Oxidative inactivation of nitric oxide and endothelial dysfunction in stroke-prone spontaneous hypertensive rats

This study tested the hypothesis that increased nitric oxide (NO) inactivat ion and concurrent peroxynitrite formation is responsible for endothelial d ysfunction in the spontaneously hypertensive stroke-prone rat (SHRSP). In S HRSP, 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 hi gh-salt, high-fat diet (SFD) further exacerbated hypertension and accelerat ed end-organ disease. A severe endothelial dysfunction [maximal ACh relaxat ion: 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, elevat ed nitrotyrosine content (21-fold increase over WKY), and a high percentage of cells with DNA damage were observed in the aortic tissues from these an imals. Treatment of SHRSP on SFD with carvedilol restored ACh-induced vasor elaxation and NO production, inhibited nitrotyrosine formation, reduced vas cular 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 sig nificant vascular protective effects, attenuated end-organ damage, and decr eased mortality under these conditions.