Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.
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PMID:[Endothelium-derived relaxing factor (EDRF)]. 216 93

In the last years, an inhibition of aggregation by organic nitrates or by similar drugs has been demonstrated by some authors, but has also been ruled out by other authors. The present work was thus performed to study a possible inhibition of platelet aggregation by the respective drugs in comparison with the molecular mechanism of action of these drugs, that is activation of soluble guanylate cyclase. We found that in vitro, organic nitrates activate soluble guanylate cyclase and inhibit platelet aggregation only in millimolar concentrations, while sodium nitroprusside and SIN-1, the active metabolite of molsidomine, influence these parameters in micromolar concentrations. This difference between the actions of the O-NO2-containing nitrates and the NO-containing compounds nitroprusside and SIN-1 is, however, not apparent ex vivo. Ex vivo, not only molsidomine, that is converted in the liver to SIN-1, but also isosorbide-5-mononitrate inhibited platelet aggregation. Thus, it appears that organic nitrates can in vivo release nitric oxide in a tissue other than platelets in amounts that are high enough to inhibit platelet aggregation. These studies suggest, that an antiaggregatory effect may participate in the clinical actions not only of drugs that directly resemble EDRF, such as SIN-1, but also by the organic nitrates. However, since nitrates cannot be activated directly by the platelets, it appears that also the antiaggregatory effects of nitrates, but not of molsidomine, underlie the mechanisms of tolerance development.
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PMID:[Inhibition of platelet aggregation by endothelium-derived relaxing factor-like agents]. 218 3

Molsidomine is an established drug for the treatment of coronary heart disease. It acts via the metabolite SIN-1 through liberation of NO. Experiments have proven the identity of NO and EDRF. Investigation of the molecular mechanism of action of molsidomine/SIN-1 indicate that molecular oxygen initiates NO formation through a one-electron abstraction from the intermediate. Ex vivo experiments in rats and in vitro studies in human coronary arteries showed that marked tolerance is induced with glyceryl trinitrate, whereas prolonged exposure to SIN-1 does not cause tolerance. Responsiveness to SIN-1 is not modified in nitrate-tolerant human arteries. Stimulation of soluble guanylate cyclase underlies the antiaggregatory actions of EDRF. Likewise SIN-1 inhibits platelet aggregation in various models. In dogs and pigs with critical stenosis molsidomine reduced significantly the frequency and the severity of cyclical reductions of coronary blood flow.
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PMID:Molsidomine. 224 48

Changes in viscous drag acting upon the endothelial lining and a number of circulating agonists (ATP, ADP, serotonin, thrombin) stimulate the release of EDRF from intact endothelial cells. EDRF is probably identical with nitric oxide (NO), the vasoactive compound which is also formed in the metabolism of nitrovasodilators in the vasculature (some of them directly release NO without the essential foregoing bioconversion step). Albuminally released NO stimulates soluble guanylate cyclase (sGC) in the vasculature initiating vasodilation; luminally released NO stimulates, sGC in platelets and increases cyclic GMP inhibiting platelet activation and aggregation. Endothelial impairment brings about loss of dilator and antiaggregant capacity.
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PMID:[Inhibition of thrombocyte aggregation and adhesion by endothelium-derived relaxant factor (EDRF) and their pathophysiologic significance]. 251 72

We studied the effects and the mechanism of action of the cyclic GMP-lowering substance 6-anilino-5,8-quinolinedione (LY 83583) on cyclic GMP-mediated inhibition of platelet function. The activation of washed human platelets by thrombin was counteracted by 8-bromo-cyclic GMP and the direct activators of soluble guanylate cyclase, sodium nitroprusside and endothelium-derived relaxant factor (EDRF = nitric oxide). LY 83583 significantly antagonized the inhibitory effect of sodium nitroprusside and EDRF, but not that of 8-bromo-cyclic GMP, on thrombin-induced aggregation, ATP-release, adhesion to native endothelial cells and increase in concentration of free intracellular calcium ions. In accordance, increases in intracellular cyclic GMP by sodium nitroprusside and EDRF were attenuated by LY 83583. The inhibition of cyclic GMP-mediated effects on platelets by LY 83583 could be related to inhibition of platelet soluble guanylate cyclase, as the activation of the purified enzyme from platelets by sodium nitroprusside was directly inhibited by LY 83583. This effect of LY 83583 was attenuated in the presence of superoxide dismutase. Our findings support the hypothesis that sodium nitroprusside and EDRF inhibit platelet activation by stimulation of soluble guanylate cyclase via nitric oxide. Consequently, inhibition of nitric oxide-induced cyclic GMP formation by LY 83583, which may act by intracellular generation of superoxide anions, facilitates platelet activation.
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PMID:LY 83583 (6-anilino-5,8-quinolinedione) blocks nitrovasodilator-induced cyclic GMP increases and inhibition of platelet activation. 255 29

