Effect of the Calcium-Entry Blocking Agent Nifedipine on Activation of Human Platelets and Comparison with Verapamil

Summary

The effects of the calcium-entry blocking agent nifedipine on the activation of human platelets by various agonists has been studied and compared with verapamil. Like verapamil, nifedipine inhibited platelet aggregation and secretion caused by collagen, the second phase of ADP-induced aggregation, and aggregation caused by the ionophore A23187. Both agents inhibited the formation of TXB₂ from endogenous arachidonate, whereas only nifedipine inhibited platelet aggregation and decreased TXB₂ formation caused by exogenous arachidonate without inhibiting uptake. These results indicate that both calcium-blocking agents may be inhibiting the release of arachidonate in platelets by phospholipases, and that nifedipine also inhibits the formation and action of thromboxane A₂ in platelets. Epinephrine-induced aggregation was inhibited by low concentrations of verapamil while nifedipine only inhibited aggregation by epinephrine at much higher concentrations. It is suggested that low concentrations of verapamil inhibit epinephrine-induced aggregation by interacting with platelet α-adrenergic receptors, and that higher concentrations of both calcium-blocking agents inhibit platelet responses to other aggregating agents by preventing intracellular calcium mobilization.

Keywords

Platelet activation - Verapamil - Collagen - ADP - Arachidonic acid - A23187 - Calcium

• References

• 1 Gerrard JM, Peterson DA, White JG. Calcium mobilization. In Platelets in Biology and Pathology -2. Gordon JL. (ed) Research Monographs in Cell and Tissue Pathology Elsevier/North Holland; Amsterdam: 1981. 5 407-436
• 2 Feinstein MB, Rodan GA, Cutler LS. Cyclic AMP and calcium in platelet function. In Platelets in Biology and Pathology -2. Gordon JL. (ed) Research Monographs in Cell and Tissue Pathology Elsevier/ North Holland; Amsterdam: 1981. 5 437-472
• 3 Ardlie NG. Calcium ions, drug action and platelet function. Pharmacol Ther 1982; 18: 249-270
• 4 Cohn JN. Calcium-entry blockers in coronary artery disease. Circulation 1982; 65 Suppl (Suppl. 01) 1-2
• 5 Vanhoutte PM. Calcium-entry blockers and vascular smooth muscle. Circulation 1982; 65 Suppl (Suppl. 01) 11-19
• 6 Thorens S, Haeusler G. Effects of some vasodilators on calcium translocation in intact and fractionated vascular smooth muscle . Eur J Pharmacol 1979; 54: 79-91
• 7 Church J, Zsoter TT. Calcium antagonistic drugs. Mechanisms of action Can J Physiol Pharmacol 1980; 58: 254-264
• 8 Owen NE, Feinberg H, LeBreton GC. Epinephrine induces Ca²⁺ uptake in human blood platelets. Am J Physiol 1980; 239: H483-H488
• 9 Owen NE, LeBreton GC. Ca²⁺ mobilization in blood platelets as visualized by chloretracycline fluorescence. Am J Physiol 1981; 241: H613-H619
• 10 Ikeda Y, Kikuchi M, Toyama K, Watanabe K, Ando Y. Inhibition of human platelet functions by verapamil. Thromb Haemostas 1981; 45: 158-161
• 11 Madsen NP. Use of toluene/triton X-100 scintillation mixture for counting C¹⁴-protein radioactivity. Anal Biochem 1969; 29: 542-544
• 12 Cameron HA, Ardlie NG. The facilitating effects of adrenaline on platelet aggregation. Prostagland Leuk Med 1982; 9: 117-128
• 13 Brown R, Albano JD M, Ekins RP, Scherzi AM, Tampion W. A simple and sensitive saturation assay method for measurement of adenosine 3’-5’ cyclic monophosphate. Biochem J 1971; 121: 561-562
• 14 Cazenave JP, Packham MA, Mustard JF. Adherence of platelets to a collagen-coated surface: development of a quantitative model. J Lab Clin Med 1973; 82: 978-990
• 15 Han P, Boatwright C, Ardlie NG. Inhibition of platelet function by antiarrhythmic drags, verapamil and disopyramide. Thromb Haemostas 1982; 47: 150-153
• 16 O’Rourke MF. Angina pectoris, coronary artery spasm and calcium entry blocking agents. Aust NZ J Med 1982; 12: 465-466
• 17 Dargie HJ, Lunch PG, Krikler DM, Harris L, Krikler S. Nifedipine and propranolol: beneficial drag interaction. Am J Med 1981; 71: 676-682
• 18 Daly K, Bergman G, Rothman M, Atkinson L, Jackson G, Jewitt DE. Beneficial effects of adding nifedipine to beta adrenergic blocking therapy in angina pectoris. Eur J Cardiol 1982; 3: 42-46
• 19 Feinstein MB. Release of intracellular membrane-bound calcium precedes the onset of stimulus-induced exocytosis in platelets. Biochem Biophys Res Commun 1980; 93: 593-600
• 20 Le Breton GC, Dinerstein RJ, Roth LJ, Feinberg H. Direct evidence for intracellular divalent cation redistribution associated with platelet shape change. Biochem Biophys Res Commun 1976; 71: 362-370
• 21 Le Breton GC, Sandler WC, Feinberg H. The effects of D₂O and Chlortetracycline on ADP-induced platelet shape change and aggregation. Thromb Res 1976; 8: 477-485
• 22 Charo IF, Feinman RD, Detwiler TC. Inhibition of platelet secretion by an antagonist of intracellular calcium. Biochem Biophys Res Commun 1976; 72: 1462-1467
• 23 Le Breton GC, Dinerstein RJ. Effect of the calcium antagonist TMB- 6 on intracellular calcium redistribution associated with platelet shape change. Thromb Res 1977; 10: 521-523
• 24 Massini P, Lüscher EF. On the significance of the influx of calcium ions into stimulated human blood platelets. Biochim Biophys Acta 1976; 436: 652-663
• 25 Bamathan ES, Addonizio VP, Shattil SJ. Interaction of verapamil with human platelet α-adrenergic receptors. Am J Physiol 1982; 242: H19-H23
• 26 Johnson H. Effects of nifedipine (adalat®) on platelet function in vitro and in vivo. Thromb Res 1981; 21: 523-528