Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat.
1. Using endothelin-1 (ET-1), endothelin-3 (ET-3), sarafotoxin 6b (SX6b) and sarafotoxin 6c (SX6c) as agonists and BQ-123 as a selective ETA 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 ETA receptors, the vasoconstriction in the kidney in vivo may be mediated predominantly via ETB-like receptors. This may be of therapeutic relevance, for an ETA-receptor-selective antagonist could offer only poor protection of the renal circulation from the deleterious effects of endogenously produced members of this peptide family.
Cristol
J P
JP
William Harvey Research Institute, St Bartholomew's Hospital Medical College, London.
Warner
T D
TD
Thiemermann
C
C
Vane
J R
JR
D000758:Anesthesia; D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014757:Viper Venoms / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C072247:cyclo(Trp-Asp-Pro-Val-Leu)