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)

Three metabolic channels producing active forms of oxygen (OH.), carbon (CO) and nitrogen (NO) were studied for their contribution to the mechanism of early activation of guanylate cyclase by hydroxysterols: ecdysterone (20-hydroxyecdysone) and calcitriol (1 alpha, 25-dihydroxyvitamin D3) which are steroid agonists of phospholipid signal system in target tissues. It is established that in the cells of target tissues (brain, heart, liver) affected by the mentioned hydroxysterols only NO- and CO- metabolic lipid channels are activated while the nucleotide metabolic channel of generation of OH--radical is blocked. It is supposed that the nucleotide OH. metabolic channel activation due to oxidation of oxypurines and dihydroorotic acid most probably takes no part in formation of the negative feedback and termination of the signal of phospholipid signalling system by means of activation of soluble guanylate cyclase in contrast to the lipid channel of OH. formation due to oxidation of arachidonic acid.
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PMID:[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Modulation of systems which generate low molecular weight activators of guanylate cyclase]. 859 87

Previous studies from our laboratory have shown that an extrinsic nitric oxide (NO) donor (i.e., nitroprusside) caused vasodilatation and negative inotropy by activating guanylate cyclase and increasing myocardial cyclic GMP. We tested the hypothesis that endogenous myocardial NO production would limit myocardial oxygen consumption and function in vivo. We used the NO synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) in nine open-chest anesthetized mongrel dogs. Either L-NAME (6 mg/kg) or L-NMMA (3 mg/kg) were infused into the left anterior descending coronary artery (LAD). The circumflex (CFX) coronary artery region served as a control. Regional segment work was calculated as the integrated product of local force (miniature transducer) and segment shortening (ultrasonic crystals). Local myocardial O2 consumption was determined using an ultrasonic LAD flow probe and local arterial-venous O2 content difference (oximetry). Cyclic GMP levels were obtained via a radioimmunoassay. Both L-NAME and L-NMMA caused a local decrease in coronary blood flow (LAD flow: 80 +/- 8 to 69 +/- 7 ml/min/100 g [means +/- SEM]) and increased O2 extraction (9.1 +/- 0.6 to 10.2 +/- 0.7 ml O2/100 ml). However, this led to no change in local O2 consumption. LAD segment force was not altered (12.1 +/- 0.7 to 11.6 +/- 0.9 g), nor was the percent shortening changed (10.8 +/- 1.8% to 10.0 +/- 1.4%) by L-NAME or L-NMMA, leading to no net change in segment work. Myocardial cyclic GMP levels were not different in a comparison between the LAD (1.7 +/- 0.4 pmoles/g) and control (1.7 +/- 0.2) regions with either L-NAME or L-NMMA. We conclude that blockade of endogenous NO production with L-NAME and L-NMMA is sufficient to cause vasoconstriction in the heart of anesthetized dogs. However, this dose did not lead to alteration in local myocardial function, O2 consumption, or cyclic GMP levels.
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PMID:Endogenous basal nitric oxide production does not control myocardial oxygen consumption or function. 861 38

Nitroglycerin and the long-acting nitrates have been used in cardiovascular medicine for >100 years. Nitrates are widely utilized for the various anginal syndromes and are also used in congestive heart failure and patients with left ventricular dysfunction. The potential mechanisms for relief of myocardial ischemia with nitrates are multiple. The nitrovasodilators are a related group of drugs that result in the formation of nitric oxide (NO) within vascular smooth muscle cells. NO stimulates the enzyme guanylate cyclase, which results in increases in cyclic guanosine monophosphate and vasodilation. In the presence of atherosclerosis, endothelial dysfunction is ubiquitous and associated with decreased NO availability, probably due to increased destruction of NO by free radical anions. Nitrovasodilators, including the nitrates, supply exogenous NO to the vascular wall and improve the vasodilator state. When nitrates are administered, endothelial-dependent stimuli cause relaxation rather than constriction in the setting of endothelial dysfunction. Nitrates also have antiplatelet effects, and recent evidence confirms that these drugs decrease platelet aggregation and thrombosis formation. This may play an important role in the therapy of acute unstable myocardial ischemia, including unstable angina and myocardial infarction. Nitrate hemodynamic effects have been long known. They are primarily modulated through a decrease in myocardial work that results from smaller cardiac chambers operating with lower systolic and diastolic pressures. These changes are caused by a redistribution of the circulating blood volume away from the heart to the venous capacitance system, with a fall in venous return to the heart. The afterload or arterial effects of nitrates are also useful in decreasing myocardial oxygen consumption. Considerable evidence confirms a variety of mechanisms whereby nitrates increase coronary blood flow, including epicardial coronary artery dilation, stenosis enlargement, enhanced collateral size and flow, improvement of endothelial dysfunction, and prevention or reversal of coronary artery vasoconstriction. These effects help increase nutrient coronary blood flow to zones of myocardial ischemia. Recent data with the nitroglycerin patch confirm that myocardial ischemia is decreased after nitrate administration. Nitroprusside, another nitrovasodilator, is a commonly used intravenous agent for lowering arterial pressure and left ventricular filling pressure. This drug is highly effective for the treatment of acute or severe hypertension and congestive heart failure. However, there are data suggesting that nitroprusside may be deleterious in the presence of acute myocardial ischemia, perhaps by shunting blood away from zones of jeopardized myocardial blood flow. Therefore, nitroprusside cannot be recommended to treat myocardial ischemia; intravenous nitroglycerin should be used in this context.
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PMID:Beneficial actions of nitrates in cardiovascular disease. 863 24

