Ethanol-induced inhibition of guanylate cyclase in liver, pancreas, stomach and intestine. 1 94

We have recently suggested that relaxation of isolated precontracted intrapulmonary arteries from calves to H2O2 or O2 may involve the activation of guanylate cyclase by peroxide metabolism via catalase. In this study, ethanol, an agent that modulates peroxide metabolism by catalase and selectively inhibits the activation of guanylate cyclase by H2O2 but not by nitric oxide-related activators, was employed to further investigate the role of catalase in pulmonary arterial relaxation and guanylate cyclase activation by O2 and H2O2. In precontracted pulmonary arteries, ethanol reverses H2O2-elicited relaxation and increases in guanosine 3',5'-cyclic monophosphate (cGMP) tissue levels without affecting similar responses to nitroprusside. The pulmonary arteries employed in this study show a hypoxic contraction that is associated with decreases in cGMP levels, and reoxygenation produces a somewhat phasic relaxation and a marked increase in cGMP levels. Ethanol produces an O2 tension-dependent contraction and reverses relaxation to reoxygenation associated with inhibition of O2-elicited increases in cGMP levels. Thus ethanol appears to function as a mimic of hypoxia by inhibiting relaxations elicited by O2. These findings support a hypothesized role for H2O2-dependent activation of guanylate cyclase in O2-dependent regulation of pulmonary arterial smooth muscle tone.
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PMID:Inhibition of cGMP-associated pulmonary arterial relaxation to H2O2 and O2 by ethanol. 197 Sep 24

The effect of ethanol was studied on the endothelium-dependent vascular responses in isolated rat aortic strips. Ethanol depressed the endothelium-dependent relaxation induced by acetylcholine and ATP but not that induced by the calcium ionophore, A23187. Endothelium-independent relaxation in response to sodium nitroprusside, a soluble guanylate cyclase activator, was not depressed by ethanol. On the other hand, ethanol significantly enhanced the contractile response to clonidine, an alpha 2-adrenoceptor agonist, in endothelium-intact strips and depressed it in endothelium-denuded strips. These results suggest that ethanol can inhibit endothelium-dependent relaxation by acting on endothelial cells but not on smooth muscle cells, and can also suppress an inhibitory effect of the endothelium on alpha 2-adrenoceptor-mediated vasoconstriction.
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PMID:Inhibitory effect of ethanol on endothelium-dependent vascular responsiveness. 251 Oct 33

In primary cultures of cerebellar granule cells of the rat, the accumulation of cyclic GMP was stimulated by glutamate, acting at the N-methyl-D-aspartate recognition site, and by atrial natriuretic factor. The response to glutamate was calcium-dependent, while the response to atrial natriuretic factor was not. Ethanol inhibited the accumulation of cyclic GMP in response to both glutamate and atrial natriuretic factor. However, the response to glutamate was much more sensitive to ethanol, with 30-40% inhibition occurring at 50 mM ethanol. Substantial inhibition of the response to atrial natriuretic factor was observed only at concentrations of ethanol of 200 mM or larger. The data suggest that a major site of action of ethanol in inhibiting the accumulation of cyclic GMP is the coupling of the glutamate receptor to soluble guanylate cyclase. The effect of ethanol on agonist-activated activity of guanylate cyclase may contribute to the pharmacological action of ethanol in vivo.
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PMID:Selective inhibition by ethanol of glutamate-stimulated cyclic GMP production in primary cultures of cerebellar granule cells. 255 55

The acute effects of ethanol were studied on the guanylate cyclase system of cultured murine neuroblastoma clone N1E-115. Using intact cells, we found that although ethanol had no effect on basal levels of cyclic GMP synthesis, it rapidly inhibited in a concentration-dependent manner cyclic GMP synthesis mediated by the agonists histamine (histamine H1 receptor) and carbachol (low-affinity muscarinic receptor) and by ionophore X537A and melittin, agents which bypass these receptors. At 200 mM ethanol, inhibition was about 40 to 50% with the agonists, X537A and melittin. Ethanol had no effect on the high-affinity muscarinic receptor, that mediates inhibition of cyclic AMP synthesis. With carbachol ethanol's inhibition was reversible and was a mixed competitive/noncompetitive type. For a series of alcohols, inhibitory potency with carbachol correlated with chain length directly. In addition, sucrose and sodium chloride, which like ethanol increases the osmolality of the incubation medium, mimicked the effects of ethanol. In a crude cellular homogenate, ethanol and other alcohols inhibited both basal and sodium nitroprusside-stimulated guanylate cyclase activity. The effect of ethanol on basal enzyme activity was noncompetitive. Thus, the inhibition by ethanol and other alcohols of receptor-mediated cyclic GMP synthesis appears to be at the level of guanylate cyclase.
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PMID:Acute effects of ethanol and other short-chain alcohols on the guanylate cyclase system of murine neuroblastoma cells (clone N1E-115). 286 20

