PHARMACOLOGY OF A NONSELECTIVE ET(A) AND ET(B) RECEPTOR ANTAGONIST, TAK-044 AND THE INHIBITION OF MYOCARDIAL INFARCT SIZE IN RATS

1 The aims of the present study were to characterize the pharmacologic al profile of a new endothelin (ET) receptor antagonist, TAK-044 and t o consider whether it limits the extension of myocardial infarct size in rats. 2 Binding of [I-125]-ET-1 to ET receptors on rabbit ventricul ar and cerebellar membrane fractions was inhibited by TAK-044 with IC5 0 values of 3.8 nM and 130 nM, respectively. 3 It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteri es in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4 In the Pat in vivo, the ET-l-induced blood pressure changes includin g transient hypotension followed by sustained hypertension, were inhib ited by TAK-044 (0.1-10 mg kg(-1), i.v.) in a dose-dependent manner. 5 Acute myocardial infarction induced by 1 h coronary occlusion followe d by 24 h reperfusion in rats caused an infarct size of 60 +/- 2% (n = 12) of the area-at-risk by weight. 6 Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-d ependent manner: 32% and 54% reductions at 1 and 3 mg kg(-1), respecti vely. 7 TAK-044 administered 10 min before or Ih after reperfusion (1 mg kg(-1), i.v.) showed similar inhibitory effects: 34% and 23% reduct ions, respectively. 8 We conclude that TAK-044 is an ET(A)/ET(B) recep tor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.