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)

Organic nitrates are believed to provide relief from angina principally by dilating the coronary vasculature. Substantial evidence exists, however, to support a potent antiplatelet effect for these agents as well. Each of these compounds ultimately is metabolized to nitric oxide (or an S-nitrosothiol congener thereof), and this metabolite, in turn, is a potent activator of platelet guanylate cyclase. Activation of guanylate cyclase increases platelet cyclic guanosine monophosphate (cGMP), and is accompanied by inhibition of agonist-mediated calcium flux, and, in turn, reduction of fibrinogen binding to the glycoprotein IIb/IIIa receptor. Since fibrinogen binding is essential for platelet aggregation regardless of the agonist involved, its inhibition appears to be the critical mechanism by which platelet function is impaired by these agents. The recently recognized role that platelet-dependent thrombotic processes play in acute coronary syndromes suggests that the inhibition of platelets by nitrates may offer an additional mechanism by which these compounds improve perfusion to ischemic myocardium.
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PMID:Antiplatelet and antithrombotic effects of organic nitrates. 152 22

Platelet hyperaggregability and associated thrombosis have been documented in a number of cardiovascular disease states. While one of the current mainstays of anti-thrombotic treatment (i.e. aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists) has been directed at reducing platelet activation and aggregation, it is apparent that there are limitations to the effectiveness of these therapies. Nitric oxide (NO) plays an important role in platelet physiology. The ability of NO to regulate cyclic guanosine-3,'5'-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. NO is not only of the endothelial source, it is also released from activated platelets, providing a negative feedback. Studies in patients with symptomatic ischemia, chronic heart failure, diabetes and various risk factors for cardiovascular disease have demonstrated that platelets from these subjects exhibit reduced responsiveness to the anti-aggregating efficacy of NO: a phenomenon termed "platelet NO resistance". It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor or EDRF), and as such may contribute to the increased risk of ischemic events. NO resistance also accounts for reduced pharmaco-activity of exogenous NO donors, e.g. organic nitrates. Platelet NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical and inactivation of soluble guanylate cyclase. NO resistance has both diagnostic and prognostic implications. The current review examines the association of platelet NO resistance with pathological hyperaggregability and discusses potential therapeutic strategies targeting this abnormality.
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PMID:Platelet hyperaggregability: impaired responsiveness to nitric oxide ("platelet NO resistance") as a therapeutic target. 1832 4

Increases in [cyclic-3',5'-GMP] in aspirin-treated platelet-rich plasma and washed platelet preparations resulted from stimulation by all excitatory agonists tested, and by other agents which induced aggregate formation. The maximal increase observed was approximately 4-fold above the resting level. The increase in [cyclic-3',5'-GMP] correlated closely in both time-, and agonist dose-dependence with aggregation as measured by an increase in light transmittance. It was delayed in time, and occurred at a higher agonist concentration, than the initial phase of aggregation as measured by loss of single platelets. The extent of increase in [cyclic-3',5'-GMP] was independent of the signal transduction pathway used by the agonist/agent. Inhibition of aggregation by removal of Ca(2+), failure to induce contact, addition of antibodies or antagonists to the glycoprotein IIb/IIIa complex or the presence of an inhibitory agonist such as PGI(2) prevented the increase in [cyclic-3',5'-GMP]. Contact with collagen fibrils causing adhesion to this matrix, or aggregate formation induced by ristocetin or by certain lectins also caused an increase in [cyclic-3',5'-GMP]. Contact of platelets either with other platelets or with a matrix therefore results in stimulation of guanylate cyclase. The mechanism responsible for such stimulation remains unclear but does not appear simply to be attributable to activation of nitric oxide synthase by Ca(2+).
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PMID:Platelet-Platelet Contact is Required to Observe Guanylate Cyclase Activation in Stimulated Platelets. 2104 59