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(Hypertension. 2001;37:516.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Role of Endothelin B Receptors in Enhancing Endothelium-Dependent Nitric Oxide–Mediated Vascular Relaxation During High Salt Diet

Jena B. Giardina; GaChavis M. Green; Anna N. Rinewalt; Joey P. Granger; Raouf A. Khalil

From the Department of Physiology and Biophysics, and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi.

Correspondence to Raouf A. Khalil, MD, PhD, Department of Physiology & Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail rkhalil{at}physiology.umsmed.edu

High salt diet is often associated with increases in blood pressure, and the state of activation of endothelium-dependent vascular relaxation pathways is critical under these conditions. Basal activation of endothelial endothelin B (ET_B) receptors by endothelin has been suggested to stimulate the release of factors that promote vascular relaxation. However, whether ET_B receptors play a role in enhancing endothelium-dependent vascular relaxation during high salt diet is unclear. In this study, we investigated whether chronic treatment with an ET_B receptor antagonist is associated with impaired endothelium-dependent vascular relaxation and enhanced vascular reactivity particularly during high salt diet. Isometric contraction 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 treated with the ET_B receptor antagonist A-192621 (30 mg/kg per day) for 5 days. The mean arterial pressure was (in mm Hg) 122±3 in NS, 132±3 in HS, 144±2 in NS/ET_B antagonist, and 171±12 in HS/ET_B antagonist rats. In endothelium-intact strips, phenylephrine (Phe, 10^-5 mol/L) increased active stress to 7.6±1.0x10³N/m² in NS rats and 8.2±0.9x10³N/m² in HS rats. Phe (10^-5 mol/L) -induced stress was significantly greater in NS/ET_B antagonist (11.3±0.9x10³N/m²) than NS and far greater in HS/ET_B antagonist (14.1±0.1.2x10³N/m²) than HS rats. Also, Phe was more potent in NS/ET_B antagonist and HS/ET_B antagonist rats (ED₅₀=0.3x10^-7 and 0.15x10^-7 mol/L) than in NS and HS rats (ED₅₀=0.8x10^-7 and 0.7x10^-7 mol/L). Removal of the endothelium enhanced Phe-induced contraction significantly in NS and to a greater extent in HS, but not in NS/ET_B antagonist or HS/ET_B antagonist rats. In endothelium-intact strips, acetylcholine (ACh) caused relaxation of Phe contraction that was less in NS/ET_B antagonist than NS and far less in HS/ET_B antagonist than HS rats. Pretreatment of endothelium-intact strips with L-NAME (10^-4 mol/L), to inhibit nitric oxide (NO) synthase, or with methylene blue (10^-5 mol/L) or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10^-6 mol/L), to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced contraction significantly in NS and HS, slightly in NS/ET_B antagonist, but not in HS/ET_B antagonist rats. Measurement of basal and ACh-induced nitrite/nitrate production from aortic strips showed a significant reduction in NS/ET_B antagonist compared with NS, and a greater reduction in HS/ET_B antagonist compared with 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 seems to be active under basal conditions and may protect against excessive vasoconstriction and increased blood pressure particularly during high salt diet.

Key Words: arterial pressure • endothelium • nitric oxide • vascular smooth muscle • contraction

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