Contribution of endogenous endothelin-1 to the maintenance of vascular tone: role of nitric oxide.
Studies were designed to compare the effect of the nitric oxide inhibitor, N omega-nitro-L-arginine (L-NNA), and the novel ETB receptor antagonist, RES-701-1, on changes in blood pressure and renal blood flow induced by exogenous endothelin receptor agonists and to determine the effect of L-NNA on basal hemodynamics in conscious, chronically instrumented rats. Infusion of low (nonpressor) doses of L-NNA or RES-701-1 potentiated systemic and renal vasoconstriction induced by bolus injections of endothelin-1 or sarafotoxin 6c. Bolus intravenous injection or sustained infusion of L-NNA alone resulted in dose-dependent increases in blood pressure and decreases in renal blood flow, similar to our recently reported results with RES-701-1. Vasoconstriction induced by inhibition of nitric oxide was attenuated by SB 209670, a mixed ETA/B receptor antagonist, but not by BQ123, an ETA receptor antagonist; neither antagonist altered basal hemodynamics. Collectively, the results indicate that: (1) endothelin plays an important role in the control of basal vascular tone by mediating both vasodilation and vasoconstriction; (2) these effects are mediated by different ETB receptor subtypes in the rat, one located on the endothelium that mediates vasodilation via the nitric oxide pathway, the other located on the vascular smooth muscle that mediates contraction.
Gellai
M
M
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. 19406-0939, USA.
De Wolf
R
R
Fletcher
T
T
Nambi
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000819:agonists; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents; D014757:Viper Venoms
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; C087120:RES 701-1; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu)