Role of Enothelin B Receptors in Enhancing Endothelium-Dependent No-Mediated Vascular Relaxation During High Salt Diet
Basal stimulation of endothelial endothelin B (ETB) 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 ETB 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 ETB 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±.4x103N/m2 in HS rats. The Phe-induced stress in NS/ETB (8.6±.5) and HS/ETB rats (12.5±.4x103N/m2) was significantly > NS and HS rats. Removal of the endothelium significantly enhanced Phe-induced stress in NS and HS, and only slightly in NS/ETB but not in HS/ETB rats. In endothelium-intact strips, acetylcholine (ACh) induced relaxation of Phe contraction was in NS > HS > NS/ETB > HS/ETB rats with an ED50 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/ETB but not in HS/ETB rats. Measurement of basal and ACh-induced nitrite/nitrate production from aortic strips showed a significant decrease in NS/ETB and HS/ETB 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 ETB 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.