Girinimbine is an antiplatelet agent isolated from Murraya euchrestifolia. In washed rabbit platelets, it inhibited arachidonic acid (AA)-, collagen-, U46619- and platelet-activating factor (PAF)- induced aggregation and ATP release in a concentration-dependent manner with ic50 values of 9.1 ± 1.5, 16.7 ± 1.7, 60.0 ± 5.1 and 71.9 ± 5.6 μM, respectively. However, it did not apparently affect thrombin-induced aggregation and ATP release even when a concentration of 80 μM was used. In citrated human platelet-rich plasma (PRP), girinimbine selectively inhibited secondary aggregation and ATP release without appearing to affect the primary aggregation induced by epinephrine and ADP. The formation of both platelet thromboxane B2 (TxB2) and prostaglandin D2 (PGD2) caused by AA was inhibited by girinimbine concentration dependently, with a maximal effect at 20 μM. Girinimbine also inhibited cyclooxygenase activity as reflected by the attenuation of prostaglandin E2 (PGE2) formation after incubation of sheep vesicular gland microsomes with arachidonic acid. In myo-[3H]inositol-labeled and fura-2-loaded platelets, [3H]inositol monophosphate generation and the increase in intracellular Ca2+ ([Ca2+]i) stimulated by AA and collagen, but not that stimulated by U46619, PAF and thrombin, were inhibited by girinimbine (20 μM). Platelet cyclic AMP levels were elevated by high concentrations of girinimbine (20 and 80 μM). These data indicate that the antiplatelet effect of girinimbine is due to the inhibition of cyclooxygenase activity and elevation of the cyclic AMP level.
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