EFFECTS OF AN ET(1)-RECEPTOR ANTAGONIST, FR139317, ON REGIONAL HEMODYNAMIC-RESPONSES TO ENDOTHELIN-1 AND [ALA(11,15)]AC-ENDOTHELIN-1 (6-21) IN CONSCIOUS RATS

1 In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ET(B)-receptor agonist, [Ala(1,3,11,15)]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala(1,3,11,15)]ET-1 (0.15, 0.3, 1 and 10 nmol kg(-1)) from MLC caused dose-dependent presser effects, accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances; there was an initial hyperaemic vasodilatation in the hindquarters which was not dose-dependent, and only with the highest dose was there a subsequent vasoconstriction. There was no significant initial depressor response to [Ala(1,3,11,15)]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent presser effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala(1,3,11,15)]ET-1 from MLC may activate ET(B)-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2 We also assessed responses to the putative ET(B)-receptor agonist, [Ala(11,15)]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ET(A)-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent presser effects (ET-1, 0.5 nmol kg(-1), BQ-3020, 10 nmol kg(-1)), and also at doses that did not affect mean arterial blood pressure, but which were matched for their renal vasoconstrictor effects (ET-1, 7.5 pmol kg(-1); BQ-3020, 0.15 nmol kg(-1)). 3 BQ-3020 (0.15, 0.3 and 1 nmol kg(-1)) had dose-dependent presser effects accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances. BQ-3020 at a dose of 10 nmol kg(-1) elicited an initial depressor response which coincided with an attenuated mesenteric vasoconstrictor effect, accompanying a marked hindquarters vasodilatation. Hence, it appears that BQ-3020 may activate both vasoconstrictor and vasodilator ET(B)-receptors. 4 FR139317 (0.5 pmol kg(-1)) caused attenuation of the presser, and renal, mesenteric and hindquarters vasoconstrictor effects of ET-1 (0.5 nmol kg(-1)) and of BQ-3020 (10 nmol kg(-1)), but the reductions of the presser and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant presser and renal, mesenteric and hindquarters vasoconstrictor responses to ET-1 and BQ-3020 still occurred, and the initial depressor and hindquarters vasodilator responses to both peptides were unchanged. 5 ET-1 at a dose of 7.5 pmol kg(-1) and BQ-3020 at a dose of 0.15 nmol kg(-1) had similar renal vasoconstrictor effects. However, the response to ET-1 was almost abolished by FR139317 whereas that to BQ-3020 was unaffected. Moreover, under these conditions, the mesenteric vasoconstrictor and hindquarters vasodilator responses to ET-I and to BQ-3020 were not changed by FR139317. 6 Collectively, these results are consistent with the haemodynamic effects of ET-1 and BQ-3020 involving ET(A)-receptors or ET(B)-receptors, or ET(A)- and ET(B)-receptors, depending on the dose of agonist and the regional haemodynamic effect considered.