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 activity of soluble guanylate cyclase (GC) and its regulation in the platelets and heart of normal rats and rats with experimental acute myocardial ischemia provoked by coronary ligation was examined. There was a synchronous reduction in platelet and heart GC activity immediately following 15 minutes after surgery along with a drastically marked drop in genuine baseline activity (with Mg2+) to 19 and 40% in the platelets and heart (both ischemic and intact areas), respectively. Following 24 hours, GC activity insignificantly rose (up to 35.5%) in the platelets with Mg2+, that with Mn2+ remained unchanged; in the ischemic area it decreased much more (to 30%), whereas in the intact area it partially restored (up to 70%). The stimulating effect of DTT on platelet GC activity 15 minutes after the surgery drastically rose (from 2.8 to 8), then returning to normal 24 hours later. The findings show an enhancement in free radical processes typical of ischemia and indicate their high response of platelet GC at the earliest stages. Sodium nitroprusside-induced activation of myocardial GC diminished in the ischemic area in 15 minutes and virtually lacked in 24 hours. There was a less pronounced decrease in GC activation in the intact area. It is suggested that lower enzymatic activatibility is associated with heme loss. The absence of sodium nitroprusside-induced stimulation of platelet GC both in health and in the abnormality under question may be due to primary heme enzymatic deficiency.
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PMID:[Soluble guanyl cyclase of blood platelets and heart of rats with experimental myocardial ischemia]. 135 20

Oxygen metabolites have been reported to produce vasoconstriction and/or vasodilation in a variety of in vitro or in vivo vascular preparations. Certain basic mechanisms appear to contribute to these responses. Hydrogen peroxide can produce either vasodilation or constriction via stimulation of prostaglandins. The soluble form of guanylate cyclase in vascular smooth muscle, an enzyme which produces the intracellular mediator of relaxation cyclic GMP, is also a site of action of vasoactive O2 metabolites. Guanylate cyclase is directly activated by nanomolar concentrations of nitric oxide (produced by endothelial cells or nitrovasodilator drugs) or H2O2 (via its metabolism by catalase). These cyclic GMP-mediated mechanisms of relaxation are inhibited by superoxide anion, produced from endogenous sources after inhibition of superoxide dismutase or produced by pharmacological agents that undergo redox cycling. In addition, O2 metabolites may modulate vascular tone via the chemical destruction of physiological contractile agents (e.g. norepinephrine) and relaxant agents (e.g. nitric oxide), and via injury to cells important for the regulation of vascular tone (e.g. endothelium). We have found in a variety of preparations that reexposure to O2 after a brief period of severe hypoxia produces vascular responses that appear to be mediated by intracellular H2O2 generation. Thus, active O2 species may contribute to vascular responses in pathophysiological situations associated with their formation (e.g. inflammation, ischemia/reperfusion, etc.) and to the physiological regulation of vascular tone produced by changes in O2 tension (e.g. reactive hyperemia, hypoxic vasoconstriction, etc).
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PMID:Activated oxygen metabolites as regulators of vascular tone. 179 78

Nicorandil and cromakalim relaxed rat aortic rings denuded of endothelium and precontracted with a low concentration of KCl (25 mM). Glibenclamide (1 microM) strongly antagonized only the effects of cromakalim while those of nicorandil were inhibited by methylene blue, an inhibitor of the soluble form of guanylate cyclase. High concentrations of nicorandil also produced vasorelaxation in aortic preparations contracted with 55 mM KCl, whereas cromakalim did not. In pentobarbital-anesthetized rats a 20-min i.v. infusion of cromakalim (5 micrograms/kg/min) or nicorandil (100 micrograms/kg/min) similarly decreased the mean carotid artery blood pressure. These effects, as well as the antihypertensive activity of nicorandil (5.0 mg/kg p.o.) and cromakalim (0.25 mg/kg p.o.) in spontaneously hypertensive rats were markedly inhibited by glibenclamide (20 mg/kg i.v.). Finally, glibenclamide (4 mg/kg i.v.) displaced to the right the control dose-coronary vasodilatory response curve to nicorandil injected into the left circumflex coronary artery of pentobarbital-anesthetized dogs. In conclusion, these results indicate that in a rat conductive vessel (aorta) nicorandil acts exclusively like nitrates, that is, it stimulates guanylate cyclase, and in resistance vessels (in the intact rat or dog coronary vascular bed) it opens K+ channels, as does cromakalim. Thus, nicorandil can be expected to have a broader spectrum of antianginal activity than drugs with a single mechanism of action. Additionally, as mentioned in the discussion section, substantial evidence exists that K+ channel opening can also afford marked cardioprotection against ischemia.
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PMID:K+ channel opening mediates the vasorelaxant effects of nicorandil in the intact vascular system. 183 48

