DISCRIMINATION BETWEEN ETA-RECEPTOR-MEDIATED AND ETB-RECEPTOR-MEDIATED EFFECTS OF ENDOTHELIN-1 AND [ALA1,3,11,15]ENDOTHELIN-1 BY BQ-123 IN THE ANESTHETIZED RAT

1 The influence of BQ-123 (a selective ET(A)-receptor antagonist) on the haemodynamic response elicited by endothelin-1 (ET-1) and [Ala1,3,11,15]ET-1 (a selective ET(B)-receptor agonist) was studied in anaesthetized rats instrumented with ultrasonic Doppler flow probes on the carotid, coeliac, mesenteric, renal and iliac arteries. 2 BQ-123 alone (1.6 mumol 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 mumol kg-1 dose of BQ-123. 3 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 mumol 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). 4 [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 mumol 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. 5 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 ET(A)-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 ET(B)-receptors in this vasodilator response. Marked regional differences were however observed which might be partly related to different levels of functional antagonism between ET(B)- and ET(A)-mediated effects, but differences in receptor types, or subtypes, cannot be excluded, mainly in the mesenteric and renals beds.