The functional shift of endothelin receptor subtypes in dogs with heart failure produced by rapid ventricular pacing

To clarify the functional role of endothelin-A/endothelin-B (ETA /ETB) receptors in congestive heart failure (CHF), we examined the effects of a non-selective endothelin receptor agonist, endothelin-1 (ET-1), and a selective ETB receptor agonist, sarafotoxin S6c. CHF was induced in dogs by rapid ventricular pacing and resulted in decreased left ventricular dp/dt(max), decreased cardiac output and increased pulmonary vascular resistance. Sarafotoxin S6c (0.3 nmol/kg) resulted in decreased left ventricular dp/dt(max) (-26 +/- 2%), decreased cardiac output (-47 +/- 13%) and increased pulmonary vascular resistance (+48 +/- 10%) in dogs without CHF. The effects of sarafotoxin S6c were attenuated in dogs with CHF (-12 +/- 5% in left ventricular dp/dt(max), -19 +/- 5% in cardiac output and +7 +/- 5% in pulmonary vascular resistance). In contrast, ET-1 (0.5 nmol/kg) had no effect on left ventricular dp/dt(max) to dogs without CHF and increased left ventricular dp/dt(max) by 16 +/- 3% in dogs with CHF. These data indicate that reduced cardiac contractile and pulmonary vasoconstrictor responses via the ETB receptor are attenuated and that responses mediated by the ETA receptor are more prominent in the context of CHF. This suggests a functional shift of endothelin receptor subtypes in CHF.