A New Model for Antiplatelet Drug Discovery

Abstract

Circulating platelet aggregates (CPA) have been observed by Wu and Hoak (Lancet 2: 294, 1974) in the blood of patients with transient ischemic attacks, acute myocardial infarction and acute peripheral arterial insufficiency. We have discovered that retired breeder (RB) male rats have spontaneous CPA which respond to therapy with clinically proven antiplatelet drugs. CPA are described as the ratio of the platelet count from blood drawn into a citrate/formalin solution compared to the platelet count from blood drawn into a citrate solution. A platelet aggregate ratio (PAR) of 1.0 is indicative of the absence of CPA. The PAR of 24 virgin male rats (0.94 ± .02, S.E.M.) was significantly greater (P<0.01) than that of 34 male RB rats (0.77 ± .02)-indicating the presence of increased CPA in the RB rats. Acetylsalicylic acid (ASA) and sulfinpyrazone (S) have been successfully used clinically in patients with CPA and transient ischemic attacks (Stroke 6: 521, 1975).RB rats treated with ASA or S (100 mg/kg/ day, i.g. for 8 days) demonstrated significantly (P < 0.01) increased PAR of 0.88 ± 0.02 and 0.99 ± 0.02 respectively. In vitro responses of RB platelets in citrate-treated platelet-rich plasma to adenosine diphosphate (0.4 yM to 3 uM/109 platelets) and collagen (420 μg to 1470 μg/109 platelets) were similar in sensitivity to platelets from virgin rats. This suggests that the hyperactivity of RB rat platelets expressed as CPA is related to an increased aggregate stimulation in vivo. The results indicate that the male RB rat may be a useful model for the preliminary evaluation of therapeutically useful antiplatelet agents.