THE POTENT INHIBITION OF VAPIPROST, A NOVEL THROMBOXANE A(2) RECEPTORANTAGONIST, ON THE SECONDARY AGGREGATION AND ATP RELEASE OF HUMAN PLATELETS

The inhibitory effects of vapiprost hydrochloride (vapiprost), a novel thromboxane A(2) receptor antagonist, an platelet aggregation and ATP release were studied using platelet rich plasma (PRP) of humans, guin ea pigs, rabbits and rats. In in vitro experiments with human platelet , vapiprost inhibited the aggregation and ATP release stimulated with U-46619, collagen or arachidonic acid (AA) at an IC50 of less than 2.1 x 10(-8) M. Vapiprost did not inhibit the primary aggregation or ATP release of human platelets stimulated with adenosine 5'-diphosphate (A DP), epinephrine (Epi) or platelet activating factor (PAF), but inhibi ted the secondary aggregation stimulated with those agonists at an IC5 0 of less than 1.3 x 10(-7) M. The sensitivity of platelets in various species of animals to vapiprost was in the following order: human gre ater than or equal to guinea pigs > rats > rabbits. In ex vivo experim ents with guinea pigs which received a single oral dose of vapiprost, the agent demonstrated strong inhibition of ATP release from platelets stimulated with U-46619, collagen or AA at an ID50 of less than 25.8 mu g/kg. These inhibitory effects were observed within 30 min and sust ained for 24 h at a single dosage of 5 mg/kg of vapiprost. In AA-induc ed pulmonary infarction models of mice, the sudden death rates decreas ed significantly with the oral administration of 10 mg/kg or more of v apiprost. These results indicate that vapiprost effectively inhibits t he secondary aggregation and ATP release of human platelets stimulated with various agonists, and that guinea pig and human platelets are si milar in response to vapiprost. Furthermore, it was demonstrated in ex vivo experiments with guinea pigs that the inhibitory action of vapip rost appears rapidly and lasts for long periods.