Vasoconstriction in the rat kidney induced by endothelin-1 is blocked by PD 145065.
We have previously shown that the receptors mediating the renal and systemic vasoconstrictor effects of endothelin-1 (ET-1) are of two distinct endothelin receptor subtypes. Here, we evaluate the effect of PD 145065, a nonselective endothelin receptor antagonist, on the renal vasoconstrictor effects of ET-1 in the rat kidney. ET-1 induced concentration-dependent increases in perfusion pressure in the isolated perfused kidney of the rat. The ETA receptor-selective antagonists BQ-123 (10 microM) and FR 139317 (10 microM) lowered the ET-1-induced rise in perfusion pressure by 57% and 61%, respectively, at 3 x 10(-10) M ET-1. By comparison, the ET-1-induced vasoconstriction was fully antagonized (96% inhibition) by PD 145065 (10 microM). In the anesthetized rat, ET-1 produced a dose-dependent increase in mean arterial pressure, which was attenuated by PD 145065. The initial depressor response to ET-1 was completely blocked by PD 145065, as were the reduction in renal blood flow and increase in renal vascular resistance induced by ET-1. These results suggest that both the ETA and a non-ETA receptor subtype play an important role in mediating the vasoconstrictor effects of ET-1 in the rat kidney.
Wellings
R P
RP
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, England.
Warner
T D
TD
Thiemermann
C
C
Cristol
J P
JP
Corder
R
R
Vane
J R
JR
D000595:Amino Acid Sequence; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D009842:Oligopeptides; D010456:Peptides, Cyclic; C079574:FR 139317; C082887:PD 145065; C072247:cyclo(Trp-Asp-Pro-Val-Leu)