Changes in platelet response to adenosine 5'-diphosphate caused by verapamil

Verapamil is widely used in the treatment of patients with coronary artery disease. The effect of verapamil on vascular smooth muscle cells is well documented. This effect is mediated by the inhibition of calcium fluxes across plasma membranes. Some data suggest that verapamil may affect platelet functions in thrombosis, but those observations were made for much higher verapamil concentration than could be achieved in vivo. Our current investigations are focused on an influence of low doses of verapamil (0.1-1.0 microM) on platelet response to ADP. We have found that verapamil at concentration of 0.1 microM can inhibit platelet aggregation (by 10%) evoked in PRP by 1.0-1.5 microM ADP. Moreover, the inhibitory effect is potentiated by prolonged time of platelet preincubation with verapamil. On the other hand, we have found a significant reduction in the number of fibrinogen receptors exposed on the platelet surface of patients (n = 21) treated with therapeutic doses (240 mg/day) of verapamil during two weeks of drug administration. The mean number of exposed receptors was reduced from 75,000 to 40,000 per platelet, with significance p < 0.0001. In vitro platelet preincubation with verapamil, even in much higher concentrations, did not affect fibrinogen binding to ADP activated platelets. It suggests, that in vitro exposure of platelets to verapamil for a short time has no effect on the expression of fibrinogen receptors on platelets, but prolonged in vivo interaction of this drug with platelets results in reduction of the fibrinogen receptor exposition. Thus, observed inhibition of platelet aggregation does not relay on a simple reduction of the number of exposed receptors, but intraplatelet signalling has to be affected. In fact, we have observed, in platelets pretreated with low doses of verapamil, significantly reduced release of calcium ions upon activation by ADP, whereas the calcium influx under such conditions does not seem to be affected.