Adenosine potentiates the inhibitory effects of calcium channel antagonists on human platelet aggregation induced by thromboxane A2 or U46619.
Calcium channel antagonists inhibit platelet function in vitro and ex vivo, but the mechanism responsible has not been clearly defined. The concentrations of these agents required to inhibit platelet aggregation in vitro are several fold higher than those attained in vivo. Adenosine, a known inhibitor of platelet function, is produced in large quantities in ischemic myocardium. In order to test the hypothesis that adenosine may potentiate the platelet-inhibitory effects of calcium channel antagonists, we studied the effect of adenosine plus nifedipine, verapamil or diltiazem on human platelet aggregation induced by thromboxane A2 or the stable endoperoxide/thromboxane A2 mimic, U46619 +/- epinephrine. Adenosine, in concentrations achieved in the plasma during myocardial ischemia (0.01-0.1 microM), enhanced the inhibitory effects of nifedipine, verapamil and diltiazem on platelet aggregation 5-100 fold. The same concentrations of adenosine alone did not inhibit platelet aggregation. In the presence of non-inhibitory concentrations of adenosine, nifedipine, in concentrations approaching those attained in vivo following standard therapeutic doses (as low as 0.29 microM), significantly inhibited thromboxane A2-induced platelet aggregation. Therefore, adenosine potentiates the in vitro inhibitory effects of calcium channel antagonists on platelet aggregation induced by thromboxane A2 or thromboxane A2 plus epinephrine. These results suggest that adenosine production by ischemic myocardium may augment the inhibitory effect of calcium channel antagonists on platelets.
Department of Medicine, Hematology/Oncology, Cardiology, University of Minnesota, Minneapolis.
G J
GJ
Johnson
L A
LA
Leis
G S
GS
Francis
D000241:Adenosine / Q000494:pharmacology*; D000527:Alprostadil / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009543:Nifedipine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D013928:Thromboxane A2; D014700:Verapamil; D004110:Diltiazem; D000527:Alprostadil; D009543:Nifedipine; D000241:Adenosine; D004837:Epinephrine