MEDIATION VIA DIFFERENT RECEPTORS OF THE VASOCONSTRICTOR EFFECTS OF ENDOTHELINS AND SARAFOTOXINS IN THE SYSTEMIC CIRCULATION AND RENAL VASCULATURE OF THE ANESTHETIZED RAT

1 Using endothelin-I (ET-1), endothelin-3 (ET-3), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists and BQ-123 as a selective ET(A) receptor antagonist, we have examined the endothelin receptor subtypes mediating the systemic pressor and renal vasoconstrictor effects of the ET/SX family of peptides. 2 In anaesthetized rats, bolus intravenous injections of ET-1, ET-3, SX6b or SX6c (0.1, 0.25 and 0.50 nmol kg-1) produced initial transient depressor responses followed by sustained and dose-dependent increases in mean arterial pressure (MAP) with the following rank order of potency: SX6b>ET-1 > > SX6c > ET-3. In contrast, in the renal vasculature these peptides caused equipotent dose-dependent falls in renal blood flow (RBF) (ET-1 = ET-3 = SX6b = SX6c). 3 BQ-123 (1 mg kg-1, i.v. bolus) significantly reduced the systemic pressor effects of all the peptides but was largely ineffective against the renal vasoconstrictions. 4 These results indicate that although the systemic pressor effects of the ET/SX peptides are mediated via ET(A) receptors, the vasoconstriction in the kidney in vivo may be mediated predominantly via ET(B)-like receptors. This may be of therapeutic relevance, for an ET(A)-receptor-selective antagonist could offer only poor protection of the renal circulation from the deleterious effects of endogenously produced members of this peptide family.