Effects of the ETA/ETB receptor antagonist, bosentan on endothelin-1-induced myocardial ischaemia and oedema in the rat.
1. The purpose of this study were to assess the role of ETB receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema in rats and to study the inhibitory action of the novel nonpeptide ETA/ETB receptor antagonist, bosentan on these actions of ET-1. 2. Intravenous bolus injection of ET-1 (1 nmol kg-1) into anaesthetized rats produced marked ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30-50 s and persisted for at least 30 min following injection of the peptide. 3. Pretreatment of the animals with bosentan (10 mg kg-1, i.v.) inhibited on average by 96% the ST segment elevation elicited by ET-1 (1 nmol kg-1) compared to the 82% inhibition observed with the ETA receptor-selective antagonist, FR 139317 (2.5 mg kg-1, i.v.). 4. Bolus injection of ET-1 (1 nmol kg-1, i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged pressor effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. ET-1 (1 nmol kg-1) enhanced albumin extravasation by 119 and 93% in the left ventricle and right atrium, respectively, as measured by the local extravascular accumulation of Evans blue dye. 5. Pretreatment of the animals with bosentan (10 mg kg-1) inhibited by 71 and 90% the depressor and pressor actions of ET-1 (1 nmol kg-1) and the accompanying tachycardia and bradycardia, respectively. FR 139317 (2.5 mg kg-1) attenuated the pressor response to ET-1 and accompanying bradycardia by 75%, without affecting the depressor action and accompanying tachycardia. ET-1-induced albumin extravasation was completely inhibited by bosentan (10 mg kg-1) both in the left ventricle and right atrium, compared to the 86% inhibition observed with FR 139317 (2.5 mg kg-1).6. Like ET-1, the ETB receptor-selective agonist, IRL 1620 (0.3 and 1 nmol kg-1, i.v.) also produced dose-dependent ST segment elevation in anaesthetized rats and enhanced albumin extravasation (up to141% of control) in the left ventricle and right atrium, respectively, in conscious rats. These effects ofIRL 1620 were completely prevented by bosentan (10 mg kg-1).7. These results indicate that ETB receptors, albeit to a lesser extent than ETA receptors, are also involved in mediating ET-1-induced myocardial ischaemia and oedema in the rat, and suggest the therapeutic potential for bosentan in the treatment of ischaemic myocardial diseases.
Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, P.Q., Canada.
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D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D000077300:Bosentan; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy*; D004562:Electrocardiography; D016232:Endothelins / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*
D016232:Endothelins; D013449:Sulfonamides; D000077300:Bosentan