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(Hypertension. 2004;44:935.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

Cuihua Zhang; Travis W. Hein; Wei Wang; Matthew W. Miller; Theresa W. Fossum; Michelle M. McDonald; Jay D. Humphrey; Lih Kuo

From the Department of Medical Physiology (C.Z., T.W.H., W.W., L.K.), College of Medicine, Texas A&M University System Health Science Center, College Station, Tex; the Michael E. DeBakey Institute (M.W.M., T.W.F., M.M.M.), Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, Tex; and the Department of Biomedical Engineering (J.D.H.), Dwight Look College of Engineering, Texas A&M University, College Station, Tex.

Correspondence to Lih Kuo, PhD, Department of Medical Physiology, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76504. E-mail LKUO{at}tamu.edu

One characteristic of hypertension is a decreased endothelium-dependent nitric oxide (NO)-mediated vasodilation; however, the underlying mechanism is complex. In endothelial cells (ECs), L-arginine is the substrate for both NO synthase (NOS) and arginase. Because arginase has recently been shown to modulate NO-mediated dilation of coronary arterioles by reducing L-arginine availability, we hypothesized that upregulation of vascular arginase in hypertension contributes to decreased NO-mediated vasodilation. To test this hypothesis, hypertension (mean arterial blood pressure >150 mm Hg) was maintained for 8 weeks in pigs by aortic coarctation. Coronary arterioles from normotensive (NT) and hypertensive (HT) pigs were isolated and pressurized for in vitro study. NT vessels dilated dose-dependently to adenosine (partially mediated by endothelial release of NO) and sodium nitroprusside (endothelium-independent vasodilator). Conversely, HT vessels exhibited reduced dilation to adenosine but dilated normally to sodium nitroprusside. Adenosine-stimulated NO release was increased 3-fold in NT vessels but was reduced in HT vessels. Moreover, arginase activity was 2-fold higher in HT vessels. Inhibition of arginase activity by N-hydroxy-nor-L-arginine or incubation with L-arginine partially restored NO release and dilation to adenosine in HT vessels. Immunohistochemistry showed that arginase expression was increased but NOS expression was decreased in arteriolar ECs of HT vessels. These results suggest that NO-mediated dilation of coronary arterioles is inhibited in hypertension by an increase in arginase activity in EC, which limits L-arginine availability to NOS for NO production. The inability of arginase blockade or L-arginine supplementation to completely restore vasodilation may be related to downregulation of endothelial NOS expression.

Key Words: arginine • hypertension • microcirculation • nitric oxide synthase • vasodilation

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