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)

The formation of cyclic GMP (cGMP) by guanylate cyclase, and the properties of the soluble and particulate isoenzymes, are reviewed. Regulation of guanylate cyclase and cGMP accumulation in intestinal mucosa and vascular smooth muscle with and without endothelium are summarized. The effects of E. coli heat-stable enterotoxin, nitrovasodilators, endothelium-dependent vasodilators, and atrial natriuretic factors in these systems are discussed. A potential role for free radicals, Ca, and unsaturated fatty acids in cGMP synthesis is reviewed. These tissue systems (intestinal mucosa and vascular smooth muscle with or without intact endothelium) are presented as model systems and as examples of the regulation of cGMP accumulation in a single cell type by peptides, drugs, and cell-cell interactions that are required to generate cGMP with a hormone or drug.
J Cardiovasc Pharmacol 1986
PMID:Regulation of cyclic GMP synthesis and the interactions with calcium. 243 27

As cyclic 3',5'-guanosine monophosphate (cGMP) is still discussed as a possible mediator of the negative inotropic effects of cholinergic agents, the influence of acetylcholine (ACh) on force of contraction and cGMP tissue levels was studied in isolated, electrically driven guinea pig auricles in the presence of methylene blue, an inhibitor of guanylate cyclase activation, as well as of M & B 22,948, an inhibitor of cGMP breakdown. Nitroprusside-Na (NP), a potent stimulator of guanylate cyclase, was tested for comparison under the same conditions. ACh at concentrations of 10(-7)-5 X 10(-6) M dose-dependently diminished force of contraction down to cardiac arrest, whereas NP only had a slight negative inotropic effect that was maximum at 10(-5) M and reduced force of contraction to 89% of control. Although ACh was much more effective in reducing force of contraction than NP, only NP significantly increased myocardial cGMP levels. The rise in cGMP produced by NP was attenuated by methylene blue (5 X 10(-5) M) and augmented by M & B 22,948 (3.7 X 10(-4) M), whereas the contractile effects (similar as those of ACh) remained unchanged. These results suggest that the negative inotropic action of ACh is not mediated by cGMP.
J Cardiovasc Pharmacol
PMID:Lack of second messenger function of cyclic GMP in acetylcholine-induced negative inotropism. 243 40

Pinacidil is a novel, clinically effective vasodilator used for the treatment of hypertension whose mechanism of action has not been precisely defined. In vitro, pinacidil (ED50 = 0.3 microM) was approximately 30-fold less potent than nitroglycerin and 700-fold more potent than minoxidil or hydralazine in relaxing rat aortic strip preparations. Aortic relaxations produced by nitroglycerin and acetylcholine were dramatically antagonized by methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase. In contrast, relaxation to hydralazine or minoxidil was unaffected and relaxation to pinacidil was only modestly inhibited (approximately threefold) by methylene blue (10(-5) M). Furthermore, aortic relaxation to pinacidil was similar in preparations with and without an intact endothelium. Relaxation induced by pinacidil (10(-7)-10(-4) M) was not associated with any elevation in either cyclic AMP (cAMP) or cyclic GMP (cGMP) levels in vitro, although nitroglycerin (10(-6) M) but not minoxidil (10(-3) M) or hydralazine (10(-3) M) significantly elevated cGMP levels. Thus, pinacidil was a potent relaxant agonist in vitro, in contrast to minoxidil and hydralazine, which were considerably weaker in this regard. Vascular relaxation produced by pinacidil was independent of an intact endothelium and was not associated with elevations in either cAMP or cGMP. These data are consistent with the proposal that the antihypertensive activity of pinacidil is due to nonspecific arterial vasodilation.
J Cardiovasc Pharmacol
PMID:Effects of pinacidil on serotonin-induced contractions and cyclic nucleotide levels in isolated rat aortae: comparison with nitroglycerin, minoxidil, and hydralazine. 243 46

A brief review is given of the vasodilators that require an intact vascular endothelium to exert their relaxing effect. Then some major issues of the phenomenon of endothelium-dependent smooth muscle relaxation are discussed in more detail: The chemical structure of the endothelium-derived relaxing factor (EDRF), which mediates this type of vasodilation, is still unclear. There is agreement that EDRF is chemically unstable, but determinations of its biological half-life have yielded discrepant values (6-50 s). Recent evidence suggests that oxygen and/or activated oxygen species accelerate the evanescence of the factor. The biochemical mechanisms involved in the production of EDRF are still largely unknown. Both stimulators of phospholipase A2 and inhibitors of lysolecithin acyltransferase were found to induce EDRF-mediated relaxation, while several phospholipase inhibitors block these relaxations. These findings suggest that cleavage of phospholipids (and formation of free fatty acids and lysophosphatides) play an important role in EDRF production. EDRF-mediated relaxations are associated with increased levels of cyclic GMP in vascular smooth muscle cells. Endothelial cells were found to produce a factor that directly stimulates the enzymatic activity of soluble guanylate cyclase. This stimulating factor is likely to be identical with EDRF. The significance of the endothelium-dependent relaxing mechanism in resistance vessels is still largely unclear. In the blood-perfused hind limb of the rabbit, two irreversible inhibitors of endothelium-dependent vasodilation (gossypol and p-bromophenacyl-bromide) blocked the vasodilation induced by the endothelium-dependent agent acetylcholine, but not the response to the endothelium-independent vasodilator prostaglandin E1.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1986
PMID:Properties and mechanisms of production and action of endothelium-derived relaxing factor. 243 90

