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)

The objective of this study was to ascertain whether "endothelium-derived relaxing factor" (EDRF) released from bovine intrapulmonary artery and vein is capable of directly activating soluble guanylate cyclase, thereby accounting for elevated vascular levels of cyclic GMP during EDRF release. Isolated arterial and venous rings, after equilibration and depolarization in bath chambers, were transferred to reaction tubes and incubated with soluble guanylate cyclase that had been purified to homogeneity from bovine lung. Addition of test agents to either bath chambers or enzyme reaction mixtures enabled the determination of their sites of action. Arterial and venous rings caused an endothelium-dependent 2- to 3-fold enzyme activation that was inhibited by methylene blue. Endothelium-dependent enzyme activation in artery but not vein was enhanced several-fold by acetylcholine in an atropine-sensitive manner. Bradykinin, which relaxes both artery and vein when endothelium is intact, activated guanylate cyclase upon addition of endothelium-intact rings to enzyme reaction mixtures. Vasoactive intestinal peptide, which causes endothelium-dependent relaxation of artery but not vein, also activated guanylate cyclase in the presence of endothelium-intact artery but not vein. Arachidonic acid activated the enzyme directly as well as through EDRF release from artery but not vein. Atrial peptides, prostacyclin, isoproterenol and nitroglycerin were inactive. Methylene blue was a powerful inhibitor of EDRF-elicited activation of guanylate cyclase but was without effect when rings were merely pretreated with methylene blue in bath chambers with no further addition to enzyme reaction mixtures. Thus, methylene blue did not interfere with the formation, release or chemical stability of EDRF, but rather inhibited its influence on guanylate cyclase. No agent was found to inhibit EDRF generation or release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. 287 27

Guanylate cyclase in high speed supernatant fractions obtained from rat thoracic aorta or human coronary arteries pretreated with nitroglycerin exhibited a marked desensitization to activation by nitroglycerin, nitroprusside, and nitric oxide. However, activation of soluble guanylate cyclase by arachidonic acid was unaffected by pretreatment of vessels with nitroglycerin. Furthermore, activation of soluble guanylate cyclase by protoporphyrin IX was increased 4-fold when vessels were pretreated with nitroglycerin. Soluble guanylate cyclase partially purified from nitroglycerin-pretreated rat thoracic aorta by immunoprecipitation with a specific monoclonal antibody exhibited persistent desensitization to nitrate-induced activation. These data suggest that nitroglycerin-induced desensitization of guanylate cyclase to activation by nitrovasodilators represents a stable alteration of the enzyme. In contrast, activation by protoporphyrin IX of guanylate cyclase immunoprecipitated from nitroglycerin-pretreated or control vessels was not significantly different. This suggests that the mechanism of protoporphyrin activation of guanylate cyclase is different than the mechanism with nitrovasodilators. Activation of particulate guanylate cyclase by Lubrol-PX, hemin, or atrial natriuretic factor was not significantly different with enzyme prepared from nitroglycerin-pretreated or control vessels from rat and human. Thus, nitroglycerin-induced desensitization of rat thoracic aorta or human coronary artery results in a relatively stable molecular alteration of soluble guanylate cyclase such that the enzyme is specifically less sensitive to activation by nitrovasodilators whereas the effects of other activators of the enzyme are either unchanged or increased.
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PMID:Desensitization to nitroglycerin in vascular smooth muscle from rat and human. 287 10

Organic nitrates produce their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E. C. 4.6.1.2). We could show that the stimulatory effect of organic nitrates on the activity of guanylate cyclase is strongly dependent on the number of nitrate residues per molecule. The EC50 values found for the tetra-, tri- di-, and mononitrates differed from each other by the factor 4. In contrast to investigations carried out with the perfused isolated Langendorff heart there was no correlation between the lipophilicity of these substances and the EC50 in our guanylate cyclase preparation, as penetration of cell membranes is not required. Other authors have found that organic nitrates are able to activate the enzyme guanylate cyclase only in the presence of cysteine. There is general agreement in the literature that organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis the nitric oxide radical is liberated as the essential stimulatory agent. We found a strict correlation between the liberation of nitric oxide from different organic nitrates (GTN, IMDN, IIDN, ISDN, IS-2-N, IS-5-N) and the degree of enzyme activation. The Ec50 values of the organic nitrates were calculated from the concentration response curves which were obtained with a guanylate cyclase preparation from rat liver in the presence of cysteine. The degradation of the organic nitrates was measured under the same conditions by means of HPLC. The amount of nitric oxide set free was calculated by using the velocity constants k of organic nitrate degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Thiol-dependent activation of guanylate cyclase by organic nitrates]. 287 91

