Role of endogenous endothelin in extension of rabbit myocardial infarction.
The role of endogenous endothelin-1 (ET-1) in myocardial infarction was investigated in a rabbit ischemia-reperfusion model and in rabbit Langendorff hearts. AwETN40, a monoclonal antibody against ET-1, at 10 mg/kg i.v. inhibited hypertension and hypotension induced by ET-1 (0.3 nmol/kg i.v.): about 70-100% inhibition lasted for 24 h. In a coronary occlusion (30 min)-reperfusion (24 h) model, AwETN40 (10 mg/kg i.v.) reduced the infarct size from 60.9 +/- 4.6% (infarct region/ischemic region in weight, IgG1 kappa control; n = 5) to 37.1 +/- 5.2% (n = 5, p < 0.05). Plasma ET-1 levels were increased significantly by coronary occlusion-reperfusion and returned to control level 24 h after reperfusion. Effects of ET-1 on the coronary vessels and cardiac contractility were studied in the Langendorff heart. ET-1 increased the perfusion pressure from concentrations as low as 10 pM, whereas the developed left ventricular pressure was not altered. These results suggest that ET-1 decreases oxygen supply to the cardiac muscles by constricting coronary vessels and that this, in turn, worsens the ischemic condition of the heart to extend the infarct size.
Kusumoto
K
K
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Awane
Y
Y
Fujiwara
S
S
Watanabe
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects; D004195:Disease Models, Animal; D016232:Endothelins / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D011817:Rabbits
D000911:Antibodies, Monoclonal; D016232:Endothelins