title: Nebivolol suppresses asymmetric dimethylarginine and attenuates cyclosporine-induced nephrotoxicity and endothelial dysfunction in rats.
abstract: 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 β-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 (30mg/kg/day)-treated or CsA+nebivolol (30mg/kg and 1mg/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.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors.forename: Wafaa A
authors.initials: WA
authors.lastname: Hewedy
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Electronic address: dalia.kashishy@alexmed.edu.eg.
authors.forename: Dalia K
authors.initials: DK
authors.lastname: Mostafa
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D008297:Male; D000068577:Nebivolol / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D007166:Immunosuppressive Agents; D000068577:Nebivolol; C018524:N,N-dimethylarginine; D016572:Cyclosporine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: ADMA; Cyclosporine; Endothelium; NO; Nebivolol; Nephrotoxicity