Administration of atrial natriuretic factor (ANF) in animals results in increases in renal blood flow, natriuresis, and a decrease in arterial blood pressure, supporting a role for the atrial peptide system in cardiovascular regulation. However, little is known about the vascular effects of synthetic ANF (26 amino acid) on coronary artery smooth muscle. We studied the coronary vascular effects of synthetic ANF in feline artery preparations in vitro. In isolated coronary arteries perfused at constant flow, ANF (3-300 nM) concentration dependently decreased perfusion pressure ranging from 2.6 +/- 0.7 mm Hg (p less than 0.02) at 3 nM to 28.6 +/- 3.7 mm Hg (p less than 0.001) at 300 nM. Perfusion with the prostacyclin analog, iloprost (20-100 nM), failed to alter the coronary vasodilator response to ANF. ANF also relaxed feline coronary helical strips when contracted by U-46,619 (an endoperoxide analog), serotonin, and leukotriene D4. This relaxant effect was independent of the presence of endothelial cells and occurred in the presence of a guanylate cyclase inhibitor, methylene blue. The ANF had no direct effect on electrically driven isolated feline papillary muscles, signifying a lack of direct inotropic activity of ANF in cat cardiac muscle. These results suggest that ANF may produce coronary vasodilation that therefore could contribute to coronary regulation, without directly altering myocardial performance.
J Cardiovasc Pharmacol 1987 Sep
PMID:Coronary vascular actions of synthetic atrial natriuretic factor in isolated vascular preparations. 244 81

Vascular relaxation by the organic (nitroglycerin) and inorganic (sodium nitroprusside) nitrovasodilators and the endothelium-dependent vasodilators (acetylcholine and histamine) has been associated with cyclic GMP accumulation. Tolerance to vasodilation by nitroglycerin commonly occurs following prolonged exposure to nitroglycerin. This study investigates the effects of in vivo nitroglycerin therapy on vascular relaxation and cyclic GMP accumulation induced by the nitrovasodilators and the endothelium-dependent vasodilators. Rats were injected with nitroglycerin or the propylene glycol diluent control for 4-7 days. Thoracic aortas from the nitroglycerin-treated rats were 750-fold less sensitive to the relaxant effects of nitroglycerin. In contrast, these aortas were only threefold less sensitive to the relaxant effects of sodium nitroprusside, while the maximum relaxation to acetylcholine and histamine was depressed by 50 and 41%, respectively. Desensitization to relaxation was associated with reduced cyclic GMP elevations to all the vasodilators. Relaxation to 8-bromo cyclic GMP, dibutyryl cyclic AMP, or diltiazem was unaffected by nitroglycerin therapy. Tolerance was also associated with an increased sensitivity to the contractile effects of low concentrations of norepinephrine. This increased sensitivity to norepinephrine was associated with a decrease in cyclic GMP levels. The present results suggest that: (1) desensitization to nitroglycerin, sodium nitroprusside, acetylcholine, and histamine by nitroglycerin therapy may be at the level of cyclic GMP accumulation; (2) cyclic GMP is the common mediator of relaxation induced by the nitro- and endothelium-dependent vasodilators; (3) the mechanisms involved in the activation of guanylate cyclase and relaxation by sodium nitroprusside, acetylcholine, and histamine are probably different than those of nitroglycerin; and (4) cyclic GMP may be acting as a physiological negative feedback signal in agonist-induced contraction.
J Cardiovasc Pharmacol 1987 Oct
PMID:Effect of in vivo nitroglycerin therapy on endothelium-dependent and independent vascular relaxation and cyclic GMP accumulation in rat aorta. 244 89

