Antithrombotic efficacy of MV1 serine protease in a canine model of unstable angina

Objective To determine the antiplatelet and antithrombotic efficacies of MV1 serine protease on coronary arterial thrombosis in a canine model of unstable angina.Methods Pentobarbital-anesthetized Beagles(total of 30)were used in which acute damage of the proximal left circumflex coronary artery,together with mechanical stenosis,produced the phenomenon of cyclic flow reduction(CFR)in the Folts model of unstable angina.When the platelet plug was removed by rubbing the vessel,the occlusion returned reproducibly for at least 3 hours in control studies.To evaluate the antithrombotic efficacy of MV1,CFR was first established over a period of one hour,thereafter,MV1(0.3,0.6 mg·kg-1 i.v.bolus),Batroxobin(0.3 BU·kg-1 i.v.bolus),Tirofiban(40 μg·kg-1,i.v.bolus),or vehicle was administered and observations continued for two additional hours.Platelet aggregation induced by adenosine diphosphate(ADP),arachidonic acid(AA),collagen(CG)was measured by the method of born,and thrombin time(TT),prothrombin time(PT),activated partial thromboplastin time(APTT)and fibrinogen(Fbg)were measured using coagulation methods,bleeding time was measured according to previous described methods.Results MV1 dramatically inhibited the frequency of CFR dose-dependently and the frequency of CFR decreased by 65%,80% respectively at 1 h than that in control group's after MV1 0.3,0.6 mg·kg-1 administration,further more the frequency decreased by 75%,90% respectively at 2 h.MV1 eliminated thrombus formation in 5 of 6 dogs at 0.6 mg·kg-1,and the time for CFR absolute disappearances of MV1 at a dose of 0.6 mg·kg-1 was shortened to 5±2 min(the time was more than 120 min in all dogs of control group).Platelet aggregation induced by ADP,AA,CG was inhibited effectively by MV1 0.3,0.6 mg·kg-1 TT,PT prolonged gently after MV1 administration,and MV1 produced an approximate 40% degradation of Fbg,but MV1 did not have any effects on APTT.There was a tendency for prolonged bleeding time with MV1 administration.Conclusions These studies showed that as a novel serine protease,MV1 provides favorable antithrombotic activity in vivo with inhibition of platelet aggregation and fibrinogenolytic activity.The results indicated that MV1 has reliable therapeutical efficacy on unstable angina pectoris.