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)

This paper review the actual knowledges about the physiological role of nitric oxide, sintetized from amino acid L-arginine. The nitric oxide sintetized in the vascular endothelium has a fundamental role in vascular tone, blood flow and arterial pressure control, acting stimulating guanylate cyclase on vascular smooth muscle. Nitric oxide could be considered the endogenous nitrovasodilator. Its action on the cardiovascular system are imitated by nitroglycerine, sodium nitroprusside and related compounds. Probably the disturbance in the synthesis or release of nitric oxide may be involved in the pathophysiology of hypertension, vasospasm and atherosclerosis. Recently has been shown that nitric oxide synthesis from L-arginine also occurs in other different cells like macrophages, central nervous system, liver, neutrophils, adrenal glands, playing different biological effects. Changes in nitric oxide synthesis or action in those systems, could be related to different pathological disorders as inflammation, atherosclerosis and cancer. The found of a substance as simple as nitric oxide, let suppose that we are in the presence of a biological mediator with a very early evolutionary origin, probably widespread in all the animal kingdom, and which represents the universal transduction system for activation of the soluble guanylate cyclase enzyme.
Rev Esp Cardiol
PMID:[Nitric oxide: from endogenous vasodilator to biologic mediator]. 209 54

Since the diminished vasodilatation characterizing tolerance to organic nitrates is associated with lower rises in 3', 5'-cyclic guanosine monophosphate (cGMP) levels, the possibility that nitrovasodilators desensitized guanylate cyclase (GC) when pre-incubated with coronary supernatants was studied. In the absence of cysteine, pre-incubation with nitroglycerin (NG) decreased GC-activity during subsequent incubation to 24 +/- 7% of control values, whereas six other nitrovasodilators had much smaller effects. When cysteine was present during pre-incubation, NG-stimulation of GC remained significantly higher (59 +/- 3%; P less than 0.05), whereas the effects of other nitrovasodilators were not significantly changed. We also found that GC-activity, when reduced by pre-incubation with NG could only be restored by readdition of native coronary supernatant, suggesting that the enzyme became inactivated. NG pre-incubation of GC (in contrast to coronary strips) almost completely abolished the direct and thiol-independent stimulatory effect of 3-morpholinosydnonimine (SIN-1) down to 4.5 +/- 0.2%, whereas pre-incubation with other nitrovasodilators reduced the stimulatory response to SIN-1 to only 59 to 98%. Increasing concentrations of NG during pre-incubation dose-dependently (IC50 = 0.13 mM) reduced the activating effect of SIN-1 during incubation. There was also a time dependence in NG-induced inactivation of GC which followed first order kinetics with a calculated half life of 2.5 min in the absence of a thiol. The latter was increased to 4.0 or 19.2 min, respectively, when glutathione or cysteine-methylester were present during pre-incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1989 Jan
PMID:Tolerance to nitroglycerin is caused by reduced guanylate cyclase activation. 256 81

According to our present understanding organic nitrates like glycerine trinitrate mediate their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E.C. 4.6.1.2.) [1, 10]. The exact molecular mechanism underlying the process of enzyme activation is still a matter of controversial discussion. But there is general agreement in literature about the fact that organic nitrate compounds are able to activate the enzyme guanylate cyclase only in the presence or by the interaction of the amino acid cysteine [3, 5]. The stimulatory activity of nitric oxide-containing compounds may be due, at least in part, to the formation of active, unstable intermediate S-nitrosothiols, i.e. S-nitrosocysteine in case of the organic nitrates [7]. According to Craven and DeRubertis [2], the active intermediates of guanylate cyclase stimulation are represented by nitric oxide-heme complexes. There is, however, substantial evidence that the 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, nitric oxide radicals are reductively split off the molecule from which (via the intermediate formation of salpetric acid) the nitric oxide is liberated as the essential stimulatory agent. In this study we examined the transformation of glycerine trinitrate and other organic nitrates under the influence of different thiols and a purified soluble rat liver guanylate cyclase preparation. At the same time the stimulation of guanylate cyclase in the presence of the thiols mentioned was quantitatively estimated. Only in case of cysteine did we find a strict correlation between the liberation of nitric oxide from different organic nitrates and the degree of enzyme activation. Several other thiols were also able to liberate nitric oxide, but surprisingly enough, there was no equivalent stimulation of guanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1985 Sep
PMID:Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. 286 57