Intestinal brush border guanylate cyclase was previously reported to be activated by the Escherichia coli enterotoxin (STa). This system was reexamined in order to develop a hypothesis for the mechanism of activation. The extent of activation was previously underestimated, since by using sodium azide to inhibit competing reactions and ethylene glycol bis(beta-aminoethyl ether) N,N-tetraacetic acid to chelate Ca2+, which is inhibitory, maximal activations of 30- to 50-fold were obtained. Ca2+ inhibition was only partially relieved by the calmodulin inhibitor calmidazolium. Inhibitors of the O2-dependent activation of soluble guanylate cyclase had no effect on STa activation; hence, it was concluded that STa activation did not involve arachidonate release and oxidation. STa was able to further increase activity already elevated by the nonionic detergent Lubrol PX. The membrane-active agent filipin, which was previously reported to inhibit both basal and agonist-stimulated adenylate cyclase, did not inhibit STa activation of guanylate cyclase. Digitonin, another cholesterol binder, inhibited STa activation at low concentrations, which disappeared at higher concentrations. Both of these agents stimulated basal activity. Dimethyl sulfoxide produced a concentration-dependent inhibition of STa activation, while increasing basal activity 7-fold. Ethanol inhibited both basal and STa-stimulated activity, with the former being more affected. Benzyl alcohol, like ethanol, a "fluidizer" of cell membranes, also inhibited both basal and activated enzymes. We concluded that STa directly activates this guanylate cyclase and, because of the differential effects of inhibitors on basal and STa-stimulated activity, propose a receptor-mediated mechanism.
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PMID:Characterization of intestinal brush border guanylate cyclase activation by Escherichia coli heat-stable enterotoxin. 286 96

It has previously been shown that alcohol can suppress reproduction in humans, monkeys, and small rodents by inhibiting release of luteinizing hormone (LH). The principal action is via suppression of the release of LH-releasing hormone (LHRH) both in vivo and in vitro. The present experiments were designed to determine the mechanism by which alcohol inhibits LHRH release. Previous research has indicated that the release of LHRH is controlled by nitric oxide (NO). The proposed pathway is via norepinephrine-induced release of NO from NOergic neurons, which then activates LHRH release. In the present experiments, we further evaluated the details of this mechanism in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO, prostaglandin E2 (PGE2), conversion of arachidonic acid to prostanoids, and production of cGMP. The results have provided further support for our theory of LHRH control. Norepinephrine increased the release of NO as measured by conversion of [14C]arginine to [14C]citrulline, and this increase was blocked by the alpha 1 receptor blocker prazosin. Furthermore, the release of LHRH induced by nitroprusside (NP), a donor of NO, is related to the activation of soluble guanylate cyclase by NO since NP increased cGMP release from MBHs and cGMP also released LHRH. Ethanol had no effect on the production of NO by MBH explants or the increased release of NO induced by norepinephrine. Therefore, it does not act at that step in the pathway. Ethanol also failed to affect the increase in cGMP induced by NP. On the other hand, as might be expected from previous experiments indicating that LHRH release was brought about by PGE2, NP increased the conversion of [14C]arachidonic acid to its metabolites, particularly PGE2. Ethanol completely blocked the release of LHRH induced by NP and the increase in PGE2 induced by NP. Therefore, the results support the theory that norepinephrine acts to stimulate NO release from NOergic neurons. This NO diffuses to the LHRH terminals where it activates guanylate cyclase, leading to an increase in cGMP. At the same time, it also activates cyclooxygenase. The increase in cGMP increases intracellular free calcium, activating phospholipase A2 to provide arachidonic acid, the substrate for conversion by the activated cyclooxygenase to PGE2, which then activates the release of LHRH. Since alcohol inhibits the conversion of labeled arachidonic acid to PGE2, it must act either directly to inhibit cyclooxygenase or perhaps it may act by blocking the increase in intracellular free calcium induced by cGMP, which is crucial for activation of of both phospholipase A2 and cyclooxygenase.
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PMID:Ethanol inhibits luteinizing hormone-releasing hormone (LHRH) secretion by blocking the response of LHRH neuronal terminals to nitric oxide. 772 77

The authors tested the hypothesis that ethanol or its metabolite acetaldehyde might interfere in cyclic guanosine monophosphate (GMP) metabolism in coronary smooth muscle cells. Ethanol at the physiologically relevant concentration of 4.0 mg/mL or more significantly decreased basal guanylate cyclase activity and inhibited activation of the enzyme by sodium nitroprusside (SNP) in cultured porcine coronary smooth muscle cells. Two isoforms of phosphodiesterase (PDE), cyclic GMP-specific form and calmodulin-stimulated form, were both inhibited by 12.0 mg/mL or more ethanol. Intact cell study revealed that although 12.0 mg/mL or more ethanol was needed to significantly decrease cyclic GMP accumulation in control cells, 4.0 mg/mL or more ethanol significantly inhibited the increase of cyclic GMP accumulation induced by 1 microns SNP. Acetaldehyde showed similar effects, but the concentrations involved were more than physiological. Thus, ethanol may decrease cellular cyclic GMP levels and attenuate cyclic GMP accumulation in response to SNP in coronary smooth muscle cells by inhibiting soluble guanylate cyclase activity at physiologically relevant concentrations.
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PMID:Ethanol modulates cyclic GMP metabolism in cultured coronary smooth muscle cells. 809 30

