Effect of Diltiazem and Low-Dose Aspirin on Platelet Aggregation and ATP Release Induced by Paired Agonists

Summary

The authors studied the effects of diltiazem, administered alone and together with low-dose aspirin, on the platelet response to paired agonists. After a baseline period, 25 healthy volunteers were given oral diltiazem for 1 week (120, 240, or 360 mg/day), and then crossed over randomly between 1 week on diltiazem plus aspirin (81 mg/day), and 1 week on aspirin (81 mg/day) alone. Platelet function was tested on 2 consecutive days in each period. Synergistic platelet aggregation and ATP release were obtained at baseline using a subthreshold concentration of arachidonic acid combined with platelet activating factor, ADP, or epinephrine. Diltiazem resulted in a significant decrease from baseline in platelet aggregation and ATP release using the arachidonic acid-epinephrine combination (35% and 40% decrease, respectively, p <0.01) and a significant decrease in aggregation using the arachidonic acid-ADP combination (22% decrease, p <0.01). The effects were neither dose-related, nor accompanied by any significant change in serum thromboxane B₂ levels or bleeding times. There was no significant difference between the effects of aspirin alone and aspirin plus diltiazem on the synergistic platelet aggregation and ATP release induced by the paired agonists, or on thromboxane B₂ levels or bleeding times. Diltiazem administered in vivo partially inhibits the synergistic platelet aggregation and ATP release induced by paired agonists; however, in contrast to a previous in vitro study it does not potentiate the platelet-inhibitory effect of aspirin.

• References

• 1 Kiyomoto A, Sasaki Y, Odawara A, Morita T. Inhibition of platelet aggregation by diltiazem. Comparison with verapamil and nifedipine and inhibitory potencies of diltiazem metabolits. Circ Res 1983; 52 (Suppl. 01) 115-119
• 2 Vinge E, Andersson TLG, Larsson B. Effects of some calcium antagonists on aggregation by adrenalin and serotonin and on α-adrenoreceptor radioligand binding in human platelets. Acta Physiol Scand 1988; 133: 407-416
• 3 Onoda JM, Sloane BF, Honn KV. Antithrombogenic effects of calcium channel blockers: synergism with prostacyclin and thromboxane syntheses inhibitors. Thromb Res 1984; 34: 367-378
• 4 Yamada Y, Furui H, Furumichi T, Suzuki T, Yamauchi K, Yokota M, Hayashi H, Saito H. Inhibitory effects of endothelial cells and calcium channel blockers on platelet aggregation. Jpn Heart J 1990; 31: 201-215
• 5 Wade PJ, Lunt DO, Lad N, Tuffin DP, McCullagh KG. Effect of calcium and calcium antagonists on [³H]-PAF-acether binding to washed human platelets. Thromb Res 1986; 41: 251-262
• 6 Valone FH. Inhibition of platelet-activating factor binding to human platelets by calcium channel blockers. Thromb Res 1987; 45: 427-435
• 7 Ware JA, Johnson PC, Smith M, Salzman EW. Inhibition of human platelet aggregation and cytoplasmic calcium response by calcium antagonists: studies with aequorin and quin 2. Circ Res 1986; 59: 39-42
• 8 Addonizio VP, Fisher CA, Strauss JF, Wachtfogel YT, Colman RW, Josephson ME. Effects of verapamil and diltiazem on human platelet function. Am J Physiol 1986; 250: H366-H371
• 9 Mehta J, Mehta P, Ostrowski N. Calcium blocker diltiazem inhibits platelet activation and stimulates vascular prostacyclin synthesis. Am J Med Sci 1986; 291: 020-024
• 10 Yamauchi K, Furui H, Taniguchi N, Sotobata I. Effects of diltiazem hydrochloride on cardiovascular response, platelet aggregation and coagulating activity during exercise testing in systemic hypertension. Am J Cardiol 1986; 57: 609-612
• 11 Cremer KF, Pieper JA, Joyal M, Mehta J. Effects of diltiazem, dipyridamole, and their combination on hemostasis. Clin Pharmacol Ther 1984; 36: 641-644
• 12 Ring ME, Corrigan JJ, Fenster PE. Effects of oral diltiazem on platelet function: alone and in combination with “low-dose” aspirin. Thromb Res 1986; 44: 391-400
• 13 Altman R, Scazziota A, Dujovne C. Diltiazem potentiates the inhibitory effect of aspirin or platelet aggregation. Clin Pharmacol Ther 1988; 44: 320-325
• 14 Greco NG, Arnold JH, O’Dorisio TM, Cataland S, Panganamala RV. Action of platelet-activating factor on type 1 diabetic human platelets. J Lab Clin Med 1985; 105: 410-416
• 15 Mantel N. Assessing laboratory evidence for neoplastic activity. Biometrics 1980; 36: 381-399
• 16 Sordahl LA, Rex KA, Benedict CR. In vivo inhibition of platelet aggregation and occlusive coronary thrombus formation by a new calcium antagonist (R023-6152). J Cardiovasc Pharmacol 1991; 18: 504-510
• 17 Altman R, Scazziota A. Synergistic actions of PAF-acether and sodium arachidonate in human platelet aggregation. 2. Unexpected results after aspirin intake. Thromb Res 1986; 43: 113-120
• 18 Rao GHR, Johnson GJ, White JG. Influence of epinephrine on the aggregation response of aspirin-treated platelets. Prost Med 1980; 5: 45-48
• 19 Rao GHR, White JG. Aspirin, prostaglandin E₁ and Quin-2 AM-induced platelet dysfunction: restoration of function by noradrenalin. Prost Leuk Ess F Acids 1990; 39: 141-146
• 20 Greer IA, Walker JJ, Calder AA, Forbes CD. Aspirin with an adrenergic or a calcium-channel-blocking agent as new combination therapy for arterial thrombosis. Lancet 1985; i: 351-352
• 21 Zucker ML, Trowbridge C, Woodroof J, Chernoff SB, Reynoso L, Dujovne CA. Low- vs high-dose aspirin. Effects on platelet function in hyperlipoproteinemic and normal subjects. Arch Intern Med 1986; 146: 921-925