title: Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats.
abstract: 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 [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 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 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 ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Awane
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: S
authors.initials: S
authors.lastname: Fujiwara
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: K
authors.initials: K
authors.lastname: Kusumoto
authors.forename: M
authors.initials: M
authors.lastname: Wakimasu
authors.forename: M
authors.initials: M
authors.lastname: Fujino
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D008566:Membranes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013552:Swine
chemical_list: D065128:Endothelin Receptor Antagonists; D007457:Iodine Radioisotopes; D010456:Peptides, Cyclic; C088196:TAK 044