EFFECTS OF THE ET(A)/ET(B) RECEPTOR ANTAGONIST, BOSENTAN ON ENDOTHELIN-1-INDUCED MYOCARDIAL-ISCHEMIA AND EDEMA IN THE RAT

1 The purposes of this study were to assess the role of ET(B) receptors in mediating endothelin-l (ET-1)-induced myocardial ischaemia and oedema in rats and to study the inhibitory action of the novel nonpeptide ET(A)/ET(B) 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 (I nmol kg(-1)) compared to the 82% inhibition observed with the ET(A) 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 presser 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 presser actions of ET-1 (1 nmol kg(-1)) and the accompanying tachycardia and bradycardia, respectively. FR 139317 (2.5 mg kg(-1)) attenuated the presser response to ET-I and accompanying bradycardia by 75%, without affecting the depressor action and accompanying tachycardia. ET-l-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 ET(B) receptor-selective agonist, IRL 1620 (0.3 and 1 nnol kg(-1), i.v.) also produced dose-dependent ST segment elevation in anaesthetized rats and enhanced albumin extravasation (up to 141% of control) in the left ventricle and right atrium, respectively, in conscious rats. These effects of IRL 1620 were completely prevented by bosentan (10 mg kg(-1)). 7 These results indicate that ET(B) receptors, albeit to a lesser extent than ET(A) receptors, are also involved in mediating ET-l-induced myocardial ischaemia and oedema in the rat, and suggest the therapeutic potential for bosentan in the treatment of ischaemic myocardial diseases.