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)

In a submaximal concentration carbachol contracted the rabbit colon muscle and increased the cyclic GMP level. The cyclic AMP level was reduced. In a Ca++-depleted muscle carbachol reduced the cyclic GMP level while the effect on the cyclic AMP content of the muscle was unchanged. Carbachol had no effect on the guanylate cyclase activity of the "plasma membrane fraction" (the 35-45% fraction). In the homogenate and the microsomal fractions Ca++ had no effect on the guanylate activity while it stimulated the enzyme in a soluble fraction. In the "plasma membrane fraction" cyclic GMP released Ca++ from the preloaded fraction and inhibited the Ca++ accumulation. These effects were not found in the vesicular microsomal fraction (the 35% fraction). In both fractions, however, cyclic GMP counteracted the stimulating effect of cyclic AMP. These results indicate that cyclic AMP and GMP may have antagonistic roles on the Ca++ metabolism in the colon muscle. It is suggested that cyclic GMP may act as some kind of positive feedback mechanism which may have a modulating effect on the release of Ca++ from one pool to another in rabbit colon.
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PMID:Effects of carbachol and calcium on the cyclic guanosine-3',5'-monophosphate (cyclic GMP) metabolism in intestinal smooth muscle. 1 81

Relaxation of the lower esophageal sphincter (LES) results from activation of its intrinsic innervation. This relaxation is associated temporally with an increase in the guanosine 3',5'-cyclic monophosphate (cGMP) content of the muscle. This study tests the hypothesis that variations in the production of cGMP mediate resting LES tone and nerve-induced relaxation. We examined the effects of guanylate cyclase inhibitors, such as cystamine and methylene blue (MB), on the resting tone, resting membrane potential, electrical field stimulation (EFS)-induced relaxation, and cGMP content of circular smooth muscle from the LES of the opossum. Strips of sphincter muscle were placed in a tissue bath and stretched to 125% resting length. Both cystamine and MB increased the resting tone of LES muscle in a concentration-dependent manner (EC50 = 1.1 +/- 0.2, n = 12, and 1.6 +/- 0.4 mM, n = 10, respectively). The increase in tone by cystamine was not blocked by tetrodotoxin, atropine, or propranolol. Cystamine (1 mM) did not alter the resting membrane potential of circular muscle cells of the LES. The removal of extracellular Ca2+ by the addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA, 4 mM) and nifedipine (1 microM) shortened the duration but not the amplitude of the response to cystamine. Pretreatment with caffeine (5 mM) in the presence of EGTA and nifedipine to deplete intracellular Ca2+ stores blocked the increase in tone by cystamine. Cystamine (1 mM) failed to inhibit LES relaxation induced by EFS. Carbachol, at a concentration that induced a similar increase in base-line tone, attenuated the nerve-mediated relaxation. Cystamine did not alter basal cGMP levels, but inhibited the rise in cGMP induced by EFS. The data indicate that cystamine increases LES tone but does not inhibit EFS-induced relaxation, even though it inhibits EFS-induced increases in cGMP content. The increase in tone is dependent on the presence of intracellular Ca2+ stores.
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PMID:Guanylate cyclase inhibitors: effect on tone, relaxation, and cGMP content of lower esophageal sphincter. 135 4

STa, the heat-stable enterotoxin of Escherichia coli, stimulates membrane-bound guanylate cyclase in enterocytes, elevates cyclic GMP, and results in intestinal secretion of ions and fluid. Using the T84 colon carcinoma cell line as a model. Weikel et al. reported that phorbol esters enhance STa-stimulated cyclic GMP production by 60-140% [(1990) Infect. Immun. 58, 1402-1407]. In the present report we demonstrate that the acetylcholine analog carbachol enhanced toxin-stimulated cyclic GMP accumulation in intact T84 cells by 50-100% and that this effect was blocked by 10 microM atropine and 10 microM sphingosine. Pertussis toxin treatment of the T84 cells did not affect the subsequent response to carbachol. Carbachol, which elevates intracellular calcium in these cells, may act through protein kinase C to enhance cyclic GMP production.
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PMID:Carbachol mimics phorbol esters in its ability to enhance cyclic GMP production by STa, the heat-stable toxin of Escherichia coli. 217 3

