Nebivolol suppresses asymmetric dimethylarginine and attenuates cyclosporine-induced nephrotoxicity and endothelial dysfunction in rats

Background: Cyclosporine A (CsA)-induced nephrotoxicity is a challenging problem complicating its chronic use in a large array of autoimmune diseases, as well as in organ transplantation. A considerable body of evidence points to the involvement of nitric oxide (NO) and its endogenous synthesis inhibitor, asymmetric dimethylarginine (ADMA), in CsA-induced renal and cardiovascular adverse effects. In this study, the potential of the third generation beta-blocker, nebivolol, to modify the NO/ADMA system is hypothesized to play a role in protection against CsA-induced renal injury and endothelial dysfunction. Methods: Both in vivo and in vitro studies were carried out on 36 male Wistar rats randomly divided into three groups; normal control, CsA (30 mg/kg/day)-treated or CsA+ nebivolol (30 mg/kg and 1 mg/kg daily, respectively)-treated groups. After four weeks, blood pressure, lipid profile, renal functions, renal oxidative status, NO, inducible NO synthase and ADMA were assessed. In vitro evaluation of vascular relaxant responses of norepinephrine pre-contracted aortic rings to acetylcholine (ACh) and sodium nitroprusside were evaluated. Results: Concurrent nebivolol treatment significantly attenuated CsA-induced hypertension, impairment of renal functions, oxidative stress and restored the balance in renal NO system with lowering of the elevated ADMA. This was associated with favourable effects on lipid profile. Nebivolol treatment also abrogated the CsA-induced impairment of relaxant responses of aortic rings to ACh. Conclusions: Nebivolol possesses multifaceted actions that make it advantageous to combat the CsA-induced toxic effects on renal and endothelial functions. (C) 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.