Inhibition of platelet aggregation and thromboxane production by pinacidil.
We examined the effects of pinacidil on in vitro platelet function and arachidonic acid metabolism. Pinacidil is an arterial vasodilator currently undergoing clinical trials. Although its mechanism of action is yet undetermined, there is evidence that the activity of other vasodilators may in part be mediated through their effects on arachidonic acid metabolism. Alterations in platelet function were investigated by measuring ADP-induced aggregation in aliquots of human platelet rich plasma that were preincubated with pinacidil. Changes in arachidonic acid metabolism were determined using washed platelets incubated with 14C labeled arachidonic acid after preincubation with pinacidil or indomethacin. The arachidonate metabolites formed were extracted, separated by thin layer chromatography and quantitated via liquid scintillation spectrometry. Pinacidil inhibited platelet aggregation in a concentration dependent manner with 94% inhibition at 0.005M pinacidil. Pinacidil also caused concentration dependent inhibition of TXB2 production (63% inhibition at 0.01M) with reciprocal increases in PGE2 and PGF2 alpha production. There was no significant alteration in arachidonic acid utilization. Indomethacin (0.01M), as expected, inhibited TXB2 as well as PGE2 and PGF2 alpha synthesis. We conclude that, under the conditions of our assay, pinacidil inhibits platelet aggregation and specifically inhibits thromboxane synthetase, an action different from that of indomethacin. Alterations in the relative synthesis of vasodilating and vasoconstricting prostaglandins may be one mechanism whereby pinacidil exerts its antihypertensive activity.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015237:Dinoprost; D015232:Dinoprostone; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D020110:Pinacidil; D010974:Platelet Aggregation / Q000187:drug effects*; D011458:Prostaglandins E / Q000097:blood; D011460:Prostaglandins F / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000097:blood*
D001095:Arachidonic Acids; D006146:Guanidines; D011458:Prostaglandins E; D011460:Prostaglandins F; D013931:Thromboxanes; D016718:Arachidonic Acid; D013929:Thromboxane B2; D020110:Pinacidil; D015237:Dinoprost; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D007213:Indomethacin