Discrimination between ETA‐ and ETB‐receptor‐mediated effects of endothelin‐1 and [Ala1,3,11,15]endothelin‐1 by BQ‐123 in the anaesthetized rat

Abstract

The influence of BQ‐123 (a selective ETA‐receptor antagonist) on the haemodynamic response elicited by endothelin‐1 (ET‐1) and [Ala1,3,11,15]ET‐1 (a selective ETB‐receptor agonist) was studied in anaesthetized rats instrumented with ultrasonic Doppler flow probes on the carotid, coeliac, mesenteric, renal and iliac arteries. BQ‐123 alone (1.6 μmol kg−1, i.v.) induced a decrease in femoral mean arterial pressure (AP), accompanied by a systemic vasodilatation. The response was maximal after 3 min and then returned slowly to baseline. None of these effects was observed after a 0.016 μmol kg−1 dose of BQ‐123. ET‐1 (1 nmol kg−1, i.v.) induced a biphasic response characterized by a transient initial decrease in AP accompanied by regional vasodilatation (mainly in the carotid and iliac beds) and by immediate mesenteric and renal vasoconstrictions. This was followed, within 1 min, by a marked and prolonged increase in AP accompanied by systemic vasoconstriction. Pretreatment with BQ‐123 (1.6 μmol kg−1, i.v., 8 min before ET‐1) increased and prolonged the vasodilator effect of ET‐1 (mainly in the carotid, coeliac, mesenteric and iliac beds) and reduced its systemic vasoconstrictor effects with marked regional differences (the coeliac, mesenteric and renal beds being poorly affected). [Ala1,3,11,15]ET‐1 (3 nmol kg−1, i.v.) induced an initial and marked decrease in AP accompanied by regional vasodilatation (mainly in the carotid, coeliac and iliac beds) and by mesenteric and renal vasoconstrictions. This was followed, within 5 min, by a small increase in AP and systemic vasoconstriction. All these effects were dose‐dependent. Pretreatment with BQ‐123 (1.6 μmol kg−1; 8 min before ET‐1) did not modify the early effect of [Ala1,3,11,15]ET‐1, but abolished its secondary vasoconstrictor effect except in the mesenteric bed. This study demonstrates that pretreatment with BQ‐123 not only reduced a large part of the sustained vasoconstrictor activity of ET‐1, suggesting the involvement of ETA‐receptors, but also enhanced the early vasodilator activity of ET‐1 revealing a functional antagonism between the two effects. The vasodilator effect of [Ala1,3,11,15]ET‐1 was not affected by BQ‐123 and ET‐1 induced a similar vasodilatation, that was potentiated by BQ‐123, suggesting the involvement of ETB‐receptors in this vasodilator response. Marked regional differences were however observed which might be partly related to different levels of functional antagonism between ETB‐ and ETA‐mediated effects, but differences in receptor types, or subtypes, cannot be excluded, mainly in the mesenteric and renals beds. 1992 British Pharmacological Society