Disparate effects of the calcium-channel blockers, nifedipine and verapamil, on α2-adrenergic receptors and thromboxane A2-induced aggregation of human platelets

G. J. Johnson, L. A. Leis, G. S. Francis

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Abstract

Calcium-channel blockers inhibit human platelet aggregation in vitro and ex vivo. To further evaluate the mechanism(s) responsible for the inhibition induced by this structurally heterogenous group of compounds, we studied the effect of nifedipine and verapamil on human platelet aggregation response of platelet-rich plasma to threshold concentrations of ADP, sodium arachidonate, epinephrine, or collagen. However, both 10 μM verapamil inhibited epinephrine-potentiated, thromboxane A2 (TXA2)-induced aggregation of aspirin-incubated, gel-filtered platelets. Aggregation of similarly prepared platelets induced by TXA2 alone was abolished by 10 μM nifedipine but not by 10 μM verapamil. Even 100 μM verapamil gave only partial and inconsistent inhibition of aggregation. Both drugs had essentially the same effects on platelet aggregation induced by stable endoperoxide and TXA2 mimic, U46619, with or without epinephrine. Neither 10 μM nifedipine nor 10 μM verapamil elevated platelet cyclic AMP. Verapamil (10 μM) inhibited binding of [3H]-yohimbine (an α2-adrenergic receptor antagonist) to intact human platelets (K(D) 10.5 nM vs 2.4 nM for control platelets) without altering the number of binding sites. In contrast, 10 μM nifedipine had no effect on K(D) or number of binding sites. These results indicate that nifedipine and verapamil inhibit epinephrine-potentiated, TXA2-induced human platelet aggregation by different mechanisms. Verapamil inhibits the epinephrine contribution to the aggregation response by blocking α2-adrenergic receptor binding. These observations have potential clinical implications with regard to the mechanisms by which calcium-channel blockers inhibit vascular spasm and myocardial ischemia.

Original languageEnglish (US)
Pages (from-to)847-854
Number of pages8
JournalCirculation
Volume73
Issue number4
DOIs
StatePublished - Jan 1 1986

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