Nitrovasodilators relax vascular smooth muscle by stimulating guanylate cyclase. Ignarro et al. (1981) proposed a mechanistic scheme according to which organic nitrates release nitrite in the presence of thiols. The corresponding nitrous acid would decay leading to nitric oxide, which then would react with another thiol to nitrosothiol. Dose-response relations with regard to guanylate cyclase stimulation of organic nitrates and sodium nitrite were compared in the presence of cysteine and its closely related methylester. Nitrite formation from ED95 concentrations of organic nitrates was also measured and compared with that present under an equi-effective concentration of sodium nitrite. In addition, the proposed formation of nitrosothiol from nitric oxide was re-examined. In the presence of cysteine, organic nitrates as well as sodium nitrite stimulated guanylate cyclase, but nitrite formation under ED95 concentrations of organic nitrates was 1000-fold smaller than that present under an equi-effective concentration of sodium nitrite. In the presence of cysteinemethylester, liberation of nitrite from organic nitrates was similar but no stimulation of guanylate cyclase was obtained. Sodium nitrite, however, showed a stimulating activity similar to that in the presence of cysteine. These results clearly demonstrate that guanylate cyclase stimulation by organic nitrates is not mediated by nitrite and subsequent formation of nitrosothiol. Since nitrous acid did not decay to nitric oxide in the pH range studied, the formation of nitrosothiol is apparently due to a direct reaction of nitrous acid with thiol.
J Mol Cell Cardiol 1988 May
PMID:Guanylate cyclase activation by organic nitrates is not mediated via nitrite. 290 90

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilatations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such varying stimuli as increases in blood flow and hypoxia, as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells, resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented, which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.
Basic Res Cardiol
PMID:The role of endothelium in the control of vascular tone. 300 Mar 43

Dietary intake of unsaturated fatty acid of eicosapentaenoic acid (EPA) is thought to reduce the size and incidence of myocardial infarction. These beneficial effects are postulated to be due to chronic antithrombotic properties of EPA itself. We studied the possible direct effects of EPA on vascular smooth muscle as well as the ability of EPA to modify the vasoactivity of constrictor mediators in rabbit and cat aortic rings and isolated cat coronary arteries. EPA concentration-dependently (30 to 300 microM) relaxed rabbit and cat aortic rings having an intact endothelium, while EPA did not show any significant vasodilator effects on rings without an endothelium. This EPA-induced vasorelaxation was not altered by the cyclooxygenase inhibitor ibuprofen, but was totally abolished by the guanylate cyclase inhibitor methylene blue, indicating an endothelium-dependent smooth muscle relaxation mechanism. In isolated perfused cat coronary arteries, EPA (3 to 300 microM) exerted a dilator effect which was endothelium-independent and not affected by ibuprofen. The response was attenuated by propyl gallate, a lipoxygenase inhibitor. EPA also inhibited leukotriene (LT) C4, (50 nM) and LTD4 (50 nM)-induced vasoconstriction of isolated cat coronary arteries ranging from a blockade of 10% to 15% (P less than 0.05) at 3 microM of EPA to a blockade of 89% to 93% (P less than 0.01) at 300 microM. In contrast, the thromboxane analog, CTA2, induced coronary constriction was not significantly altered by EPA. Thus, EPA produces endothelium-dependent relaxation in rabbit and cat aorta and endothelium-independent vasodilation in cat coronary arteries (i.e., intact vessels or helical strips). Moreover, EPA exerts acute anti-leukotriene actions in coronary arteries. In the case of long-term dietary intake of EPA, these actions may contribute to the protective action of EPA in myocardial ischemia.
Basic Res Cardiol
PMID:Vasoactive effects of eicosapentaenoic acid on isolated vascular smooth muscle. 303 70

