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Effects of the ET A /ET B receptor antagonist, bosentan on endothelin‐1‐induced myocardial ischaemia and oedema in the rat
Author(s) -
Filep János G.,
Fournier Alain,
FöldesFilep Éva
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16657.x
Subject(s) - bosentan , medicine , endothelin receptor , bradycardia , endocrinology , antagonist , receptor antagonist , ventricle , bolus (digestion) , tachycardia , endothelin receptor antagonist , extravasation , endothelin 1 , anesthesia , receptor , blood pressure , heart rate , immunology
1 The purposes of this study were to assess the role of ET B receptors in mediating endothelin‐1 (ET‐1)‐induced myocardial ischaemia and oedema in rats and to study the inhibitory action of the novel non‐pep tide 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 (1 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 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 ET B 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 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‐1‐induced myocardial ischaemia and oedema in the rat, and suggest the therapeutic potential for bosentan in the treatment of ischaemic myocardial diseases.