Oxidative stress in cyclosporine-induced hypertension: Evidence of beneficial effects or tolerance development with nitrate therapy

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Reis, F (Author) Other; Rocha Pereira, P (Author) Other; Teixeira de Lemos, ET (Author) Other; Parada, B (Author) Other; Baptista, S (Author) Other; Figueiredo, A (Author) Other; Santos Silva, A (Author) FFUP; Costa Almeida, C (Author) Other; Mota, A (Author) Other; Teixeira, F (Author) Other

Journal

Title: Transplantation Proceedings

Vol. 39 No. 8

Pages: 2494-2500

ISSN: 0041-1345

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 15 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Basic medicine

CORDIS: Health sciences

Other information

Authenticus ID: P-004-7CR

DOI: 10.1016/j.transproceed.2007.07.030

Resumo (PT): 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 CsAinduced 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
mol/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. <br> <br> <a target="_blank" href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VJ0-4PYHTPY-C&_user=2460038&_coverDate=10%2F31%2F2007&_rdoc=11&_fmt=high&_orig=browse&_srch=doc-info(%23toc%236080%232007%23999609991%23671337%23FLA%23display%23Volume)&_cdi=6080&_sort=d&_docanchor=&_ct=61&_acct=C000057398&_version=1&_urlVersion=0&_userid=2460038&md5=321b9b2a6cbfe3becc019e7d7f878d90"> Texto integral</a> <br> <br>

Abstract (EN): 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 antioxiclant 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 mu mol/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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7