Analysis of the potassium channel openers celikalim, pinacidil and cromakalim in platelet models of thrombosis

The antihypertensive agents pinacidil, cromakalim and celikalim lower blood pressure by opening potassium channels in vascular smooth muscle. The role of these compounds in inhibiting human platelet aggregation and preventing white thrombus formation in a rabbit arteriovenous shunt model was examined. None of these agents (100 μM), substantially inhibited platelet aggregation induced by epinephrine or arachidonic acid. Only celikalim (100 gM) inhibited collagen (45%), ADP (56%), or serotonin (61%) induced platelet aggregation and ADP- (41%) or epinephrine-potentiated (61%) serotonin-induced platelet aggregation. Celikalim inhibited white thrombus formation at i.v. doses of 0.25 mg/kg (46% inhibition) but not 0.1 mg/kg; (14.6%); equihypotensive doses of pinacidil (0.5 mg/kg; 21.7%) and cromakalim (0.2 mg/kg, 7.5%; 0.4 mg/kg, 33%) were less effective. Glyburide (i.v. dose of 0.5 mg/kg) inhibited the antithrombotic activity of celikalim and to a lesser extent cromakalim. The greater antithrombotic activity of celikalim in vivo may be related to beneficial effects on blood rheology and reduced red blood cell deformability.