The present study examined the effects of two highly selective endothelin-1 (ET-1) receptor antagonists, ABT-627 (ETA blocker) and A-192621 (ETB blocker), on the systemic and renal haemodynamic effects of ET-1 in normal rats and in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Intravenous injection of ET-1 (1.0nmol·kg-1 of body weight) to anaesthetized normal rats produced sustained decreases in renal blood flow (RBF) (assessed by ultrasonic flowmetry) and glomerular filtration rate (GFR), and significant increases in renal vascular resistance (RVR) and mean arterial pressure (MAP). Pretreatment with ABT-627 (1mg·h-1·kg-1 of body weight) abolished the pressor response to ET-1 without affecting the depressor phase, and significantly impaired the renal vasoconstriction. The systemic and renal vasoconstrictive effects of ET-1 in normal rats were significantly augmented by pretreatment with 3.0mg·h-1·kg-1 of A-192621. Baseline RBF and GFR in rats with CHF were reduced significantly compared with control rats, whereas RVR was elevated. The hypertensive effect of ET-1 was attenuated in rats with CHF. In the presence of ETA blockade, the pressor response to ET-1 was completely abolished in CHF rats. Furthermore, pretreatment with ABT-627 enhanced the recovery from ET-1- dependent vasoconstriction and remarkably reversed the ET-1-induced hypofiltration. Blockade of ETB receptors in rats with CHF further exposed the exaggerated ET-1-induced renal vasoconstriction. Our data demonstrate that experimental CHF is associated with altered responsiveness to ETA- and ETB-mediated systemic and renal effects of ET-1. Furthermore, in CHF, as in control rats, the ETB-mediated vasodilatory response may serve as an important compensatory counterbalance to the adverse ETA-mediated effects.
The Seventh International Conference on Endothelin was held at the University of Edinburgh, UK, 16-19 September 2001