title: Disparate effects of the calcium-channel blockers, nifedipine and verapamil, on alpha 2-adrenergic receptors and thromboxane A2-induced aggregation of human platelets.
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 heterogeneous group of compounds, we studied the effect of nifedipine and verapamil on human platelet aggregation in vitro. Neither 10 microM nifedipine nor 10 microM verapamil consistently inhibited the aggregation response of platelet-rich plasma to threshold concentrations of ADP, sodium arachidonate, epinephrine, or collagen. However, both 10 microM nifedipine and 10 microM verapamil 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 microM nifedipine but not by 10 microM verapamil. Even 100 microM verapamil gave only partial and inconsistent inhibition of aggregation. Both drugs had essentially the same effects on platelet aggregation induced by the stable endoperoxide and TXA2 mimic, U46619, with or without epinephrine. Neither 10 microM nifedipine nor 10 microM verapamil elevated platelet cyclic AMP. Verapamil (10 microM) inhibited binding of [3H]-yohimbine (an alpha 2-adrenergic receptor antagonist) to intact human platelets (KD 10.5 nM vs 2.4 nM for control platelets) without altering the number of binding sites. In contrast, 10 microM nifedipine had no effect on KD 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 alpha 2-adrenergic receptor binding. Nifedipine blocks the platelet response to TXA2 without affecting alpha-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.
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000032:analysis / Q000378:metabolism; D002850:Chromatography, Gel; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000502:physiology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013928:Thromboxane A2 / Q000494:pharmacology*; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology*; D015016:Yohimbine / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011942:Receptors, Adrenergic, alpha; D014316:Tritium; D016718:Arachidonic Acid; D015016:Yohimbine; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D014700:Verapamil; D000242:Cyclic AMP; D009543:Nifedipine; D004837:Epinephrine