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Pharmacology of a non‐selective ET A and ET B receptor antagonist, TAK‐044 and the inhibition of myocardial infarct size in rats
Author(s) -
Watanabe Toshifumi,
Awane Yumiko,
Ikeda Shota,
Fujiwara Shuji,
Kubo Kazuki,
Kikuchi Takashi,
Kusumoto Keiji,
Wakimasu Mitsuhiro,
Fujino Masahiko
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13296.x
Subject(s) - antagonist , pharmacology , chemistry , receptor , medicine
1 The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK‐044 and to consider whether it limits the extension of myocardial infarct size in rats. 2 Binding of [ 125 I]‐ET‐1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK‐044 with IC 50 values of 3.8 n m and 130 n m , respectively. 3 It inhibited ET‐1, ET‐2 and ET‐3‐induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET‐1, ET‐2) and a non‐competitive (ET‐3) manner. 4 In the rat in vivo , the ET‐1‐induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited 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 followed 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‐dependent manner: 32% and 54% reductions at 1 and 3 mg kg −1 , respectively. 7 TAK‐044 administered 10 min before or 1 h after reperfusion (1 mg kg −1 , i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8 We conclude that TAK‐044 is an ET A /ET B receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion‐reperfusion in rats.