Myocardial effects of ETB receptor stimulation

Endothelin-1 (ET-1) is an endogenous peptide whose effects are mediated by two distinct types of receptors, ETA and ETB. Whereas the ETA receptors promote vasoconstriction and mitogenesis and increase inotropism, ETB receptors have vasodilatory and anti-mitogenic properties mediated by nitric oxide release. In this study we investigated the myocardial effects of selective ETB receptor stimulation.

The study was performed on right papillary muscles (n = 30) from New Zealand white rabbits (Krebs-Ringer; 1.8 mM CaCl2; 35 degrees C). The effects of selective ETB receptor activation by Sarafotoxin S6c (0.2 microM; n = 6) and of non-selective ETA and ETB receptor activation by ET-1 (1 nM; n = 9) were studied. The effects of ET-1 were also evaluated in the presence of a selective ETA receptor antagonist, BQ-123 (0.1 microM; n = 9) and of a selective ETB receptor antagonist BQ-788 (0.1 microM; n = 6). Only significant results (mean +/- SE; p < 0.05) are given, expressed as % baseline.

Sarafotoxin S6c reduced active tension (AT) by 8.1 +/- 5.5% and peak rate of tension development (dT/dtmax) by 8.6 +/- 5.6%. Alone, ET-1 increased AT by 64.2 +/- 18.2% and dT/dtmax by 58.6 +/- 20.2%. These effects of ET-1 were exacerbated in the presence of BQ-788 (AT increased by 82.6 +/- 17.5% and dT/dtmax by 121.3 +/- 26.6%) and inverted in the presence of BQ-123 (AT decreased by 12.8 +/- 2.7% and dT/dtmax by 16.1 +/- 3.0%).

This study demonstrates, for the first time, that selective stimulation of ETB receptors has a negative inotropic effect. Detailed characterization of the effects of stimulation of each type of ET-1 receptor is of particular relevance as selective and non-selective inhibitors of these receptors are currently being tested for treatment of heart failure.