Nitrovasodilators relax vascular smooth muscle by one common mechanism, the activation of soluble guanylate cyclase leading to increased formation of cGMP. The considerable differences in potency between various nitrovasodilators appear, at least in part, to be due to the different pathways of their transformation into activators of guanylate cyclase such as nitrous oxide or nitrosothiol. Major differences were also found in the ability of these compounds to induce tolerance in isolated bovine coronary artery strips. Although the mechanism of tolerance development is still not clarified, it appears likely that cysteine deficiency may be responsible for this phenomenon since this thiol appears to be required for the transformation of certain nitrovasodilators (e.g. nitroglycerin) into stimulators of guanylate cyclase and also in the final step of activation of this enzyme.
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PMID:Mode of action of nitrates with regard to vasodilatation and tolerance. 287 92

We examined the effect of nitroglycerin (GTN) tolerance on an important determinant of nitrate-antianginal action, large coronary artery dilation, in 11 chronically instrumented conscious dogs. In addition, endothelium-mediated coronary artery dilation was studied because this shares a common dilator pathway with the nitrates, i.e., activation of soluble guanylate cyclase. With long-term GTN (1.5 micrograms/kg/min iv for 5 days) the diameters of the left circumflex and anterior descending coronary arteries showed an initial increase of 8.2 +/- 0.3% and 10.8 +/- 0.9%, respectively, returning to control levels by the second to third day of treatment. On days 4 and 5, the dose-response relations for GTN-induced epicardial artery dilation were shifted (p less than .01) to 17- to 20-fold higher doses. However, there was no attenuation of epicardial artery dilation induced by SIN-1 (n = 7), another activator of guanylate cyclase, or of endothelium-mediated dilation assessed both as flow-dependent dilation (n = 7) and as direct intra-arterial acetylcholine-induced dilation (n = 4). In addition, there was no clear tolerance to the peripheral vascular actions of GTN responsible for reflex tachycardia and increased coronary flow. We conclude that a moderate degree of nitrate tolerance to epicardial artery dilation does not affect the responsiveness to other exogenous or endogenous activators of guanylate cyclase. However, this tolerance to epicardial artery dilation, together with the maintenance of peripheral vascular actions that can induce reflex tachycardia, result in a potentially unfavorable balance of GTN effects.
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PMID:Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. 288 35

Nitrovasodilators relax vascular smooth muscle by stimulating soluble guanylate cyclase (GC). The resulting rise in cGMP probably initiates Ca extrusion from the smooth muscle cell which causes relaxation. Since repeated administration of organic nitrates, particularly nitroglycerin, leads to tolerance, i.e. a decrease in the vasodilator effect, it was studied whether (a) tolerance was a peripheral phenomenon occurring in the vascular smooth muscle, and (b) was due to an impairment of GC activation. In isolated circular strips of bovine coronary arteries, 90 min pretreatment with nitroglycerin greatly lowered the relaxing as well as the cGMP increasing response to nitroglycerin, indicating tolerance induction. Tolerance, although to a lesser extent, was also obtained with other organic nitrates under similar conditions, including IS 5-MN. Little (nitroprusside Na) to negligible tolerance was obtained with sodium nitrate and SIN-1, the active metabolite of molsidomine. The latter group of drugs stimulated soluble GC in vitro in the absence of cysteine whereas organic nitrates required the presence of this thiol. Preincubation with nitroglycerin almost completely inactivated GC whereas other organic nitrates had little effect. The results indicate that tolerance is caused by an impairment of GC function in the smooth muscle cell, particularly when elicited by nitroglycerin, and that differences in the degree of tolerance development by various nitrovasodilators are possibly due to different mechanisms of activation and inactivation of GC as well as differences in cysteine requirement.
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PMID:Mechanism of vasodilation by nitrates: role of cyclic GMP. 288 20

