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1 Department of Cell and Molecular Physiology, University of North Carolina Chapel Hill, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: just{at}med.unc.edu.
The vascular actions of endothelin-1 (ET-1) reflect the combination of vasoconstrictor ETA and ETB receptors on smooth muscle cells and vasodilator ETB 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 %. ETA antagonist BQ-123 attenuated this response to a 15±1 % decrease in RBF (p<0.01), indicating net constriction by ETB receptors. Combined receptor blockade (BQ-123 + BQ788) resulted in a renal vasoconstriction of 7±1 % (p=0.001 vs. BQ-123), supporting constrictor action of ETB receptors. In marked contrast, the ETB antagonist BQ-788 enhanced the ET-1 RBF response to 60±5 % (p<0.001), suggesting ETB-mediated net dilation. Consistent with ETA blockade, the ETB 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 0.2-100 pmol. Both antagonists (BQ-123, BQ-788) were equally effective at 3-fold lower than the standard doses suggesting complete inhibition. We conclude that ETB receptors alone exert a net constrictor effect, but cause a net dilator influence when co-stimulated with ETA receptors. Such opposing actions indicate more complex than additive interaction between receptor subtypes. Model analysis suggests ETA-mediated constriction is appreciably greater without than with co-stimulation of ETB receptors. Possible explanations include ET-1 clearance by ETB receptors and/or a dilator ETB receptor function that counteracts constriction.
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