Endothelin receptors mediating contraction in goat cerebral arteries

Abstract

1 The aim of the present study was to identify the subtype of receptor mediating contraction to endothelin-1 and sarafotoxin S6b in goat isolated middle cerebral arteries. 2 Endothelin-1, endothelin-2 and endothelin-3 contracted cerebral arteries in a concentration-dependent manner. Although the three peptides were full agonists, the order of potency was endothelin-1 = endothelin-2 > endothelin-3, with a relative potency of endothelin-1 and endothelin-2 versus endothelin-3 of -280. Sarafotoxin S6b induced concentration-dependent contractions with lower potency than endothelin-1 /endothelin-2, higher potency than endothelin-3 and a higher maximum response than the three endothelins.3 The selective ETA-receptor antagonist, BQ-123, did not induce changes in either the resting tension or in the active tone developed by depolarization. In contrast, BQ-123 produced concentrationdependent relaxations of endothelin-1-precontracted cerebral arteries, and to a greater extent of sarafotoxin S6b-precontracted arteries. 4 Concentration-response curves to endothelin-1 and sarafotoxin S6b were competitively antagonized by BQ-123 (pA2 of 7.43 ± 0.12 and 8.41 ± 0.09, respectively). In contrast, BQ-123 had no effect on 5-hydroxytryptamine-elicited contractions even at 10-6 M. 5 It is concluded that both the order of potency of endothelin isopeptides and the antagonism of BQ-123 point to the existence of ETA receptors mediating vasoconstriction to endothelin-1 and sarafotoxin S6b in the goat middle cerebral artery. The different antagonistic potency of BQ-123 against endothelin-I and sarafotoxin S6b suggests the existence of subtypes of ETA receptors.

Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

“…For example, we and others have previously demonstrated that BQ123 is a more potent inhibitor of S6b-mediated vascular responses than ET-1 (Bodelsson and Stjernquist, 1993;Maguire et al, 1996;Salom et al, 1993). Data from our present study provide evidence that the affinity of BQ123 as an antagonist of ET A -mediated β-arrestin recruitment was agonist-dependent, consistent with an allosteric mode of action of this compound [44] (Sokolowsky, 1993) whereas in the ET B assay BQ788 did not distinguish between the different agonists.…”

Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries

“…Furthermore, the inhibitory effect of BQ 123 on the ET-l-induced contraction seemed to be less than would have been anticipated for a pure ETA receptor-mediated response. Assuming a competitive inhibition at a single receptor population, the rightward shift of the ET-1 concentration-response curve produced by BQ 123 would yield a pKB value of 6.3, which is below the range of pA2 values (6.9-7.4) previously reported for vasoconstrictor responses claimed to be mediated by ETA receptors (Ihara et al 1992;Sumner et al 1992;Salom et al 1993;Feger et al 1994). This could indicate that ETB receptors also contribute to the endothelin-induced contractile responses in the rabbit basilar artery.…”

“…Previous studies of cerebral arteries from man (Adner et al 1994;Davenport et al 1995), goat (Salom et al 1993), rat (Feger et al 1994) and guinea-pig (Adner et al 1993) have indicated the presence of ETA receptors mediating vasoconstriction in these vessels. In the present study, the order of potency of the endothelins (ET-1 > ET-3) was in accordance with the properties of an ETA receptor (Masaki et al 1994).…”

Comparison of the contractile effects and binding kinetics of endothelin‐1 and sarafotoxin S6b in rat isolated renal artery

“…In preparations containing ET A receptors, for example, BQ‐123 is frequently more potent in inhibiting contractions induced by sarafotoxin S6b (StxS6b) and ET‐3, than similar responses to ET‐1. Such agonist‐dependent antagonist potency has been observed in rat aorta (Sumner et al , 1992), goat cerebral artery (Salom et al , 1993), human saphenous vein (Bax et al , 1993), human coronary artery (Godfraind, 1993), human umbilical artery (Bodelsson & Sjernquist, 1993) and human omental vein (Riezebos et al , 1994), as well as in rat vas deferens (Eglezos et al , 1993). These findings have prompted speculation concerning the possible existence of a population of BQ‐123‐insensitive ET A receptors (see Bax & Saxena, 1994 for review).…”