Normalizing the expression of nitric oxide synthase by low-dose AT(1) receptor antagonism parallels improved vascular morphology in hypertensive rats

In essential hypertension, stroke and kidney damage may result from an impa ired interaction of vasoregulatory systems. Stroke-prone spontaneously hype rtensive rats (SHRSP) were studied to analyze the effects of a low-dose tre atment of the angiotensin II type 1 receptor (AT(1)) blocker candesartan ci lexetil on the expression of nitric oxide synthases (NOS) and on vascular s tructure. Both treated and untreated SHRSP were kept on a stroke-promoting dietary regimen, and compared with Wistar Kyoto rats (WKY). Early mortality of untreated SHRSP was prevented by the treatment. In untreated SHRSP. cer ebral intraparenchymal vessels of the parietal lobe showed lesions of the v ascular wall and its periphery, such as proteinaceous deposits, perivascula r dilated spaces, increase in phagocytic cells, and decreased actin immunos taining. Renal lesions were more pronounced comprising arteriolar occlusion , extensive loss of actin, increased alpha 1(IV) collagen expression, and g lomerular sclerotic as well as tubulointerstitial lesions. Beneficial effec ts of the AT(1) blockade were more pronounced in brain than in kidney. Acti vity profile of NOS showed increased NADPH diaphorase staining in media and endothelium of SHRSP; endothelial NOS3 immunoreactivity was decreased, but instead, inducible NOS2 increased in untreated SHRSP. These changes were l argely prevented in the treated group. NOS activity in macula densa cells w as unchanged, whereas afferent arteriolar renin levels were increased in un treated SHRSP. Results demonstrate an effective reduction of hypertensive v ascular changes with a nonpressor dose of candesartan. A "role switch" of v ascular NOS in hypertension from physiologic NOS3 toward deleterious NOS2 i s suggested, and its prevention by the AT(1) blocker points to an angiotens in II-dependent, nitric oxide-mediated pathway that may impair endothelial function and aggravate defects of the blood-brain barrier and kidney struct ures.