Levels of calcitonin gene-related peptide (CGRP), a vasodilator peptide present in nerves and airway endocrine cells of the rat respiratory tract, are increased in hypoxic lung and decreased in plasma, suggesting impaired CGRP release. We wanted to determine whether there was an adaptive functional response to reduced CGRP levels in hypoxia. Density of binding sites for CGRP were compared with its vascular actions following hypoxia, and with binding following administration of the sensory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of lung sections incubated with 125I-labelled CGRP and other vasoactive peptides was used to quantify their binding sites, in male Wistar rats exposed to periods of hypoxia (inspiratory oxygen fraction (FI,O2) = 0.1) ranging 0-10 days (n = 5 each), in controls, and in rats treated neonatally with capsaicin. Relaxation to CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding was seen in the vascular endothelium and was significantly elevated after 5 days of hypoxia (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol.mm-2). CGRP-induced (5 x 10(-7)M) relaxation of pulmonary artery was reduced, compared with controls, following 8 and 21 days of hypoxia (mean +/- SEM) percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3, respectively) and was abolished by removal of endothelium. Capsaicin treatment also significantly elevated vascular CGRP binding. Atrial natriuretic peptide (ANP) binding levels were decreased in smooth muscle of all blood vessels after 7 days of hypoxia, but endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP) binding was unchanged. We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.
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PMID:Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites. 866 97

In the present study, we demonstrated that NO synthase (cNOS) and xanthine oxidase (XO) of human keratinocytes can be activated to release NO, superoxide (O2-) and peroxynitrite (ONOO-) following exposure to ultraviolet B (UVB) radiation. We defined that this photo induced response may be involved in the pathogenesis of sunburn erythema and inflammation. Treatment of human keratinocytes with UVB (290-320 nm) radiation (up to 200 mJ/cm2) resulted in a dose-dependent increase in NO and ONOO- release that was inhibited by N-monomethyl-L-arginine (L-NMMA). NO and ONOO- release from keratinocytes was accompanied by an increase in intracellular cGMP levels. Treatment of human keratinocyte cytosol with various doses of UVB (up to 100 mJ/cm2) resulted in an increase in XO activity that was inhibited by oxypurinol. UVB radiation (up to 100 mJ/cm2) of keratinocytes resulted in a 15-fold increase in S-nitrosothiol formation, which directly increased purified soluble guanylate cyclase (sGC) activity by a mechanism characteristic of release of NO from a carrier molecule. In reconstitution experiments, when UVB-irradiated (20 mJ/cm2) purified cNOS isolated from keratinocyte cytosol was combined with UVB-irradiated (20 mJ/cm2) purified XO, a 4-fold increase in ONOO- production, as compared to nonirradiated enzymes, was observed. ONOO- synthesized by NO and O2- following UVB radiation of cNOS and XO was inhibited by oxypurinol (100 microM). UVB radiation of keratinocyte cytosol resulted in an increase in oxygen free radical production, consistent with the increased production of ONOO- by UVB-irradiated keratinocyte cytosol. In in vivo experiments, when experimental animals were subjected to UVB radiation, a protection factor (PF) of 6.5 +/- 1.8 was calculated when an emulsified cream formulation containing nitro-L-arginine (L-NA) (2%) and L-NMMA (2%) was applied to their skin. The present study indicates that UVB radiation acts as a potent stimulator of cNOS and XO activities in human keratinocytes. NO and ONOO- may exert cytotoxic effects in keratinocytes themselves, as well as in their neighboring endothelial and smooth muscle cells. This may be a major part of the integrated response leading to erythema production and the inflammation process.
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PMID:Alterations of nitric oxide synthase and xanthine oxidase activities of human keratinocytes by ultraviolet B radiation. Potential role for peroxynitrite in skin inflammation. 868 88

Methylene blue (MB) is a thiazine dye used in the treatment of methemoglobinemia. It may represent a new class of anti-oxidant drugs which competitively inhibit the reduction of molecular oxygen to superoxide by acting as an alternative electron acceptor for tissue oxidases. Because of its strong free radicals scavenging effect MB was experimentally used in the treatment of reperfusion syndrome. MB is soluble guanylate cyclase inhibitor. It was found to inhibit the stimulation of soluble guanylate cyclase by nitric oxide and vasodilatators. Another effect of MB is inhibition of prostacyclin synthesis by endothelial cells and isolated arteries independently of its effects on cGMP accumulation. We investigated the MB in series of experimental endocrine situations in which its free radicals scavenging effect could play a role. We observed that MB partly inhibited the increase in adenohypophyseal weight, cAMP and blood prolactin levels in male rats after the administration of estrogens. MB also blocked the increase of another free radicals scavenger-the metalloenzyme ceruloplasmin in the blood of estrogenized rats and prevented the increase of bone mineral after estradiol treatment. MB produced a decrease in adenohypophyseal ascorbic acid content. The blood thyroxine levels increased and the anterior pituitary TSH concentration decreased after MB treatment.
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PMID:Methylene blue--an endocrine modulator. 871 76