1. The aim of this study was to examine the possible role of the release of guanosine 3':5'-cyclic monophosphate (cyclic GMP) into the extracellular space in the regulation of rat aortic cyclic GMP content. 2. Rat aortic segments incubated in physiological solution released cyclic GMP into the medium in a time-dependent manner. This release was greatly enhanced when intact instead of tissues without endothelium were used. After 120 min of observation, a maximal 33 fold difference in extracellular cyclic GMP content was detected. 3. Treatment of rat aortic preparations with either a Ca2+-free solution or methylene blue, both conditions known to inhibit endothelium-derived relaxing factor (EDRF)-mediated responses, markedly reduced the extracellular accumulation of cyclic GMP from tissues with but not without endothelium. 4. Endothelium-dependent vasodilators such as acetylcholine (10 microM) and carbachol (10 microM) greatly increased tissue cyclic GMP content, in a time-dependent manner in rat aortic preparations with endothelium, but only slightly in tissues without. Maximal increases in intact tissues were obtained after about 1 min of agonist contact and amounted to about 35 and 15 fold respectively, thereafter tissue cyclic GMP content rapidly declined. Histamine (10 microM) elicited only minor effects on tissue cyclic GMP content of both intact preparations and those without endothelium. 5. Acetylcholine (10 microM), carbachol (10 microM) and histamine (10 microM) stimulated a time-dependent release of the cyclic nucleotide into the incubation medium from tissues with endothelium. After 120 min of observation, extracellular accumulation of cyclic GMP from intact tissues was increased by about 2.6, 6.6 and 1.7 fold respectively. Carbachol and histamine induced only minor effects on release from tissues without endothelium. 6. Sodium nitroprusside (0.3 and 10 microM), a direct activator of soluble guanylate cyclase, induced a concentration-dependent accumulation of cyclic GMP in tissues with and without endothelium that was associated with a concentration-dependent accumulation of cyclic GMP in the extracellular space. Peak tissue cyclic GMP content reached similar levels in preparations with and without endothelium, while extracellular cyclic GMP levels were about two times greater when experiments were performed with intact compared to endothelium-denuded tissues. 7. Atriopeptin II, an activator of particulate guanylate cyclase, increased tissue cyclic GMP content by about 8 and 18 fold respectively in tissues with and without endothelium. As was the case with sodium nitroprusside, atriopeptin II-stimulated release was markedly enhanced from intact tissues compared with those without endothelium. After 120 min of observation, there was a 16 fold difference in the amount of extracellular cyclic GMP.
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PMID:Effect of endothelium on basal and on stimulated accumulation and efflux of cyclic GMP in rat isolated aorta. 254 88

We have examined the properties of soluble guanylate cyclase activity in the human neutrophil. The enzyme showed complex regulation by metal ions. A 10-fold higher activity was observed in the presence of Mn2+ than Mg2+, while Ca2+ caused an increase in activity only in the presence of Mg2+ ion. Sodium nitroprusside (SNP), azide and hydrogen peroxide were activators of the enzyme. Dithiothreitol blocked the activation by SNP, suggesting the involvement of thiol groups in the activation process. Carbachol acting through the muscarinic cholinergic receptor caused a dose-dependent activation, which was blocked by atropine. Higher concns of carbachol were required to activate guanylate cyclase than were required for the modulation of enzyme release elicited by N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Nordihydroguaracetic acid inhibited carbachol stimulation of guanylate cyclase. By contrast, trifluoperazine (TFP), a calmodulin antagonist, caused a biphasic modulation of basal activity in the presence or absence of carbachol. Our results indicate that: allosteric interactions of metal ions are important to the regulation of the enzyme, the free radical nitroxide as well as hydrogen peroxide enhances enzyme activity, agonist occupancy of the muscarinic cholinergic receptor activates neutrophil guanylate cyclase probably through a mechanism involving calcium influx and the activation of the lipoxygenase pathway, and a TFP-sensitive site (possibly calmodulin) is involved in the selective regulation of basal enzyme activity.
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PMID:Regulation of human neutrophil guanylate cyclase by metal ions, free radicals and the muscarinic cholinergic receptor. 286 50

The dependence of relaxation of rabbit aortic strips by carbachol and by the inhibitory factor from the bovine retractor penis (BRP) on the presence of endothelium has been compared. Carbachol-induced relaxation is abolished by removing the endothelium, inhibitory factor-induced relaxation is unimpaired. The inhibitory factor, therefore, does not act by releasing an endothelium-derived relaxing factor (EDRF). The effect of inhibitors of eicosanoid metabolism on relaxation was examined. Quinacrine and nordihydroguaiaretic acid abolished the relaxant effect of carbachol and flurbiprofen had no effect. The relaxation produced by the inhibitory factor was unaffected by quinacrine and flurbiprofen while nordihydroguaiaretic acid potentiated the response. No eicosanoid appears, therefore, to be involved in the relaxant effect of the inhibitory factor from the BRP. Methylene blue, a drug reported to inhibit guanylate cyclase, in a concentration of 10 microM selectively abolished the relaxation produced by carbachol. However, at the higher concentration of 30 microM it abolished almost completely the response to inhibitory factor from the BRP and reduced inhibition by sodium nitroprusside. It is not possible from these results to exclude the possibility that the EDRF and the inhibitory factor from the BRP are chemically related.
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PMID:A comparison of the action of the endothelium-derived relaxant factor and the inhibitory factor from the bovine retractor penis on rabbit aortic smooth muscle. 286 8