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

The effect of different organic nitrates on the activity of soluble guanylate cyclase prepared from rat liver was investigated. We found a close correlation between the number of nitrate ester groups and the potency of guanylate cyclase activation. For erythrityl tetranitrate (ETN, EC50 = 14.5 microM), glyceryl trinitrate (GTN, EC50 = 60 microM), isoidide dinitrate (IIDN, EC50 = 0.24 mM) and isosorbide-5-nitrate (IS-5-N, EC50 = 1 mM), we were able to set up an equation by which the EC50 could be calculated from the number of nitrate groups per molecule. Compared to these results, the effect of sterical factors and lipophilicity on organic nitrate-induced activation of guanylate cyclase was small. However, there were still significant differences in the EC50 values for the cyclic mononitrates. Isosorbide-2-nitrate (IS-2-N, EC50 = 0.75 mM) was found to be more potent than the stereoisomeric isosorbide-5-nitrate. Similarly, the cyclic dinitrates isomannide dinitrate (IMDN, EC50 = 0.20 mM), isoidide dinitrate and isosorbide dinitrate (ISDN, EC50 = 0.28 mM) exhibited small but significant differences in their guanylate cyclase stimulatory potency. Two lipophilic ester derivatives of isosorbide-5-nitrate showed a 2-fold potency difference for vasodilation but were equipotent for activation of guanylate cyclase (EC50 = 0.85 mM). Also, the increase in lipophilicity due to esterification of the free hydroxylic group had no major influence on guanylate cyclase activation by isosorbide-5-nitrate. These results demonstrate that in a cell-free system, the potency of organic nitrates for guanylate cyclase activation is mainly determined by the number of nitrate groups. Since organic nitrate-induced activation of guanylate cyclase may involve the formation of nitric oxide free radicals, it is conceivable that the differences in potency reflect a varying degree of nitric oxide release from each compound tested.
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PMID:Structure-activity relationship of organic nitrates for activation of guanylate cyclase. 289 14

We continuously studied the quantitative formation of nitric oxide (NO), nitrite and nitrate ions from several organic nitrate esters in the presence of various thiol-containing compounds by spectroscopy and HPLC. The results indicate that there are different pathways of decomposition depending on the chemical nature of the mercaptan tested. The amino acid cysteine is known to function as an essential cofactor for guanylate cyclase activation by organic nitrates in vitro. For comparison we investigated several structural analogues with respect to their nitric oxide or nitrite ion releasing potency. Both were found to represent the main products resulting from nitrate ester breakdown besides the respective alcohols. We found that only those compounds were able to activate the enzyme in the presence of nitroglycerin (GTN) which induce the release of NO as well. On the other hand, nearly all other thiols tested caused an in vitro decomposition of organic nitrates by producing excess nitrite and the corresponding disulfide without the formation of NO. Thus, the decomposition of organic nitrates to nitrite ions does not contribute at all to activation of guanylate cyclase. Our results confirm that the liberation of nitric oxide is the common principle of action for all nitrovasodilators. In addition, our results suggest that the thiol consuming transformation of organic nitrates into nitrite ions (ratio NO/nitrite 1:10) may lead to a depletion of cysteine stores, resulting in a decreased formation of NO and, consequently, in a decrease of guanylate cyclase activation, clinically arising as nitrate tolerance.
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PMID:Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation. 290 Jul 66

An association between guanosine 3',5'-monophosphate (cyclic GMP) and the nonadrenergic noncholinergic inhibitory system (NANCIS) has been demonstrated in the isolated bovine tissue (Bowman and Drummond, 1984). In order to investigate this association in the guinea pig trachea, we used cyclic GMP derivatives, guanylate cyclase activators (N-methylhydroxylamine (NMH) and nitroglycerin (NG)] and inhibitors [oxyhemoglobin (HbO2) and methylene blue (MB)]. Under general anesthesia paralysis, the animals were ventilated and hourly injected with atropine (0.2 mg/kg) and propranolol (1 mg/kg). Cervical segment of the trachea was converted to a closed tracheal pouch and then filled with Kreb's solution augmented with atropine (1 microM) and propranolol (3.5 microM). A decrease in the pouch pressure (Pp) reflected NANCIS nerve transmural stimulation (TS)--or drug-induced relaxation. Pharmacological agents were applied intravenously. At 2-11 min after injection, NMH and NG decreased baseline Pp and reduced TS-induced relaxation. NMH, which is more potent than NG in activating particulate guanylate cyclase activity, potentiated the TS-induced relaxation at high frequencies, but NG did not. HBO2 inhibited the TS-induced relaxation at high but not at low frequencies. In contrast, MB inhibited the relaxation at low but not high frequencies. The results suggest that activation of particulate or membrane bound guanylate cyclase potentiates NANCIS-induced decrease in Pp. Therefore, there is a possible association between cyclic GMP and the NANCIS in the guinea pig trachea.
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PMID:Cyclic GMP affecting the tracheal nonadrenergic noncholinergic inhibitory system. 290 72


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