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.
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PMID:Vascular responses to sodium nitroprusside in the human fetal-placental circulation. 874 64

Nitric oxide (NO) was discovered to be a potent vasodilator, inhibitor of platelet aggregation, and active species of nitroglycerin before the discovery of endothelium-derived relaxing factor (EDRF) in 1980. Subsequent studies revealed that EDRF is NO, and is synthesized by mammalian cells from L-arginine through a complex oxidation reaction catalyzed by the flavo-hemoprotein NO synthase (NOS). NOS catalyzes the NADPH- and oxygen-dependent oxygenation of L-arginine to NO plus L-citrulline in a reaction that requires at least six cofactors including NADPH, FAD, FMN, tetrahydrobiopterin, heme, and calmodulin. NO elicits its known physiological actions by activating cytosolic guanylate cyclase, which converts GTP to cyclic GMP. Endothelial NOS and neuronal NOS are constitutively present and activated by increases in intracellular calcium triggered by endogenous chemicals. NO then diffuses into nearby target cells to elevate cyclic GMP levels and thereby trigger cell function. NOS activity can also be regulated by a negative feedback mechanism involving NO itself. Much greater quantities of NO are produced pathophysiologically by a distinct form of NOS that can be induced in vascular endothelium, smooth muscle and macrophages by endotoxin and cytokines. This high-output production of NO is not regulated by calcium and is cytotoxic by mechanisms involving interaction with iron-containing proteins.
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PMID:Physiology and pathophysiology of nitric oxide. 874 1

Nitroglycerin and its derivatives are among the most potent drugs to treat angina pectoris. The compounds relax all smooth muscle cells by stimulating the soluble guanylate cyclase. The clinical application takes advantage of the different sensitivities of the vascular smooth muscles (veins > arteries > arterioles) to nitrates. Selective vasodilation of capacity veins and coronary arteries leads to reduced myocardial oxygen consumption and improved myocardial perfusion. Hypotension due to effective dilation of resistance arteries limits the antianginal effects because of reduced coronary perfusion. Treatment of symptoms in stable angina is well established and unquestioned as long as the dose regimen avoids tolerance; however, there is no evidence of reducing mortality with nitrates in these patients. In acute coronary syndromes such as unstable angina pectoris and acute myocardial infarction nitrates, but not nitroprusside, can be applied safely to relief symptoms and to treat vasospasm, if the dose is titrated to avoid hypotension. Recent large multicenter trials (GISSI-3, ISIS-4) have not confirmed the postulate derived from previous studies, that nitrates reduce the mortality from acute myocardial infarction within the first month.
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PMID:[Use of nitrates in coronary heart disease including acute myocardial infarct]. 876 22

1. We have previously found that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction which sustains contractile tone. Our proposal, however, has been questioned on the evidence of findings in other blood vessels implicating the guanylyl cyclase-based relaxing mechanism as the target for CO. To investigate this issue further, we have carried out experiments in the isolated ductus from near-term foetal lambs and have examined the effect of CO concomitantly on muscle tone and cyclic GMP content, both in the absence and presence of guanylyl inhibitors, or during exposure to monochromatic light at 450 nm. 2. CO (65 microM) reversed completely, or nearly completely, the tone developed by the vessel in the presence of oxygen (30%) and indomethacin (2.8 microM). Cyclic GMP content tended to increase with the relaxation, but the change did not reach significance. Sodium nitroprusside (SNP), a NO donor, mimicked CO in relaxing the ductus. Contrary to CO, however, SNP caused a marked accumulation of cyclic GMP with levels being positively correlated with the relaxation. 3. Methylene blue (10 microM) reduced marginally the CO relaxation, whilst LY-83583 (10 microM) had an obvious, albeit variable, inhibitory effect. Basal cyclic GMP content was lower in tissues treated with either compound and rose upon exposure to CO. However, the levels attained were still within the range of values for tissues prior to any treatment. Furthermore, the elevation in cyclic GMP was not related to the magnitude of the CO relaxation. 4. Illumination of the ductus with monochromatic light at 450 nm reversed the CO relaxation and any concomitant increase in cyclic GMP. In the absence of CO, light by itself had no effect. 5. Ductal preparation with only muscle behaved as the intact preparations in reacting to CO, both in the absence and presence of guanylyl cyclase inhibitors, or during illumination. 6. We conclude that the primary action of CO in the ductus arteriosus is not exerted on the guanylyl cyclase heme and that cyclic GMP may only have an accessory role in the relaxation to this agent. This finding reasserts the importance of a cytochrom P450-based mono-oxygenase reaction for generation of tone and as a target for CO in the ductus.
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PMID:Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase. 884 33


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