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Vol. 298, Issue 3, 879-885, September 2001

Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats

Xin-Liang Ma, Feng Gao, Allen H. Nelson, Bernard L. Lopez, Theodore A. Christopher, Tian-Li Yue and Frank C. Barone

Department of Surgery, Division of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania (X.-L.M., B.L.L., T.A.C.); Department of Physiology, Fourth Military Medical University, Xian, People's Republic of China (F.G.); and Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania (A.H.N., T.-L.Y., F.C.B.)

This study tested the hypothesis that increased nitric oxide (NO) inactivation and concurrent peroxynitrite formation is responsible for endothelial dysfunction in the spontaneously hypertensive stroke-prone rat (SHRSP). In SHRSP, the aortic vasorelaxation to acetylcholine (ACh) was decreased (p < 0.05), but NO production was unchanged. Nitrotyrosine staining, a footprint of peroxynitrite (ONOO-) formation, was detected. Exposure of SHRSP to a high-salt, high-fat diet (SFD) further exacerbated hypertension and accelerated end-organ disease. A severe endothelial dysfunction [maximal ACh relaxation: 49.8 ± 2.1 versus 94.5 ± 1.8% in Wistar-Kyoto rats (WKY), p < 0.01], increased basal NO production (482 ± 17 versus 356 ± 21 nM, p < 0.01), decreased ACh-stimulated NO production (57 ± 6 versus 112 ± 6 nM, p < 0.01), extensive inducible NO synthase and nitrotyrosine staining, elevated nitrotyrosine content (21-fold increase over WKY), and a high percentage of cells with DNA damage were observed in the aortic tissues from these animals. Treatment of SHRSP on SFD with carvedilol restored ACh-induced vasorelaxation and NO production, inhibited nitrotyrosine formation, reduced vascular cell DNA damage, and reduced end-organ injury. These data demonstrate that endothelial dysfunction was caused by increased NO inactivation alone (SHRSP) or in combination with decreased NO production from endothelial NO synthase (SHRSP on SFD). Antioxidant treatment with carvedilol exerted significant vascular protective effects, attenuated end-organ damage, and decreased mortality under these conditions.

0022-3565/01/2983-0879$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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