The activity of soluble guanylate cyclase (GC) of rat heart and the regulatory activity of dithiothreitol (DTT) and sodium nitroprusside under ischemic myocardium damage caused by ligation of left coronary artery has been investigated. After coronary occlusion the GC activity in the presence of Mn2+ or Mg2+ decreases both in ischemic and in intact zones (40% from normal) in 15 min, in 24 h it more diminishes (up to 30%) in the ischemic zone, in intact zone it partially normalizes (up to 70%). The stimulatory effect of DTT on the GC activity in studied heart zones doesn't differ from control. The activation of GC by nitroprusside in ischemic zone decreases in 15 min, it is practically absent in 24 h. The decrease of GC activation in intact zone is less expressed. It is suggested that the reduction of GC activation by sodium nitroprusside is due to the loss of the heme by the enzyme during ischemia.
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PMID:[Cardiac guanylate cyclase in rats with ischemic damage to the myocardium]. 197 76

Activity of soluble guanylate cyclase and regulation of the enzyme were studied in thrombocytes of intact rats and under conditions of acute myocardial ischemia caused by ligation of left coronary artery. Distinct decrease in the enzymatic activity was detected already within 15 min after the operation: down to 19% and 46%, in presence of Mg2+ and Mn2+, respectively, as compared with control values. Within 24 hrs of the ischemia the guanylate cyclase activity was slightly increased up to 33.5% in Mg2(+)-containing mixture and was unaltered (46%) in presence of Mn2+. Considerable activation of the enzyme by 2.10(-4) M dithiotreitol (from 288% to 790%, respectively) was observed after 15 min of myocardial ischemia with subsequent normalization (down to 340%) within 24 hrs. The data obtained suggest elevation of free-radical reactions, specific for myocardial ischemia, as well as high sensitivity of guanylate cyclase in thrombocytes to these reactions beginning from the early steps of the disease. Absence of the sodium nitroprusside stimulating effect on rat thrombocyte guanylate cyclase, found under conditions of both normal state and myocardial ischemia, may be due to initial hemdeficiency of the enzyme.
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PMID:[Soluble guanylate cyclase from rat platelets during experimental myocardial ischemia]. 197 94

Changes in the levels of cyclic AMP (cAMP) and cyclic GMP (cGMP) have been measured in brains of 20-day-old rat fetuses exposed to global intrauterine ischemia. Ischemia of different duration (0.5-30 minutes) did not alter the level of cAMP. In contrast, cGMP levels increased as a result of ischemia. This increase was seen even after a short period of ischemia (less than 5 minutes) and was maximal after 5 minutes, where a threefold increase could be observed. This stimulation was transient: after 30 min of ischemia, cGMP returned to the control level. Accumulation of cGMP can be related to the activation of guanylate cyclase, the activity of which is doubled after 15 minutes of ischemia. Immunoprecipitation of guanylate cyclase after in vivo labeling of the fetal brain with 32Pi revealed a threefold increase in the phosphorylation of the enzyme after 15 minutes of ischemia. The possible role of these modifications in cGMP metabolism during the course of ischemia is discussed.
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PMID:Cyclic GMP alterations in fetal rat cerebrum after global intrauterine ischemia: role of guanylate cyclase phosphorylation. 198 36

Distinct increase and then decrease in content of cyclic nucleotides was observed in dog myocardium ventricles and auricles within early periods of heart infarction (10 min-4 hrs). Within a day after ligation of artery the ratio cAMP/cGMP was considerably decreased as a result of activation of guanylate cyclase and cAMP-phosphodiesterase as well as due to a decrease in activity of adenylate cyclase. Acute ischemia of small area of the heart left ventricle caused impairment of cyclic nucleotide metabolism in all the heart muscle.
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PMID:[The cyclic nucleotide system in various sections of the dog myocardium in experimental infarction]. 256 32