Using 5% ethanol as a deciliating agent, 20 mm colchicine to prevent reciliation and 1 mm amiloride to affect ion fluxes in Paramecium we examined the compartmentation and function of Ca2+ fluxes employing the biosynthesis of cGMP and the stereotypic swimming behavior as indicators for Ca2+ entry. As a function of extracellular Ca2+ Paramecia responded to colchicine and amiloride with a short-lived ciliary augmentation (fast swimming) which indicated hyperpolarization, and formation of cGMP, i.e., the reported hyperpolarization-activated Ca2+ inward current in the somatic membrane is coupled to intracellular generation of cGMP. This is comparable to the coupling of the depolarization-activated, ciliary Ca2+ inward current and ciliary cGMP formation.Ethanol-deciliated cells and ethanol-treated, yet ciliated control cells did not respond to a depolarization with backward swimming or formation of cGMP. Both responses recovered with similar kinetics. A persistent effect of an ethanol exposure on the axonemal apparatus or on guanylyl cyclase activity of ciliated control cells was excluded using permeabilized cells and cell-free enzyme, respectively. Further, in the presence of 20 mm colchicine ethanol-treated cells only recovered the depolarization-dependent avoiding reaction whereas the formation of cGMP remained depressed, i.e., the drug dissected both responses. Similarly, ethanol exposure of Paramecia did not affect the fast swimming response towards the hyperpolarizing agent amiloride whereas the cGMP formation was abrogated and recovered over a period of 7 hr, i.e., amiloride dissected the hyperpolarization-elicited behavioral response from the intracellular cGMP formation. The data demonstrate that in Paramecium depolarization- and hyperpolarization-stimulated behavioral responses and cGMP formation are not coupled. The behavioral changes are triggered by smaller Ca2+ inward currents than the formation of intracellular cGMP.
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PMID:Hyperpolarization- and depolarization-activated Ca2+ currents in Paramecium trigger behavioral changes and cGMP formation independently. 909 66

Alcohol suppresses reproduction in humans, monkeys and small rodents by suppressing release of luteinizing hormone (LH). The major action is on the hypothalamus to decrease release of LH-releasing hormone (LHRH). The release of LHRH is controlled by nitric oxide (NO). The hypothesized pathway is via norepinephrine-induced release of NO from NOergic neurons which activates LHRH release. We have evaluated details of this process in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO and metabolites generated by NO which control LHRH release. Norepinephrine increased release of NO as measured by determining the content of the enzyme at the end of the experiment (30 min) by adding [14C]arginine to the homogenate and measuring its conversion to [14C]citrulline since this is formed in equimolar quantities with NO by nitric oxide synthase (NOS). Since this increase in content presumably caused by activation of the enzyme by norepinephrine was blocked by the alpha 1 receptor blocker prazosin, it appears that alpha 1 receptors activate NOS by increasing intracellular free calcium in the NOergic neuron which combines with calmodulin to activate nitric oxide synthase. The release of LHRH induced by nitroprusside (NP), a donor of NO, results in an increase in cyclic (c)GMP in the medium supporting the activation of guanylate cyclase by nitroprusside. This activation is important in releasing LHRH since addition of 8-monobutyryl cGMP also released the peptide. Ethanol had no effect on the content of NO or the increase in content induced by norepinephrine indicating that it did not act on NOS. Earlier experiments indicated that prostaglandin E2 (PGE2) was important in releasing LHRH. PGE2 is produced by activation of cyclooxygenase by NO since this could occur following addition of the NO donor nitroprusside. Not only does NP increase PGE2 release, but also the conversion of [14C]arachidonic acid to its metabolites, particularly PGE2. Ethanol acts at this step since it completely blocks the release of LHRH induced by NP and the increase in PGE2 induced by NP. Therefore, the results support the theory that norepinephrine acts to stimulate NO release from NOergic neurons. This NO diffuses to the LHRH terminals, where it activates guanylate cyclase, leading to an increase in cGMP. At the same time, it also activates cyclooxygenase. The increase in cGMP increases intracellular free calcium, required for activation of phospholipase A2. Phospholipase A2 converts membrane phospholipids into arachidonic acid, the substrate for conversion by the activated cyclooxygenase to PGE2 which then activates the release of LHRH. Since alcohol inhibits conversion of labeled arachidonic acid to PGE2, it must act either directly to inhibit cyclooxygenase or by some other mechanism which, in turn, inhibits the enzyme.
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PMID:The mechanism of action of alcohol to suppress gonadotropin secretion. 932 22


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