Dissociation of antiplatelet effects from myocardial cytoprotective activity during acute myocardial ischemia in cats by a new carbacyclin derivative (ZK 36 375).
We studied the potential therapeutic value of the chemically stable carbacyclin analogue ZK 36 375 during acute myocardial ischemia and compared the cardiovascular and anti- and disaggregatory effects of the compound in vitro and ex vivo. In anesthetized cats the left anterior descending coronary artery was ligated, and 30 min later an intravenous infusion of ZK 36 375 (3.6 micrograms/kg X min) or vehicle was initiated and continued for 4.5 h. ZK 36 375 reduced the ST-segment elevation at 2-5 h (p less than 0.01) when compared to vehicle-treated cats. ZK 36 375 significantly inhibited both the loss of creatine phosphokinase--specific activity and the decrease in the percentage of bound cathepsin D in the infarcted area of the myocardium (p less than 0.05). ZK 36 375 did not reverse ischemia-induced formation of platelet aggregates in vivo and was found ex vivo to be two to three orders of magnitude less active in preventing platelet aggregation, redispersing platelet aggregates, and relaxing bovine coronary arteries than prostacyclin (PGI2) or its (5E) stereoisomer ZK 36 374. It is concluded that ZK 36 375 has a significant cardioprotective activity in acute myocardial ischemia of the cat that can be dissociated from antiplatelet effects in vivo.
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002402:Cathepsin D; D002403:Cathepsins / Q000378:metabolism; D002415:Cats; D002417:Cattle; D003327:Coronary Disease / Q000503:physiopathology*; D003331:Coronary Vessels / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D016285:Iloprost; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000494:pharmacology*; D013237:Stereoisomerism
D011453:Prostaglandins; D011464:Epoprostenol; D003402:Creatine Kinase; D002403:Cathepsins; D002402:Cathepsin D; D016285:Iloprost