Role of Enothelin B Receptors in Enhancing Endothelium-Dependent No-Mediated Vascular Relaxation During High Salt Diet

Abstract

P21 Basal stimulation of endothelial endothelin B (ET B ) receptors and the ensuing release of endothelium-derived relaxing factors has been hypothesized to protect against excessive vasoconstriction and increased blood pressure particularly during high salt diet. To test this hypothesis, we investigated whether chronic infusion of ET B receptor antagonist is associated with impaired endothelium-dependent vascular relaxation and enhanced vascular reactivity particularly with high salt diet. Active stress was measured in aortic strips isolated from male Sprague-Dawley rats on normal sodium (NS, 1%) and high sodium diet (HS, 8%) for 7 days and untreated or infused with the ET B receptor antagonist A-192621 (30 mg/kg/day) for 5 days. In endothelium-intact strips, phenylephrine (Phe,10 -5 M) increased stress to 6.9±.3 in NS and to 7.2±.4x10 3 N/m 2 in HS rats. The Phe-induced stress in NS/ET B (8.6±.5) and HS/ET B rats (12.5±.4x10 3 N/m 2 ) was significantly > NS and HS rats. Removal of the endothelium significantly enhanced Phe-induced stress in NS and HS, and only slightly in NS/ET B but not in HS/ET B rats. In endothelium-intact strips, acetylcholine (ACh) induced relaxation of Phe contraction was in NS > HS > NS/ET B > HS/ET B rats with an ED 50 of 0.3x10 -6 , 0.4x10 -6 , 0.7x10 -6 and 1.1x10 -6 M, respectively. Pretreatment of endothelium-intact strips with L-NAME (10 -4 M), to inhibit nitric oxide (NO) synthase, or methylene blue (10 -5 M), to inhibit cGMP production in smooth muscle, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in NS and HS, and only slightly in NS/ET B but not in HS/ET B rats. Measurement of basal and ACh-induced nitrite/nitrate production from aortic strips showed a significant decrease in NS/ET B and HS/ET B compared to NS and HS rats. Relaxation of Phe contraction with sodium nitroprusside was not significantly different among the different groups of rats. Thus, an endothelial ET B receptor-mediated pathway of vascular relaxation involving release of NO is active under basal conditions and may protect against excessive vasoconstriction and increased blood pressure particularly during high salt diet.