ENDOTHELIN-1-INDUCED MYOCARDIAL-ISCHEMIA AND EDEMA IN THE RAT - INVOLVEMENT OF THE ET(A) RECEPTOR, PLATELET-ACTIVATING-FACTOR AND THROMBOXANE A(2)

1 The objectives of the present experiments were to assess the role of ET(A) receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of platelet-activating factor (PAF) and thromboxane A(2) (TxA(2)) in these actions of ET-1 in rats. 2 Intravenous bolus injection of ET-1 (0.1-2 nmol kg(-1)) into anaesthetized rats induced ST segment elevation of the electrocardiogram in a dose-dependent manner without causing arrhythmias. ST segment elevation developed within 20-90 s and persisted for at least 10-20 min following administration of ET-1. 3 Pretreatment of the animals with the selective endothelin ET(A) receptor antagonist, FR 139317 (2.5 mg kg(-1), i.v.) inhibited by 86% the ST segment elevation elicited by ET-1 (1 nmol kg(-1)). Pretreatment with intravenous administration of BM 13505 (1 mg kg(-1)), a TxA(2) receptor antagonist, OKY-046 (10 mg kg(-1)), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg(-1)) or BN 52021 (10 mg kg(-1)) markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg(-1) bolus plus 2 mg kg(-1) h(-1)) did not significantly affect ET-1-induced ST segment elevation. 4 Bolus injection of ET-1 (1 nmol kg(-1), i.v.) to conscious rats resulted in a prolonged presser effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia. ET-1 enhanced albumin leakage by 87 and 120% in the left ventricle and right atrium, respectively, as measured by the extravasation of Evans blue dye. 5 The selective ET(A) receptor antagonist, FR 139317 (2.5 mg kg(-1)) significantly blunted the presser action of ET-1 and the accompanying bradycardia without affecting the depressor response. Furthermore, FR 139317 almost completely abolished the permeability effect of ET-1 in both vascular beds studied. 6 Pretreatment of the animals with BM 13505 (1 mg kg(-1)), OKY-046 (10 mg kg(-1)), WEB 2086 (1 mg kg(-1)) or BN 52021 (10 mg kg(-1)) significantly reduced ET-1 (1 nmol kg(-1))-induced albumin extravasation both in the left ventricle and right atrium. The PAF receptor antagonists, WEB 2086 and BN 52021 were equally potent inhibitors in the left ventricle, whereas BN 52021 appeared to be a more potent inhibitor than WEB 2086 in the right atrium. Pretreatment with indomethacin (3 mg kg(-1) plus 2 mg kg(-1) h(-1)) did not modify the permeability response to ET-1. None of these compounds affected significantly ET-1-induced changes in mean arterial blood pressure and heart rate. 7 These results indicate that intravenous administration of ET-1 provokes ST segment elevation and myocardial oedema and suggest that these events are mediated, in part, through release of secondary mediators, such as PAF and TxA(2) via the activation of ET(A) receptors.