Preglomerular sudanophilia in L-NAME hypertensive rats - Involvement of endothelin

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries. and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21+/-2% and 42+/-3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72+/-6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26+/-2% and 36+/-3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.