Antithrombogenic effects of calcium channel blockers: Synergism with prostacyclin and thromboxane synthase inhibitors

Abstract

Four calcium channel blockers (nimodipine, nifedipine, verapamil and diltiazem) of three chemical classes were tested in vitro for inhibition of platelet aggregation using heparinized human platelet rich plasma. Both ADP- and thrombin-induced aggregation were inhibited as was the biosynthesis of thromboxane A 2 in response to ADP or thrombin. However, the IC 50's for the calcium channel blockers were ≥ 110μM. Nimodipine was also tested in combination with prostacyclin, the potent platelet antiaggregatory agent, or with a thromboxane synthase inhibitor, U63557A. At concentrations at which neither nimodipine or prostacyclin inhibited platelet aggregation ≥ 10%, the two compounds in combination synergistically inhibited both ADP- and thrombin-induced platelet aggregation. U63557A inhibited biosynthesis of thromboxane A 2 by platelets in response to ADP or thrombin, but did not inhibit either ADP- or thrombin-induced platelet aggregation. However, U63557A in combination with a threshold inhibitory concentration of nimodipine resulted in a synergistic inhibition of platelet aggregation induced by ADP or thrombin. These results suggest that calcium channel blockers may be of therapeutic value as a new class of antithrombogenic agents when used in combination with agents that inhibit either platelet aggregation or synthesis of platelet thromboxane A 2.