Dual constrictor and dilator actions of ETB receptors in the rat renal microcirculation: interactions with ETA receptors

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Abstract
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+BQ-788) resulted in a renal vasoconstriction of 7 ± 1% ( P = 0.001 vs. BQ-123), supporting a 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 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 ETB receptors alone exert a net constrictor effect but cause a net dilator influence when costimulated 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 costimulation of ETB receptors. Possible explanations include ET-1 clearance by ETB receptors and/or a dilator ETB receptor function that counteracts constriction.