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.

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation

“…As has been demonstrated previously for the experimental conditions of the present study, all of the conditions of elevated PVD risk were associated with an impaired endothelial function, as evidenced by a reduced upper bound of the acetylcholine concentration-response relationship (9,17,19,24,33,34,39,49,58), although the degree of impairment was similar in magnitude regardless of the severity of the PVD risk score. However, the contribution of oxidant stress to each condition of PVD risk was more variable, with some of the states of more severe PVD risk showing a robust role for oxidant stress in compromising endothelial function while others demonstrated a more modest or minimal contribution.…”

Colonic blood flow responses in experimental colitis: time course and underlying mechanisms

“…Endothelium-dependent vasodilation has been demonstrated in virtually all vascular beds, and a defective response of arterioles to endothelium-dependent vasodilators has been described in many chronic pathologic conditions that include a significant inflammatory component such as atherosclerosis, diabetes, obesity, and hypertension (15,17,22,29). NO plays a major role in mediating endothelium-dependent arteriolar dilation, and the inactivation of endothelial cell-derived NO by superoxide is frequently invoked to explain the impaired endothelium-dependent dilation that is associated with chronic inflammatory diseases (12,24).…”

Endothelial arginase: A new target in atherosclerosis

“…Indeed, the role of arginase in endothelial dysfunction has been recently extended to other pathophysiologic conditions associated with vascular disorders in animal models such as aging [42,43], ischemia-reperfusion-induced endothelial dysfunction [44], and various types of hypertension [45,46,47 …”