RT Journal Article
SR Electronic
T1 Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 879
OP 885
VO 298
IS 3
A1 Xin-Liang Ma
A1 Feng Gao
A1 Allen H. Nelson
A1 Bernard L. Lopez
A1 Theodore A. Christopher
A1 Tian-Li Yue
A1 Frank C. Barone
YR 2001
UL http://jpet.aspetjournals.org/content/298/3/879.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics