Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular...

In essential hypertension, stroke and kidney damage may result from an impaired interaction of vasoregulatory systems. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied to analyze the effects of a low-dose treatment of the angiotensin II type 1 receptor (AT1) blocker candesartan cilexetil on the expression of nitric oxide synthases (NOS) and on vascular structure. 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, cerebral intraparenchymal vessels of the parietal lobe showed lesions of the vascular wall and its periphery, such as proteinaceous deposits, perivascular dilated spaces, increase in phagocytic cells, and decreased actin immunostaining. Renal lesions were more pronounced comprising arteriolar occlusion, extensive loss of actin, increased alpha1(IV) collagen expression, and glomerular sclerotic as well as tubulointerstitial lesions. Beneficial effects of the AT1 blockade were more pronounced in brain than in kidney. Activity 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 largely prevented in the treated group. NOS activity in macula densa cells was unchanged, whereas afferent arteriolar renin levels were increased in untreated SHRSP. Results demonstrate an effective reduction of hypertensive vascular changes with a nonpressor dose of candesartan. A "role switch" of vascular NOS in hypertension from physiologic NOS3 toward deleterious NOS2 is suggested, and its prevention by the AT1 blocker points to an angiotensin II-dependent, nitric oxide-mediated pathway that may impair endothelial function and aggravate defects of the blood-brain barrier and kidney structures.