Effects of an ET1‐receptor antagonist, FR139317, on regional haemodynamic responses to endothelin‐1 and [Ala11,15]Ac‐endothelin‐1 (6–21) in conscious rats

Abstract

1. In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ETB-receptor agonist, [Ala1,3,11,15]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala1,3,11,15]ET-1 (0.15, 0.3, 1 and 10 nmol kg-1) from MCL caused dose-dependent pressor 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 [Ala1,3,11,15]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent pressor effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala1,3,11,15]ET-1 from MLC may activate ETB-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2. We also assessed responses to the putative ETB-receptor agonist, [Ala11,15]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ETA-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent pressor 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 pressor 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 ETB-receptors. 4. FR139317 (0.5 mumol kg-1) caused attenuation of the pressor, 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 pressor and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant pressor 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-1 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 ETA-receptors or ETB-receptors, or ETA- and ETB-receptors, depending on the dose of agonist and the regional haemodynamic effect considered.