FB 55 01.indd

Current findings suggest a role for the angiotensin II (Ang II) signalling pathway in generation of reactive oxygen species and diabetes-induced cardiac complications. In this study we aimed to investigate the effect of angiotensin II type 1 (AT 1 ) receptor blockage on some antioxidant enzy mes such as glucose-6-phosphate dehydrogenase (G6PD), 6-phoshogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S-transferase (GST), gluta thione peroxidase (GSH-Px), and catalase (CAT) in the heart of streptozotocin (STZ)-induced diabetic rats. The effect of AT 1 receptor blocker, candesartan-cilexetil (5 mg/kg/day for 4 weeks) was studied. Diabetes caused hyperglycaemia (4-fold of control) with significant increases in G6PD, 6PGD, GR, GSH-PX, CAT and no effect on GST in heart tissues as compared to normal control rats. Treatment of STZ-induced diabetic rats with candesartan-cilexetil had sig nificant beneficial effects on these parameters without any side effect on control rats. These results suggest that Ang II can take part in induction of oxidative stress in diabetic rat heart and that blockage of its activity by AT 1 receptor blocker is potentially protective against diabetes-induced cellular damage. Introduction Diabetes mellitus is a metabolic disorder that can manifest itself by cellular and functional abnormalities. Since heart is one of the most important target tissues of diabetes, the increased rate of mortality and morbidity of these patients has been attributed to diabetic cardiomyopathy (Fein and Sonnenblick, 1985; Flack et al., 1998). Furthermore, growing evidences showing impai red diastolic performance followed by depressed systolic function in diabetic patients support this hypothesis. Increased production of reactive oxygen species (ROS) as well as nitrogen species is a well-known phenomenon in hyperglycaemic conditions. Although the aetiology of the hyperglycaemia-induced cellular damage has not been clarified yet, free radicals and oxidative stress are supposed to be the contributory factors underlying these abnormalities. The autooxidation of glucose, the formation of glycation end-products and the activation of NADPH oxidase have been suggested as possible sources of the augmented oxidative stress in diabetes. Thus, elevated free radical levels activate various subcellular signal transduction pathways including abnormal gene expression, which may cause myocardial cell death. Related with these suggestions, increased production of thiobarbituric acid-reactive substances (TBARS), which is an index of oxidative stress and lipid peroxidation, was reported in diabetic hearts (Kakkar et al., 1995; 1996; Babu et al., 2006; Tsutsui et al., 2007). The antioxidant enzymes (GSH-Px, GR, SOD, CAT) respond to the increased stress as a protective mechanism of the target tissue. In most of the studies, SOD, CAT, GSH-Px activities and/ or levels were shown to be changed (Kakkar et al., 1995; 1996; Gumieniczek et al., 2002; Aksoy et al., 2003; Bukan et al., 2004; Okutan et al., 2005; Shirpoor et al., 2008) in diabetic hearts. However, there are still some controversies in these published results. While Kakkar et al. (Kakkar et al., 1995; 1996) have shown an increase in SOD, CAT and GSH-Px activities, unchanged GSH-Px (Okutan et al., 2005) and decreased Received June 6, 2008. Accepted January 5, 2009. This work was supported by grants from Ankara University Scientific Research Projects, 2001.08.09.061, 2001.08.09.040 and 2003.08.09.110. Corresponding author: Semir Ozdemir, Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey. Phone: +90 242 2496907; Fax: +90 242 2274495; e-mail: [email protected] Abbreviations: 6PGD – 6-phoshogluconate dehydrogenase, Ang II – angiotensin II, AT1 – angiotensin II type 1, CAT – catalase, CDNB – chloro-dinitro benzene, G6PD – glucose-6-phosphate dehydrogenase, GR – glutathione reductase, GSH-Px – glutathione peroxidase, GSSG – oxidized glutathione, GST – glutathione-S-transferase, ROS – reactive oxygen species, STZ – streptozotocin, TBARS – thiobarbituric acid-reactive substances. FB 55 01.indd 11 13.3.2009 11:30:45