EVIDENCE FROM RECEPTOR ANTAGONISTS OF AN IMPORTANT ROLE FOR ET(B) RECEPTOR-MEDIATED VASOCONSTRICTOR EFFECTS OF ENDOTHELIN-1 IN THE RAT-KIDNEY

1 To characterize the receptor subtype(s) mediating the renal vasoconstrictor effects of the endothelin (ET) and sarafotoxin (SX) peptides in the isolated perfused kidney of the rat, we have examined the effects of endothelin-1 (ET-I), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists, BQ-123 and FR 139317 as selective ET(A) receptor antagonists, and PD 145065 as a non-selective (ET(A) and ET(B)) receptor antagonist. We have also compared in the anaesthetized rat the systemic presser and renal vasoconstrictor effects of ET-1 and SX6c alone or after pretreatment with PD 145065. 2 In the isolated perfused kidney, ET-1, SX6b and SX6c all gave similar concentration-dependent increases in perfusion pressure. The ETA receptor selective antagonists, BQ-123 and FR 139317, both partially blocked the increase in perfusion pressure induced by ET-1. In contrast, PD 145065 completely blocked the increase in perfusion pressure caused by ET-1. 3 Indomethacin (10 mu M) had no effect on the ET-1-induced increases in perfusion pressure but significantly reduced the vasoconstriction induced by low concentrations of SX6c, without affecting responses to high concentrations. In the anaesthetized rat, indomethacin (5 mg kg(-1)) did not modify the systemic presser or renal vasoconstrictor effects of ET-1 or SX6c. 4 In anaesthetized rats, bolus intravenous injections of ET-1 or SX6c (0.1, 0.25, 0.5 or 1.0 nmol kg(-1)) produced initial transient depressor responses followed by sustained and dose-dependent increases in mean arterial pressure (MAP). Both peptides caused an equipotent fall in renal blood flow (RBF). PD 145065 (5 mg kg(-1)) partially antagonized the systemic presser effects of ET-1 and SX6c but completely blocked the fall in RBF and rise in renal vascular resistance (RVR) induced by ET-1 and SX6c. PD 145065 also antagonized the transient depressor effect following the bolus administration of either ET-1 or SX6c. 5 These results indicate that ET/SX induced renal vasoconstriction is mediated via ET(A) and ET(B)-like receptors with ET(B) receptors having a predominant role in vivo. This may be of therapeutic relevance for an ET(A) receptor-selective antagonist may offer only limited protection against the deleterious renal effects of endogenous ETs.