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1 Tulane Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA, USA
2 Michael E. DeBakey VA Medical Center,and Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: wdurante{at}bcm.tmc.edu.
Vascular tissues express arginase that metabolizes L-arginine to L-ornithine and urea, and thus reduces substrate availability for nitric oxide formation. Dahl salt-sensitive rats (Dahl-S) with salt-induced hypertension show endothelial dysfunction including decreased vascular nitric oxide formation. This study tests the hypothesis that increased vascular arginase activity contributes to endothelial dysfunction in hypertensive Dahl-S. Male Dahl-S (5-6 weeks) were placed on high (8%) or low (0.3%) NaCl diets for 4 weeks. With respect to the low-salt group, mean arterial blood pressure was increased in the high-salt animals. Immunohistochemical stainings for arginase I and II were enhanced in arterioles isolated from high-salt Dahl-S. Experiments used isolated Krebs buffer superfused first-order gracilis muscle arterioles with constant pressure (80mmHg) and no luminal flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow (0-50µL/min). In high-salt arterioles, responses to an endothelium-dependent vasodilator, acetylcholine (1nmol/L-3µmol/L), and flow-induced dilation were decreased. Acute in vitro treatment with an inhibitor of arginase, 100µmol/L (S)-(2-boronoethyl)-L-cystine, or the nitric oxide precursor, 1mmol/L L-arginine, similarly enhanced acetylcholine and flow-induced maximal dilations and abolished the differences between high and low-salt arterioles. These data show that arteriolar arginase expression is increased, and endothelium-dependent vasodilation is decreased in high-salt Dahl-S. Acute pretreatment with an arginase inhibitor or with L-arginine restores endothelium-dependent vasodilation and abolishes the differences between high and low-salt groups. These results suggest that enhanced vascular arginase activity contributes to endothelial dysfunction in Dahl-S with salt-induced hypertension, and identifies arginase as a potential therapeutic target to prevent endothelial dysfunction.
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