THE SNAKE-VENOM PEPTIDE SARAFOTOXIN S6B INHIBITS REPETITIVE PLATELET THROMBUS FORMATION IN THE STENOSED CANINE CORONARY-ARTERY

Various snake venom peptides have been extensively evaluated for use a s antithrombotic agents. Recently, it was determined that the snake ve nom peptide sarafotoxin S6b (S6b) is structurally similar to the poten t vasoactive hormone endothelin-1 (ET-1), which has been shown to inhi bit agonist-induced platelet aggregation. The potential in vivo antith rombotic activity of S6b was compared with that of ET-1, a much more p otent pressor agent than S6b, by evaluating the effects of S6b and ET- 1 (0.5 mug/kg i.v.) on repetitive platelet thrombus formation (RPTF) i n the stenosed canine circumflex coronary artery. In this model platel ets adhere to the damaged vessel wall near a mechanically produced ste nosis. As platelets aggregate at this site, blood flow gradually decli nes until the vessel is completely occluded. The thrombus is then phys ically dislodged, thus restoring flow. The blood flow pattern resultin g from RPTF is referred to as cyclic flow reductions (CFRs). Injection of S6b or ET-1 blocked RPTF, as indicated by inhibition of CFRs. On a rating system of 0 (no effect) to 3 (complete inhibition), S6b and ET -1 produced CFR ratings of 1.8 +/- 0.5 (n = 6) and 2.0 +/- 0.4 (n = 6) , respectively. This effect was not blocked by pretreatment with aspir in at 5 mg/kg i.v., a dose that abolishes arachidonic acid-induced ex vivo platelet aggregation (CFR scores for S6b and ET-1 were 2.6 +/- 0. 2, n = 5 and 2.0 +/- 0.3, n = 5, respectively). However, administratio n of aspirin at 30 mg/kg i.v. significantly inhibited the antithrombot ic effect of S6b and ET-1 (CFR scores of 0.6 +/- 0.4, n = 5 and 0.5 +/ - 0.5, n = 4). S6b and ET-1 produced a transient decrease in blood pre ssure that was attenuated by pretreatment with aspirin at 30 mg/kg but not at 5 mg/kg. ET-1 produced a significant, delayed increase in bloo d pressure, but S6b did not increase blood pressure. These results sug gest that the antithrombotic activity of S6b and ET-1 is mediated by p rostacyclin release from endothelial cells, and that the vasoactive ch aracteristics of this family of peptides do not necessarily correlate with their antithrombotic activity.