Pharmacological characterization of endothelin receptors in the rabbit iris sphincter muscle: suggestion for the presence of atypical receptors.

Abstract

Pharmacological profiles of endothelin (ET) receptors in the isolated rabbit iris sphincter were characterized. ET isopeptides caused dose-dependent contraction of the preparation. The respective EC50 values for ET-1, ET-2 and ET-3 were 39.4, 58.0 and 84.3 nM, so that ET-1 was twice as potent as ET-3. Sarafotoxin (SRTX) -b, an ET(A)/ET(B) non-selective agonist, caused very potent contraction with an EC50 of 1.13 nM. However, selective ET(B) receptor agonists SRTX-c and IRL 1620 showed no contractile activity up to 1 microM. BQ-123, a selective ET(A) receptor antagonist, shifted the dose-response curves of ET isopeptides to the right. The pA2 value for ET-1 was 5.52 with a slope of 1.06, which is not different from unity, and the pK(B) value for ET-2 was 5.06. Interestingly, very low doses of BQ-123 antagonized responses to ET-3 and SRTX-b, with a Schild plot slope of approximately 0.7 which is significantly different from unity, suggesting receptor heterogeneity. The abscissal intercepts of the Schild plots were -9.29 for ET-3 and -8.53 for SRTX-b. FR 139317, another ET(A) receptor antagonist, also preferentially antagonized responses to ET-3. RES-701-1, a selective ET(B) receptor antagonist, did not shift dose-response curves for ET-1 and ET-3. These results suggest that ET receptors in the rabbit iris sphincter muscle cannot be classified into the ET(A), ET(B) or ET(C) receptor subtypes, so far established. When compared to the established receptor subtypes, ET receptors in this preparation were quite different from the ET(B) receptor, but apparently showed a pharmacological profile most similar to the ET(A) receptor, suggesting the presence of heterogeneous and atypical ET(A) receptors.