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.
1. 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. 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 tmol kg'; 8 min before ET-1) did not modify the early effect of [Ala'3""5]ET-l, 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 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""l '5]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.
Bigaud
M
M
Marion Merrell Dow Research Institute, Strasbourg, France.
Pelton
J T
JT
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007083:Iliac Artery / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects; D014465:Ultrasonics; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C061779:endothelin 1, Ala(1,3,11,15)-; C072247:cyclo(Trp-Asp-Pro-Val-Leu)