Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hemovascular abnormalities encountered in diabetes include platelet alterations, shifts in prostaglandin metabolism and disorders of fibrinolysis. Diabetes is thus associated with increased platelet adhesiveness, increased platelet aggregation with hypersensitivity to proaggregants, increased plasma levels of beta-thromboglobulin and platelet factor 4 as an expression of platelet hyperactivity, increased levels of thromboxane A2 (TXA2) and prostacyclin (PGI2), and reduced levels of tissue plasminogen activator (t-PA). It is not clear which, if any, of these abnormalities are generated by chronic hyperglycemia and can be corrected by adequate glycemic control. Studies with gliclazide have demonstrated that it exerts hemovascular effects which can be valuable to patients. Thus, treatment with gliclazide leads to a decrease in platelet adhesiveness and aggregability. This treatment also reduces thromboxane levels and increases TPA levels. The mechanisms of action of gliclazide are not fully known but it has been demonstrated that its antiplatelet action is independent of its hypoglycemic activity and is not accompanied by clinical abnormalities of blood clotting. The mechanism of direct action on platelet activity may be mediated by inhibition of activated glycogen synthetase, activation of adenylate cyclase, modulation of arachidonic acid release from platelet membranes, stimulation of PGI2 production, and inhibition of the proaggregant action of TXA2. Thus, gliclazide not only has a hypoglycemic action but also improves hemovascular parameters in type 2 diabetes when used at normal therapeutic doses.
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PMID:Hemobiological activity of gliclazide in diabetes mellitus. 179 71

Increases in endogenous free fatty acids (FFA) induced by several stimuli are associated with increases in platelet aggregates and platelet factor 4 in man. To determine if thromboxane (TxB) release is also an associated event, we measured plasma FFA and TxB2 levels before and 5 min after bolus injection of 2,500 U of heparin prior to coronary arteriography in 27 patients with angina. Significant increases in FFA occurred in all patients (p less than 0.02) and those with critical lesions (p less than 0.01), while TxB2 levels also rose (p less than 0.02, p less than 0.05, respectively). However, linear regression showed increases in FFA and TxB2 were independent. The observed TxB2 release may be due to lipolysis-induced exposure of vascular collagen or direct inhibition of platelet adenylate cyclase by heparin.
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PMID:Effect of elevated plasma-free fatty acids on thromboxane release in patients with coronary artery disease. 737

Among various categories of antiplatelet drugs, cAMP-elevating agents and GP IIb/IIIa antagonists have been reported to inhibit platelet aggregation stimulated by a wide variety of platelet agonists. To clarify the qualitative difference between these two agents, their effects on various platelet responses in washed platelets evoked by thrombin (0.05 U/mL) were compared in vitro. Two types of cAMP-elevating drugs, cilostazol (a phosphodiesterase III inhibitor) and prostaglandin E1 (an adenylate cyclase activator), both inhibited platelet aggregation, thromboxane A2 formation, and platelet factor 4 release in a concentration-dependent manner. In addition, both agents suppressed intracellular Ca++ elevation induced by thrombin. However, two classes of GP IIb/IIIa antagonists, abciximab (Fab fragment of antibody) and tirofiban (a synthetic compound), showed no inhibitory effects against thromboxane A2 formation and platelet factor 4 release, although these drugs inhibited platelet aggregation. Essentially the same results were obtained in platelet-rich plasma stimulated with high concentration (100 microM) of thrombin receptor activating peptide. In contrast to these different profiles on thromboxane A2 formation and release reaction, both cAMP-elevating agents and GP IIb/IIIa antagonists potently suppressed procoagulant activity in thrombin-stimulated platelets. These results suggest that the development of platelet procoagulant activity induced by thrombin is exclusively dependent on platelet aggregation or aggregation-dependent processes. These observations also indicate that cAMP-elevating agents possess wider inhibitory effects on platelet responses evoked by strong agonists than GP IIb/IIIa antagonists.
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PMID:Comparative study of antiplatelet drugs in vitro: distinct effects of cAMP-elevating drugs and GPIIb/IIIa antagonists on thrombin-induced platelet responses. 1040 83