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.
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PMID:Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed. 317 68

A large amount of biochemical, physiological, and pharmacological data has been obtained which supports a mechanistic role of oxygen free radical-induced lipid peroxidation (LP) in post-traumatic spinal cord degeneration. Biochemical evidence of early and progressive lipid peroxidative reactions occurring in the injured spinal cord includes: an increase in polyunsaturated fatty acid peroxidation products (e.g., malonyldialdehyde), a decrease in cholesterol and the appearance of cholesterol oxidation products, an increase in cyclic GMP presumably due to free radical activation of guanylate cyclase, a decrease in tissue anti-oxidant levels (e.g., alpha tocopherol, reduced ascorbate), and inhibition of membrane-bound enzymes such as Na+ + K+-ATPase. In vitro CNS tissue studies have provided support for the possibility that LP may contribute to other early post-traumatic events including intracellular calcium accumulation and arachidonic acid release. Moreover, spinal tissue lactic acidosis, which occurs early after injury, can exacerbate LP reactions. The involvement of LP in the development of progressive post-traumatic spinal white matter ischemia has been strongly inferred from pharmacological studies in cats with known inhibitors of LP. For example, the dose-response curves for the ability of the glucocorticoid methylprednisolone (MP) to inhibit post-traumatic LP and to retard ischemia development are identical. This relationship between LP and post-traumatic ischemia is more directly implied from studies showing that pretreatment of cats with high doses of anti-oxidants (e.g., d-alpha tocopherol plus selenium p.o. or 1-ascorbic acid i.v.) can also significantly antagonize the progressive decrease in spinal cord blood flow that follows severe blunt injury. However, a similar efficacy of certain calcium and prostaglandin antagonists suggests an interrelationship between aberrant calcium fluxes, vasoconstrictor/platelet aggregating prostanoids, and LP in the post-traumatic ischemic phenomenon. In addition to a role of LP in ischemia development, the action of intensive d-alpha tocopherol and selenium pretreatment to retard anterograde cat motor nerve fiber degeneration after nerve section suggests that LP may also be a fundamental mechanism of "Wallerian" axonal degeneration after neural injury. Finally, a critical role of LP in the acute pathophysiology of CNS injury in general has been supported by the finding of an excellent correlation, in terms of efficacy and potency, between the action of glucocorticoid and nonglucocorticoid steroids to inhibit neural tissue LP in vitro and to promote early neurological recovery in severely head-injured mice.
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PMID:Role of lipid peroxidation in post-traumatic spinal cord degeneration: a review. 355 50

To examine whether endocardial microvascular function is preferentially impaired by ischemia and reperfusion, we studied endothelium-dependent responses of epicardial and endocardial coronary microvessels (130-220 microns) from control pigs and from pigs subjected to 1-h regional myocardial ischemia (circumflex occlusion) followed by 1-h reperfusion (n = 8) in vitro using videomicroscopy. In control animals (n = 8), no significant transmural differences were apparent in microvascular responses to the endothelium-dependent agents bradykinin or the calcium ionophore A23187, to the endothelium-independent agent sodium nitroprusside (SNP), or to adenosine. Serotonin caused a slight but statistically insignificant greater relaxation of endocardial than of epicardial microvessels. After ischemia-reperfusion, relaxations to all endothelium-dependent agents (serotonin, bradykinin, A23187) and to adenosine were significantly reduced (p < 0.05 for all agents) as compared with the respective control responses. There were no significant differences between epicardial and endocardial responses in the ischemia-reperfusion group for any of the vasoactive agents. Endothelium-independent responses to SNP were not affected by ischemia-reperfusion, indicating no alteration in the ability of vascular smooth muscle to relax through guanylate cyclase-mediated mechanisms. Control epicardial microvascular responses were examined after endothelial denudation and after pretreatment with NG-monomethyl-L-arginine (L-NMMA), indomethacin, or glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epicardial and endocardial coronary microvascular responses: effects of ischemia-reperfusion. 751 2


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