Nicorandil (SG-75) is a new organic nitrate with pronounced vasodilator properties. We studied whether nicorandil, in analogy to other nitrovasodilatators, exerted its relaxing effects on vascular smooth muscle by stimulating guanylate cyclase, and whether this effect was susceptible to tolerance development. Dose-response curves for the relaxing and cyclic guanosine monophosphate (cGMP) increasing effects of nicorandil were obtained in isolated strips of bovine coronary arteries and compared with those of other nitrovasodilatators. It was found that nicorandil dose-dependently relaxed the strips precontracted with 26.7 mM K+ and that this effect was closely associated with increases in cGMP levels (measured by RIA under various conditions). The correlation between relaxation and rises in cGMP was steeper than with other nitrovasodilatators, suggesting that nicorandil, in addition to its cGMP-mediated effect, also relaxed vascular smooth muscle by a cGMP independent mechanism. In contrast to nitroglycerin (NG), nicorandil caused little development of tolerance or cross-tolerance toward ISDN or IS-5-MN when tested after preincubation of the strips toward the respective substance. Pretreatment with N-acetylcysteine during the preincubation period prevented tolerance towards nicorandil. The results indicate that the relaxant effects of nicorandil consist of a larger cGMP-mediated component and a smaller one which is independent of this nucleotide.
J Cardiovasc Pharmacol 1987
PMID:Cyclic GMP in nicorandil-induced vasodilatation and tolerance development. 244 21

Endothelial cells are known to contain both soluble and particulate guanylate cyclase, but the functional role of cyclic guanosine monophosphate (cGMP) in endothelial cells remains unknown. We have investigated the effects of 8-bromo-cGMP on endothelium-dependent relaxations to acetylcholine, substance P, ATP, and the calcium ionophore A23187, and on endothelium-independent relaxations to sodium nitroprusside and glyceryl trinitrate (GTN). The ability of each of these agents to relax phenylephrine-preconstricted rings of rabbit aorta was tested in the absence and presence of 8-bromo-cGMP. In the presence of 8-bromo-cGMP, a greater concentration of phenylephrine had to be used to produce a similar level of tone and then endothelium-dependent relaxations to acetylcholine and substance P were inhibited, whereas endothelium-dependent relaxations to ATP and A23187 were unaffected. Endothelium-independent relaxations to sodium nitroprusside and GTN were only inhibited at the highest concentrations of nitroprusside and GTN. These results suggest that: (a) increasing GMP levels in endothelial cells inhibit agonist-induced release of endothelium-derived relaxing factor (EDRF); (b) a negative feedback mechanism may exist whereby EDRF stimulates soluble guanylate cyclase in endothelial cells to inhibit its own release; and (c) ATP does not induce EDRF release via phosphoinositol hydrolysis.
J Cardiovasc Pharmacol 1988 Dec
PMID:Release of endothelium-derived relaxing factor is inhibited by 8-bromo-cyclic guanosine monophosphate. 246 85

Several classes of vasodilators have been demonstrated to elicit their affects by activating guanylate cyclase and elevating intracellular concentrations of cyclic GMP. The nitrovasodilators, such as nitroglycerin, generate nitric oxide, which directly activates the soluble isoenzyme of guanylate cyclase resulting in increased intracellular concentrations of cyclic GMP. A second class of agents, the endothelium-dependent vasodilators, such as acetylcholine, requires an intact endothelium to elicit vascular smooth muscle relaxation, in contrast to the nitrovasodilators. These agents stimulate the release of an endothelium-derived relaxing factor (EDRF), which also activates the soluble form of guanylate cyclase, triggering the production of cyclic GMP. The third class of agents includes atrial natriuretic peptides (ANPs). These low-molecular-weight, heat-stable peptides bind to specific receptors on vascular smooth muscle. These receptors appear unique in that they have a dual function possessing both ANP binding and particulate guanylate cyclase activities. Binding to and activation of particulate guanylate cyclase, in the absence of endothelium, results in the elevation of intracellular concentrations of cyclic GMP and relaxation.
J Cardiovasc Pharmacol 1988
PMID:Biochemical mechanisms underlying vascular smooth muscle relaxation: the guanylate cyclase-cyclic GMP system. 246 67

When secreted into the vascular lumen, endothelin-1 (ET-1) potentially may act as a circulating pressor substance. We investigated whether luminal ET-1 can directly stimulate smooth muscle in isolated vascular segments. Rabbit femoral arteries and veins whose luminal and adventitial surfaces could be perfused separately were used. Luminally administered ET-1 (1 nM) induced a vasoconstriction (21 +/- 5% of outer resting diameter) in segments without endothelium whereas in segments with intact endothelium, no significant vasomotor response was observed. In segments without endothelium, however, the vasoconstrictor responses to luminal and abluminal ET-1 were not significantly different. Similar results were obtained in segments of femoral veins. No release of endothelium-derived relaxing factor (EDRF) could be detected (guanylate cyclase assay) in segments of rabbit aorta and vena cava following stimulation with ET-1 whereas there was a slight increase (by 20 +/- 13%) of PGI2 release. It is concluded that the endothelium forms a tight barrier to circulating ET-1 (up to 1 nM) in intact vessels that has no functionally significant effect on endothelial autacoid release.
J Cardiovasc Pharmacol 1989
PMID:Differential vascular sensitivity to luminally and adventitially applied endothelin-1. 247 5


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