title: Oxidative stress in cyclosporine-induced hypertension: evidence of beneficial effects or tolerance development with nitrate therapy.
abstract: The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n = 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn + CsA therapy showed, when compared with the CsA group, total prevention of CsA-induced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA + Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 +/- 1.4 vs 12.78 +/- 3.63 mumol/L; P < .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra University, 3004-504 Coimbra, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Reis
authors.forename: P
authors.initials: P
authors.lastname: Rocha-Pereira
authors.forename: E
authors.initials: E
authors.lastname: Teixeira de Lemos
authors.forename: B
authors.initials: B
authors.lastname: Parada
authors.forename: S
authors.initials: S
authors.lastname: Baptista
authors.forename: A
authors.initials: A
authors.lastname: Figueiredo
authors.forename: A
authors.initials: A
authors.lastname: Santos-Silva
authors.forename: C
authors.initials: C
authors.lastname: Costa-Almeida
authors.forename: A
authors.initials: A
authors.lastname: Mota
authors.forename: F
authors.initials: F
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects*; D006973:Hypertension / Q000139:chemically induced*; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007166:Immunosuppressive Agents; D020030:Nitric Oxide Donors; D016572:Cyclosporine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate