Research Paper

Correction of Endothelial Dysfunction in Diabetic Female Rats by Tetrahydrobiopterin and Chronic Insulin
Eliana H. Akamine^a, Elisa M. Kawamoto^a, Cristoforo Scavone^a, Dorothy Nigro^a, Maria Helena C. Carvalho^a, Rita de Cássia A. Tostes^a, Luiz R.G. Britto^b, Zuleica B. Fortes^a

Departments of
^aPharmacology, and
^bPhysiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

Address of Corresponding Author

J Vasc Res 2006;43:309-320 (DOI: 10.1159/000093196)

  Key Words

• Diabetes
• Endothelial dysfunction
• Insulin
• Microcirculation
• Nitric oxide
• Oxidative stress
• Tetrahydrobiopterin

  Abstract

Diabetes-induced vascular dysfunction has mainly been studied in males. However, the mechanisms involved may not correspond to those in females. Here we analyzed the effects of tetrahydrobiopterin (BH₄) and chronic insulin on the physiology of mesenteric arterioles of alloxan-diabetic female rats. The parameters studied were the mesenteric arteriolar reactivity (intravital microscopy), nitric oxide synthase (NOS) activity (conversion of L-arginine to L-citrulline), eNOS gene expression (RT-PCR), NO production (diaminofluorescein), reactive oxygen species (ROS) generation (intravital fluorescence microscopy) and Cu/Zn superoxide dismutase (SOD) activity (spectrophotometry) and gene expression (RT-PCR). The reduced endothelium-dependent vasodilation of diabetic females was corrected by both BH₄ and insulin. NOS activity was decreased by diabetes, but insulin did not correct it. However, NOS expression was not modified by either diabetes or insulin. Arterioles of diabetic rats exhibited lower NO production, which was fully corrected by BH₄ and only partially by insulin. ROS generation was increased in diabetic rats, and both BH₄ and insulin normalized it. Diabetes did not change SOD activity and gene expression. However, insulin increased SOD activity but not its expression. Our data suggest that, similarly to males, endothelial dysfunction in female diabetic rats involves an altered ROS/NO imbalance. In contrast to males, however, insulin does not regulate NOS in the microcirculation of diabetic females.

Copyright © 2006 S. Karger AG, Basel

  Author Contacts

Dr. Zuleica B. Fortes
Department of Pharmacology, Institute of Biomedical Sciences
University of São Paulo
BR-05508-900 São Paulo S.P. (Brazil)
Tel./Fax +55 11 3091 7317, E-Mail zbfortes@icb.usp.br

  Article Information

Received: July 6, 2005
Accepted after revision: February 19, 2006
Published online: May 8, 2006
Number of Print Pages : 12
Number of Figures : 7, Number of Tables : 3, Number of References : 39