Dual constrictor and dilator actions of ET(B) receptors in the rat renal microcirculation: interactions with ET(A) receptors.
The vascular actions of endothelin-1 (ET-1) reflect the combination of vasoconstrictor ET(A) and ET(B) receptors on smooth muscle cells and vasodilator ET(B) receptors on endothelial cells. The present study investigated the contribution of ET receptor subtypes using a comprehensive battery of agonists and antagonists infused directly into the renal artery of anesthetized rats to evaluate the actions of each receptor class alone and their interactions. ET-1 (5 pmol) reduced renal blood flow (RBF) 25+/-1%. ET(A) antagonist BQ-123 attenuated this response to a 15+/-1% decrease in RBF (P < 0.01), indicating net constriction by ET(B) receptors. Combined receptor blockade (BQ-123+BQ-788) resulted in a renal vasoconstriction of 7+/-1% (P = 0.001 vs. BQ-123), supporting a constrictor action of ET(B) receptors. In marked contrast, the ET(B) antagonist BQ-788 enhanced the ET-1 RBF response to 60+/-5% (P < 0.001), suggesting ET(B)-mediated net dilation. Consistent with ET(A) blockade, the ET(B) agonist sarafotoxin 6C (S6C) produced vasoconstriction, reducing RBF by 23+/-5%. Dose-response curves for ET-1 and S6C showed similar degrees of constriction between 0.2 and 100 pmol. Both antagonists (BQ-123, BQ-788) were equally effective at threefold lower than the standard doses, suggesting complete inhibition. We conclude that ET(B) receptors alone exert a net constrictor effect but cause a net dilator influence when costimulated with ET(A) receptors. Such opposing actions indicate more complex than additive interaction between receptor subtypes. Model analysis suggests ET(A)-mediated constriction is appreciably greater without than with costimulation of ET(B) receptors. Possible explanations include ET-1 clearance by ET(B) receptors and/or a dilator ET(B) receptor function that counteracts constriction.
Just
Armin
A
Dept. of Cell and Molecular Physiology, 6341 Medical Biomolecular Research Bldg., CB#7545, School of Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545, USA. just@med.unc.edu
Olson
Andrea J M
AJ
Arendshorst
William J
WJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D012079:Renal Circulation / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014757:Viper Venoms / Q000494:pharmacology
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009569:Nitric Oxide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)