Endothelin‐1‐induced myocardial ischaemia and oedema in the rat: involvement of the ET_A receptor, platelet‐activating factor and thromboxane A₂

Abstract

1 The objectives of the present experiments were to assess the role of ETA receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of plateletactivating factor (PAF) and thromboxane A2 (TxA2) in these actions of ET-1 in rats. 2 Intravenous bolus injection of ET-1 (0.1-2 nmol kg-') 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 ETA receptor antagonist, FR 139317 (2.5 mg kg-', i.v.) inhibited by 86% the ST segment elevation elicited by ET-l (1 nmol kg-1). Pretreatment with intravenous administration of BM 13505 (1 mg kg-'), a TxA2 receptor antagonist, OKY-046 (10 mg kg-'), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg-') or BN 52021 (10 mg kg-') markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg-' bolus plus 2 mg kg-' h-') did not significantly affect ET-1-induced ST segment elevation. 4 Bolus injection of ET-1 (1 nmol kg-', i.v.) to conscious rats resulted in a prolonged pressor effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia. ET-l 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 ETA receptor antagonist, FR 139317 (2.5 mg kg-') significantly blunted the pressor action of ET-1 and the accompanying bradycardia without affecting the depressor response. Furthermore, FR 139317 almost completely abolished the permeability effect of ET-l in both vascular beds studied. 6 Pretreatment of the animals with BM 13505 (1 mg kg-'), OKY-046 (10mg kg-'), WEB 2086 (1 mg kg-') or BN 52021 (10 mg kg-') significantly reduced ET-1 (1 nmol kg-')-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-' plus 2 mg kg-' h-') did not modify the permeability response to ET-1. None of these compounds affected significantly ET-l-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 TxA2 via the activation of ETA receptors.

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ETA and ETB receptors

“…Given that ETB receptors predominate on vascular endothelial cells (Hosoda et al, 1991), ET-1 and IRL 1620 may induce gap formation directly via activation of ETB receptors or through release of secondary mediators such as platelet-activating factor (Filep et al, 1991) or thromboxane A2 (Filep et alt, 1994) or both. Release of secondary mediators may be mediated via ETA receptors as has been reported for the rat coronary circulation (Filep et al, 1994). Regardless of the mechanisms underlying gap formation, attenuation of ET-1-induced pulmonary vasoconstriction by FR 139317 or bosentan would lead to a reduction of capillary hydrostatic pressure, which, in turn, could result in a decrease in albumin extravasation.…”

Antiischemic Properties of Fasudil in Experimental Models of Vasospastic Angina

“…Endothelin is a potent constrictor of coronary arteries (15). Furthermore, administration of endothelin evokes ECG changes (10,16), similar to the clinical phenomenon of angina, especially variant angina. Yamamoto et al (10) reported that endothelin induced myocardial dysfunction in rabbits and fasudil prevented the occurrence of endothelin-induced ischemic myocardial injury.…”

Effects of the ETA/ETB receptor antagonist, bosentan on endothelin‐1‐induced myocardial ischaemia and oedema in the rat

“…Furthermore, intracoronary or intravenous administration of ET-1 evokes ST segment elevations of the electrocardiogram, similar to the clinical phenomenon of Prinzmetal angina (Harada et al, 1993;Filep et al, 1994b) and enhances myocardial oedema formation in the rat (Filep et al, 1992;1994b).…”

“…Previous studies demonstrated that both intracoronary and intravenous administration of ET-1 elevates coronary resistance and induces ST segment elevations in rats, whereas arrhythmias could only be observed following intracoronary administration of the peptide (Harada et al, 1993;Filep et al, 1994b). It should be noted that following i.v.…”

“…vitro studies and experiments using isolated perfused hearts suggested that all of these three receptor subtypes may mediate the vasoconstrictor action of ET-1 (see Rubanyi & Polokoff, 1994). Our previous findings that the ETA receptor-selective antagonists, BQ-123 and FR 139317 effectively, though not completely, attenuated ET-1-induced ischaemia and oedema in the rat coronary circulation (Filep et al, 1992;1994b) indicated a role for ET receptor subtypes other than ETA in these events. The aim of the present experiments was to assess the involvement of ETB receptors by comparing the inhibitory effects of the novel ETA/ETB receptor antagonist, bosentan (Clozel et al, 1994) to those of the ETA receptor-selective antagonist, FR 139317 (Aramori et al, 1993;Sogabe et al, implanted into the abdominal aorta and vena cava as described previously (Filep & Fejes-Toth, 1986).…”