Vascular changes in cyclosporine A-induced hypertension and nephrotoxicityin spontaneously hypertensive rats on high-sodium diet

Functional and morphological changes of blood vessels in cyclosporine A (Cs A)-induced hypertension and nephrotoxicity were studied in spontaneously hy pertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1 )d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitant ly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicit y. CsA also impaired mesenteric and renal arterial function and caused stru ctural damage to intrarenal and extrarenal small arteries and arterioles. M edial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arter ial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excreti on or endothelial or inducible NO synthase expression in kidney, aorta or h eart) or oxidative stress (urinary excretion of 8-isoprostaglandin F-2 alph a, plasma urate concentration or total radical trapping capacity). Concomit ant L-arginine treatment did not affect CsA-induced changes in blood pressu re or histological findings but tended to alleviate the arterial dysfunctio n. The renal and cardiovascular toxicity of CsA was associated with arteria l dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidat ive stress or a defect in the L-arginine-NO pathway.