title: Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension.
abstract: 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 (Dahl-S) rats 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 rats. Male Dahl-S rats (5-6 wk) were placed on high (8%) or low (0.3%) NaCl diets for 4 wk. 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 rats. Experiments used isolated Krebs buffer-superfused first-order gracilis muscle arterioles with constant pressure (80 mmHg) and no luminal flow or constant midpoint but altered endpoint pressures to establish graded levels of luminal flow (0-50 microl/min). In high-salt arterioles, responses to an endothelium-dependent vasodilator acetylcholine (1 nmol/l to 3 micromol/l) and flow-induced dilation were decreased. Acute in vitro treatment with an inhibitor of arginase, 100 micromol/l (S)-(2-boronoethyl)-L-cystine, or the nitric oxide precursor, 1 mmol/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 that endothelium-dependent vasodilation is decreased in high-salt Dahl-S rats. 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 rats with salt-induced hypertension and identifies arginase as a potential therapeutic target to prevent endothelial dysfunction.
authors.affiliation: Tulane Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Fruzsina K
authors.initials: FK
authors.lastname: Johnson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Johnson
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: William
authors.initials: W
authors.lastname: Durante
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000302:isolation & purification; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D012965:Sodium Chloride; D014664:Vasodilation / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D012965:Sodium Chloride; D001120:Arginine; D001119:Arginase