Modulation of the myocardial effects of selective ETB receptor stimulation and its implications for heart failure

Endothelin-1 (ET-1) acts on two types of receptors, ET(A) and ET(B). Recent functional studies suggest the existence of two ET(B) receptor subtypes in the heart: ET(B1), located on endocardial endothelial cells and responsible for negative inotropism, and ET(B2), located on myocardial cells and responsible for positive inotropism. The aim of the present study was to investigate the mechanisms underlying the myocardial effects of selective ET(B) receptor stimulation.

The study was performed on right papillary muscles from New Zealand white rabbits (n = 39; Krebs-Ringer; 1.8 mM CaCl2; 35 degrees C). The effects of sarafotoxin S6c (SRTXc, ET(B) agonist; 0.2 microM) were evaluated in muscles with: (i) intact endocardial endothelium (EE) (n = 6); (ii) damaged EE (Triton X100; 0.5%; n = 6); (iii) intact EE, in the presence of N(G)-nitro-L-arginine (L-NNA, nitric oxide synthase inhibitor; n = 6); (iv) intact EE, in the presence of indomethacin (INDO, cyclooxygenase inhibitor; n = 6); (v) intact EE, in the presence of BQ-123 (ET(A) antagonist; n = 7); and (vi) damaged EE, in the presence of BQ-123 (n = 8). Only significant results (mean +/- SEM, p < 0.05) are given, expressed as % change from baseline.

In muscles with intact EE, SRTXc alone induced negative inotropic and lusitropic effects, decreasing active tension (AT) by 11.0 +/- 5.6%, maximum velocity of tension rise (dT/dt(max)) by 11.2 +/- 5.9% and maximum velocity of tension decline (dT/dt(min)) by 11.5 +/- 6.2%. However, after removal of EE, or in the presence of L-NNA or INDO, SRTXc increased AT by 35.2 +/- 11.7%, 22.8 +/- 2.9% and 15.2 +/- 3.4%, dT/dt(max) by 29.5 +/- 7.9%, 20.1 +/- 2.1% and 13.3 +/- 5.0%, and dT/dt(min) by 28.2 +/- 8.1%, 21.2 +/- 3.8% and 12.3 +/- 2.2%, respectively. In muscles with intact EE and in the presence of BQ-123, the negative inotropic and lusitropic effects of SRTXc were enhanced: AT decreased by 27.0 +/- 7.4%, dT/dt(max) by 13.3 +/- 4.9% and dT/dt(min) by 31.1 +/- 7.9%. On the other hand, the positive inotropic and lusitropic effects of SRTXc in the absence of intact EE were reversed in the presence of ET(A) blockade: AT decreased by 9.0 +/- 1.8%, dT/dt(max) by 4.1 +/- 3.5% and dT/dt(min) by 8.1 +/- 3.6%.

The present study shows that the inotropic and lusitropic effects mediated by ET(B) receptors are modulated by endocardial endothelium and by ET(A) receptor activity. These results may have pathophysiological and therapeutic implications in heart failure, a condition in which ET-1 levels are increased and endothelial dysfunction may be present.