Use of A-192621 and IRL-2500 to unmask the mesenteric and renal vasodilator role of endothelin ETB receptors

Abstract

Endothelin-1 (ET-1) is known to cause a transient (<1 min) depressor followed by a sustained (>1 h) pressor response. The former through the activation of ETB receptors, and the latter through the activation of ETA and ETB receptors. This study examines if ETB receptors mediate sustained mesenteric and renal dilation in anesthetized rats. Intravenous bolus ET-1 (0.8, 1.4, and 2 nmol/kg) and IRL-1620 (ETB agonist, 2, 5, and 10 nmol/kg) caused transient decrease followed by sustained increases in mean arterial pressure (MAP) that were accompanied by increases in total peripheral resistance (TPR), reductions in cardiac output (CO), and mesenteric and renal vasoconstriction. Pretreatment with FR-139317 (ETA antagonist, 1 mg/kg) attenuated the pressor and constrictor effects of ET-1 but did not alter responses to IRL-1620. IRL-2500 (ETB antagonist, 5 mg/kg) slightly inhibited the renal constrictor effect of IRL-1620, whereas A-192621 (ETB antagonist, 5 mg/kg) abolished all hemodynamic responses to IRL-1620. Both IRL-2500 and A-192621 markedly enhanced MAP, TPR, and mesenteric, and the renal constrictor effects of ET-1. Therefore, A-192621 was more effective than IRL-2500 in blocking IRL-1620-induced vasoconstriction, but both augmented constrictor responses to ET-1. The potentiation of ET-1-induced vasoconstriction by ETB receptor antagonists revealed a sustained vasodilator role of ETB receptors.