Platelet-activating factor (PAF) receptor antagonists inhibit arachidonic acid induced platelet aggregation in rabbit whole blood

Abstract

The potency of several platelet-activating factor (PAF) receptor antagonists was measured by observing their inhibitory effects against PAF induced platelet aggregation. Their selectivity was assessed by monitoring their effect on platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP). The antagonists inhibited platelet aggregation induced at the PAF EC₅₀ (0.023 μM) with the following rank order of potency: WEB 2086> WEB 2170> SRI 64–412> SRI 63–675> BN 52021>kadsurenone> SRI 63–441> alprazolam. While the antagonists had no inhibitory effect at the EC₅₀ for ADP (10 μM), they did inhibit platelet aggregation induced at the EC₅₀ for AA (55 μM). However, there was considerable variability in the slope of the inhibitory response and the relative potency of each antagonist against PAF induced platelet aggregation as compared to AA induced platelet aggregation. The antagonist IC₅₀ (μM) against PAF and AA were as follows, with those that showed significantly different (p<0.01) slopes indicated by an asterisk: SRI 63-441^* (3.8, 15.1); SRI 63-675 (1.4, 36.2); SRI 64-412 (0.5, 10.5); BN 52021^* (2.4, 58.9); kadsurenone^* (2.8, 28.3); alprazolam^* (10, 25); WEB 2086 (0.055, 0.220), and WEB 2170 (0.107, 0.534). Therefore, in rabbit whole blood the antagonists were potent, although not completely selective, inhibitors of PAF induced platelet aggregation. These results suggest that the mode of action of PAF and AA induced platelet aggregation may share some common features. However, since the slope of the inhibitory response against PAF and AA for some antagonists differed, mechanistic differences in their action appear to exist.