This article reviews what is known of endothelium-derived relaxing factor and its possible physiologic and pathophysiologic roles. This relaxing factor is now thought to be nitric oxide or a ready source of it. It acts as an endogenous nitrovasodilator, stimulating soluble guanylate cyclase to increase cyclic guanosine monophosphate (GMP) levels in vascular smooth muscle and platelets, with consequent relaxant and anti-aggregatory effects (predominantly when stimulated through receptor-operated channels). Its actions are thus synergistic with those of cyclic adenosine monophosphate (AMP)-mediated stimulation (for example, adenosine, prostacyclin). Endothelium-derived relaxing factor is unstable and is thought to act only very locally in vivo. Its release is continuous in the basal state and is stimulated by a number of neuropeptides and by agents released during platelet activation and thrombosis--with large differences in activity among different vessels. Endothelium-derived relaxing factor activity is also flow related, thereby coordinating vasomotor behavior in an intact vascular tree in response to changes in flow. Endothelium-derived relaxing factor activity is reduced in several pathologic states, including atherosclerosis.
J Am Coll Cardiol 1988 Sep
PMID:Endothelium-derived relaxing factor. 304 36

Endothelial intact bovine coronary artery (BCA) rings precontracted with U46619 relax to acetylcholine (Ach) and arachidonic acid (AA). Relaxation to Ach is blocked by atropine. In an attempt to elucidate the mechanisms of these responses, we found that preincubation with methylene blue, an inhibitor of soluble guanylate cyclase activity, inhibited both Ach and AA induced relaxation. Preincubation with indomethacin had no effect on Ach induced relaxation, but partially inhibited the relaxation of endothelial intact BCA rings to AA.
Can J Cardiol
PMID:Arachidonic acid and acetylcholine induced relaxation of bovine coronary artery: effect of indomethacin and methylene blue. 308 7

Endotoxin induces an enzyme that synthesizes nitric oxide (NO) from L-arginine (NO synthase) in vascular smooth muscle cells, resulting in nonendothelial NO release. In this study, we measured the NO release and its intracellular action on the Ca(2+)-activated K+ channel (KCa channel) in cultured smooth muscle cells of porcine coronary artery using a newly-developed porphyrinic-based microsensor and the patch-clamp technique. In smooth muscle cells pretreated with endotoxin, extracellular application of 10(-4) M L-arginine increased NO release, which induced rapid and prolonged activation of the KCa channel. This activation was only partially blocked by application of 10(-5) M 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-oxyl 3-oxide, which neutralizes NO. NO formation and activation of the KCa channel were suppressed by pretreatment with 10(-3) M NG-methyl-L-arginine or 10(-3) M N omega-nitro-L-arginine methyl ester, each of which is a specific antagonist of the L-arginine-NO pathway. One micromolar methylene blue, a blocker of guanylate cyclase, inhibited L-arginine-induced activation of the KCa channel. The effect of nitroprusside in opening the KCa channel was transient, although it induced production of larger amounts of NO in the bath. These results suggest that the endotoxin-induced and L-arginine pathway generates NO and directly modulates the KCa channel intracellularly in an autocrine manner.
J Mol Cell Cardiol 1994 Nov
PMID:Endotoxin-induced nonendothelial nitric oxide activates the Ca(2+)-activated K+ channel in cultured vascular smooth muscle cells. 753 31

Nitric oxide (NO) synthesized from L-arginine is a ubiquitous intercellular chemical messenger involved in signal transduction in diverse mammalian cells, including vascular endothelium and neuronal tissues. The recent isolation of molecular clones for NO synthases has permitted the characterization of several distinct enzyme isoforms and has allowed us to identify a family of related genes. NO synthesized in vascular endothelial cells appears to play an important role in the control of vascular tone and platelet aggregation, apparently through the activation of guanylate cyclase activity in target tissues mediated by NO. The role of the NO signaling pathway in the direct modulation of cardiac function is less well characterized. We have found that inhibitors of NO synthase can modulate the response of neonatal or adult rat ventricular myocytes exposed to muscarinic or adrenergic agonists. The effects of carbachol on the inhibition of the spontaneous beating rate of cultured neonatal rat cardiac myocytes are blocked by L-N-monomethylarginine, an L-arginine analog that inhibits NO synthase, and by methylene blue, an inhibitor of NO; these agents have no effect on the basal beating rate of these cells. The negative chronotropic effect of carbachol is also mimicked by analogs of cyclic guanosine monophosphate (cGMP), a second messenger implicated in mediating the action of NO in other cell types. Production of NO can be detected directly in carbachol-stimulated neonatal myocytes using a reporter cell bioassay.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Cardiol 1993 Sep 09
PMID:Nitric oxide synthases and cardiovascular signaling. 769 May 16


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