Dependence of the antagonism at human platelet 5-HT2 receptors by ketanserin on the reaction pH

The potency for the inhibition of 5-hydroxytryptamine (5-HT)-induced human platelet aggregation by ketanserin, pipamperone, spiperone, cyproheptadine and BW 501 in vitro decreased as the reaction pH increased progressively from 7.4 to 8.6, the largest shift (X 1125) in IC50 value (pH 7.4: 4 X 10(-9) M; pH 8.6: 4.5 X 10(-6) M) being found for ketanserin. With such an alkaline pH-shift, the fraction of the ionized form of the drugs decreased, reduction of the inhibitory capacity and of the ionized fraction being strongly correlated. Ketanserin (40 mg orally, - 15 h) in human volunteers, completely inhibited the 5-HT-induced platelet aggregation measured ex vivo, when tested at a reaction pH of 7.4; without gassing with CO2 5% -O2 95%, the plasma pH became alkaline and the inhibitory potency of the drug was strongly reduced (-60%). This study demonstrates the importance of the reaction pH for the aggregation of human platelets induced by 5-HT and its inhibition by ketanserin.