Various stimulants of the release of EDRF (endothelium-derived relaxing factor) increased intracellular cGMP levels in bovine aortic endothelial cells. ATP was the most effective compound tested, increasing cGMP 7-fold, followed by the calcium ionophore, A23187 (4.8-fold), and bradykinin (4.0-fold). The EC50 values were similar to those obtained when EDRF release was measured with the bioassay technique, which suggests a stimulation of endothelial guanylate cyclase by EDRF. The direct acting stimulants of soluble guanylate cyclase, sodium nitroprusside and SIN-1 (3-morpholino-sydnonimine), also increased the cGMP content of endothelial cells by 9.4 and 7.2 times, respectively. The effects of both groups of stimulants on cGMP levels were antagonized by the lipoxygenase inhibitor, nordihydroguaiaretic acid, and by the radical scavenger, phenylbutylnitrone, whereas gossypol or canavanine only antagonized the EDRF-induced effect on endothelial cGMP levels. Bradykinin, ATP and A23187 also increased the uptake of 45CaCl2 into endothelial cells but since the complete removal of extracellular Ca2+ or blockade of Ca2+ transport by LaCl3 did not affect the ability of these compounds to elevate cGMP levels, the formation of EDRF appears not to be triggered by an influx of extracellular calcium. This study provides evidence that EDRF stimulators enhance cGMP levels in endothelial cells, probably due to a direct activation of guanylate cyclase by EDRF.
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PMID:Effect of calcium on endothelium-derived relaxing factor formation and cGMP levels in endothelial cells. 255 53

The cytosolic fraction of N1E-115 neuroblastoma cells catalysed the L-arginine- and NADPH-dependent formation of a substance that relaxed endothelium-denuded strips of rabbit aorta. Relaxations in response to this substance were enhanced in the presence of superoxide dismutase. N omega-Nitro-L-arginine and NG-monomethyl-L-arginine, two inhibitors of EDRF synthesis, markedly attenuated the relaxations. Hemoglobin, a scavenger of EDRF, and methylene blue, an inhibitor of soluble guanylate cyclase, completely abolished the relaxation to N1E-115 cytosol. In contrast, the cyclo-oxygenase inhibitor indomethacin did not alter the relaxations. These data demonstrate that the cytosol of a neuronally-derived cell line is able to synthesize a substance with pharmacological properties similar to EDRF.
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PMID:The cytosol of N1E-115 neuroblastoma cells synthesizes an EDRF-like substance that relaxes rabbit aorta. 263 48

1. The effects of aging on histamine-induced vasodilatation and cyclic GMP production in rat thoracic aorta were investigated. 2. This histamine-induced dilatation of the aorta was mediated by H1-receptors and was dependent on the endothelium. 3. Histamine induced the greatest dilatation of arteries of 3-4 week old rats, progressively less of those of rats of 8 to 56 weeks old, and scarcely detectable dilatation of those of 100 week old rats. 4. Histamine induced cyclic GMP production in aorta from rats of 4 weeks old, with no change in the cyclic AMP level. This increase in the cyclic GMP level induced by histamine also decreased with age, being about 70% as great at 8 weeks, 50% as great at 50-60 weeks, and 10% as great at 130 weeks of age. 5. Removal of the endothelium completely abolished the histamine-induced increase in cyclic GMP. 6. The dilator effect of nitroprusside, which enhances cyclic GMP production by stimulating guanylate cyclase directly (not indirectly via the endothelium derived relaxing factor, EDRF), also showed age-related attenuation. 7. The dilator effect of 8-bromo cyclic GMP, which stimulates cyclic GMP-dependent protein kinase, also decreased during aging. 8. These results suggest that aging reduces the ability of the endothelium to produce EDRF, which stimulates guanylate cyclase, and so decreases cyclic GMP production. Thus the decreased dilator response of the arteries to histamine during aging is probably due to both loss of endothelial function and reduction of guanylate cyclase activity. Alteration of cyclic GMP-dependent protein kinase activity may also participate in the age-related changes.
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PMID:Age-associated decrease in histamine-induced vasodilation may be due to reduction of cyclic GMP formation. 285 55

We have investigated VIP-induced relaxation and cyclic AMP accumulation in rat thoracic aorta strips, and the importance of endothelium to both actions. The relaxation was greatly attenuated by removal of endothelium, but was unaltered by cyclo-oxygenase or lipoxygenase inhibitors. Similarly, cyclic AMP formation was nearly abolished with loss of endothelium, but was largely unaffected by inhibitors of arachidonate pathways, cytochrome P450 or guanylate cyclase. VIP may stimulate the release of a diffusible factor from endothelium (an EDRF), which activates adenylate cyclase and relaxes aortic smooth muscle.
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PMID:Vasoactive intestinal peptide evokes endothelium-dependent relaxation and cyclic AMP accumulation in rat aorta. 285 61

Taking their lead from studies which have shown that endothelium-derived relaxing factor(s) (EDRF) mediates vasorelaxation by activating smooth muscle guanyl cyclase, the authors of the current article have examined the role of the endothelium in relation to the effects of the alpha-adrenoceptor antagonist prazosin. Prazosin acted as a non-competitive antagonist of norepinephrine- (NE-) induced contraction in rat aortic preparations with intact endothelium, but as a competitive antagonist in endothelium-denuded preparations. The affinity of NE for its smooth muscle receptor was the same in the presence or absence of endothelium, but its efficacy was 7 times lower in the presence than in the absence of endothelium. Other experiments showed that inhibition of guanyl cyclase by methylene blue in the presence of endothelium (like endothelium removal) led to competitive antagonism of NE responses by prazosin, and that increasing the tissue content of cyclic GMP by pre-incubating de-endothelialized preparations with 8-Br-cyclic GMP (as in intact preparations) led to non-competitive antagonism of NE responses by prazosin. The authors concluded that EDRF, by increasing the cyclic GMP content of vascular smooth muscle of rat aorta, can modify the efficacy of NE, and thereby alter the mode of antagonism of prazosin.
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PMID:Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta. 285 49


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