The inhibitory effects of endothelium-derived relaxing factor (EDRF) on the contractions induced by norepinephrine and clonidine in rat aorta were examined. Carbachol induced a relaxation of norepinephrine-induced contraction in rat aorta with endothelium. Removal of endothelium inhibited the carbachol-induced relaxation and increased the magnitude of norepinephrine-induced contraction. Quinacrine, a phospholipase A2 inhibitor, methylene blue, a guanylate cyclase inhibitor and tetraethylammonium, a potassium permeability inhibitor, inhibited carbachol-induced relaxation and augmented the magnitude of norepinephrine-induced contraction only when endothelium was present. Clonidine induced a contraction when endothelium was removed or muscle was treated with methylene blue. The contractions induced by norepinephrine and clonidine were equally sensitive to prazosin and equally less sensitive to yohimbine. Clonidine inhibited the norepinephrine-induced contraction, whereas it potentiated the angiotensin 11- or 12 mM K-induced contractions in the aorta with endothelium. The inhibitory effect of clonidine on the norepinephrine-induced contraction was reduced by endothelium-removal and by methylene blue but not by yohimbine. These results suggest that norepinephrine has a strong direct stimulating action and clonidine has a weak one on vascular smooth muscle cells possibly mediated by alpha 1-adrenoceptors, and their contractile effects are inhibited by the spontaneously released EDRF.
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PMID:Role of endothelium in the contractions induced by norepinephrine and clonidine in rat aorta. 387 8

In this paper we show that isolated rat atria synthetized nitric oxide (NO) and its acts as intracellular messenger, increasing cGMP production that in turn modulates the muscarinic cholinergic dependent inhibition of contractility. Carbachol activating M2 muscarinic acetylcholine receptors (M2 mAchR) activated phosphoinositide turnover, stimulated nitric oxide synthase and increased production of NO. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase activities, shifted to the right the dose-response curve of carbachol upon contractility. Moreover, sodium nitroprusside and 8-bromo cGMP, induced negative inotropic effect. These results suggest that carbachol activating M2 mAchR exerts inotropic negative effect associated to an increase production of NO. The mechanism appears to occur secondarily to stimulation of phosphoinositide turnover via phospholipase C activation. This in turn, triggers cascade reactions leading to the production of NO, that contribute to the inotropic negative action of low concentrations of carbachol.
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PMID:Negative inotropic effect of carbachol on rat atria mediated by nitric oxide. 754 28

Guanosine 3',5'-cyclic monophosphate (cGMP) rise is one of the early events in neurotransmitter or hormone-induced cascade of reactions in pancreatic acinar cells. The mechanism of agonist-stimulated guanylyl cyclase activation in these cells remains, however, unknown. In the present work, mechanisms of cGMP rise, as well as of Ca2+ influx, induced by carbachol were studied on acinar cells isolated from rat and guinea pig pancreas. In both types of acinar cells, blocking nitric oxide (NO) production by inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine, abolished carbachol-induced cGMP rise in a dose-dependent manner. The inhibition was reversed by addition of excess L-arginine. L-NMMA also caused inhibition of the basal cGMP level, suggesting a role for NO in cGMP homeostasis in resting cells. Carbachol was found to increase [3H]arginine conversion to [3H]citrulline. This conversion was inhibited by L-NMMA. By contrast, inhibition of carbon monoxide production by Zn-protoporphyrin did not affect carbachol-stimulated cellular cGMP levels. There was no increase in cellular cGMP levels in response to exogenous arachidonic acid (AA). Blocking of lipoxygenase oxidation of AA by nordihydroguaiaretic acid did not produce any changes in carbachol-induced cGMP rise. Indomethacin, a cyclooxygenase inhibitor, increased basal cGMP level through L-NMMA-sensitive mechanism. Blockade of NO production inhibited carbachol-induced increase in 45Ca2+ uptake in both guinea pig and rat acinar cells. The concentration-response curves for inhibition by L-NMMA of 45Ca2+ uptake and cGMP formation were superimposable. L-NMMA also suppressed stimulation of Mn2+ quenching by carbachol in fura 2-loaded acini.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide production regulates cGMP formation and calcium influx in pancreatic acinar cells. 816 75

1. In this paper we have determined the different signalling pathways involved in muscarinic acetylcholine receptor (AChR)-dependent inhibition of contractility in rat isolated atria. 2. Carbachol stimulation of M2 muscarinic AChRs exerts a negative inotropic response, activation of phosphoinositide turnover, stimulation of nitric oxide synthase and increased production of cyclic GMP. 3. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase, shifted the dose-response curve of carbachol on contractility to the right. These inhibitors also attenuated the muscarinic receptor-dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8-bromo cyclic GMP, induced a negative inotropic effect, increased cyclic GMP and activated nitric oxide synthase. 4. These results suggest that carbachol activation of M2 AChRs, exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This in turn, triggers cascade reactions involving calcium/calmodulin and protein kinase C, leading to activation of nitric oxide synthase and soluble guanylate cyclase.
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PMID:Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor-inotropic response. 856 14


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