Therapeutic potential of sulindac against ischemia-reperfusion-induced myocardial infarction in diabetic and nondiabetic rats.

BACKGROUND: Diabetes mellitus is an independent risk factor for cardiovascular disease and is also associated with increased susceptibility to cardiovascular complications. It has been suggested that alterations in glucose metabolism and glucose flux via the aldose reductase pathway make the diabetic heart more sensitive to ischemic-reperfusion injury. Previous studies have found sulindac to have inhibitory and anti-inflammatory effects on aldose reductase. The use of aldose reductase inhibitors for the protection of ischemic myocardium is still in an exploratory state. OBJECTIVES: To evaluate the therapeutic potential of sulindac in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h) in diabetic and nondiabetic rats. METHODS: Diabetes was induced in rats by administering streptozotocin (45 mg/kg, intravenously). Myocardial infarction was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Sorbitol dehydrogenase levels in heart tissue, as well as lipid peroxide levels in serum and heart tissue, were estimated spectrophotometrically. RESULTS: Infarct size was increased in diabetic rats in comparison with normal rats. Pretreatment with sulindac significantly reduced infarct size, lipid peroxidation and sorbitol dehydrogenase levels in both diabetic and nondiabetic rats. The degree of cardioprotection was greater in diabetic rats than in nondiabetic rats. CONCLUSIONS: The present study indicates that the observed cardioprotection provided by sulindac in terms of reducing infarct size in normal rats may be due to its combined antioxidant and anti-inflammatory activities. The inhibition of aldose reductase may be responsible for the enhanced cardioprotection observed in diabetic rats treated with sulindac.

The influence of sulindac on diabetic cardiomyopathy: a non-invasive evaluation by Doppler echocardiography in streptozotocin-induced diabetic rats.

The aim of the present study was to investigate the cardioprotective activity of sulindac as an aldose reductase inhibitor in the development of cardiomyopathy by non-invasive techniques; M-mode and Doppler echocardiography. Diabetes was induced by streptozotocin (45 mg/kg, iv) in the Sprague-Dawley rats. Echocardiography, biochemical and histological studies were carried out in normal control, diabetic untreated, diabetic vehicle (sodium carboxy methyl cellulose, 1%, po) and sulindac (6 mg/kg and 20 mg/kg, po) treated animals at varying time intervals. In the diabetic untreated and vehicle treated rats at 12 weeks after induction of diabetes, there was a significant decrease in the E-wave, an increase in the A-wave and corresponding decrease in the E/A ratio was observed. Significant decrease in the Eat was found after 12 weeks (P < 0.05). Whereas systolic function variables; ejection fraction and fractional shortening were significantly decreased (P < 0.05) after 12 weeks compared to their baseline data. In the sulindac treated animals, there were no significant alterations in the systolic and diastolic parameters were found throughout the study period. Myocardial fructose levels were significantly increased in the diabetic untreated animals compared to normal control rats (P < 0.05), whereas these were significantly decreased in the sulindac (6 mg/kg and 20 mg/kg) treated animals (301.11+/-37.98, 214.11+/-25.31, vs. 914.88+/-56.01 nmol/g) compared to diabetic vehicle treated group (P < 0.05). Extensive focal ischemic myocyte degeneration was observed in the diabetic untreated and vehicle treated rats, whereas in the sulindac (6 mg/kg) treated rats, minimal necrosis was found, with no evidence of necrosis in sulindac (20 mg/kg) group. Our results show for the first time that sulindac has a cardioprotective activity as this agent prevented the development of left ventricular dysfunction in STZ-induced diabetic rats in the 12-week chronic study.

Partial reversal by rutin and quercetin of impaired cardiac function in streptozotocin-induced diabetic rats.

The present investigation was carried out to evaluate the effects of the cyclodextrin complexes quercetin and rutin on left ventricle dysfunction in streptozotocin-induced diabetic rats. Diabetes was induced by streptozotocin (45 mg/kg body mass, i.v.) in Sprague-Dawley rats. Echocardiography and biochemical and histological studies were carried out under normal control, diabetic untreated, normal and diabetic vehicle (beta-cyclodextrin, p.o.), quercetin- (100 and 300 mg/kg, p.o.), and rutin- (100 and 300 mg/kg, p.o.) treated normal and diabetic animals at varying time intervals (1 and 12 weeks). The increase in the serum triglycerides and cholesterol levels was attenuated in the cyclo dextrin complexes of rutin-treated animals significantly more than in the quercetin-treated and diabetic vehicle-treated animals. Left ventricular diastolic dysfunction was observed in diabetic vehicle-treated animals after 12 weeks of the study as determined by a significant decrease in E-wave (45.91%), an increase in the A-wave (75.55%), and a decrease in the E/A ratio (70.14%). However, the percent decrease (after 12 weeks) in the E-wave, increase in the A-wave, and decrease in the E/A ratio were less in the cyclodextrin complexes of rutin-treated animals (100 and 300 mg/kg), which had the following values: E-wave, 12.22% and 13.80%; A-wave, 25.90% and 10.40%; and E/A ratio, 31.01% and 20.52%. In the quercetin-treated animals (100 and 300 mg/kg), which had the following values: E-wave, 40.44% and 36.44%; A-wave, 52.98% and 29.28%; and E/A ratio, 61.70% and 51.11%. Histopathological studies revealed that the degree of myocardial necrosis was less in rutin-treated animals compared with quercetin and diabetic vehicle-treated animals: rutin < quercetin < beta-cyclodextrin. Myocardial fructose levels were significantly increased in the diabetic vehicle-treated animals after 12 weeks of the study, suggesting an increment in the myocardial polyol pathway activity. However, myocardial fructose levels were significantly decreased in the rutin- and quercetin-treated animals compared with the vehicle-treated animals, possibly owing to their aldose reductase inhibitory activity. Quercetin and rutin treatment did not influence the echocardiographical and histo logical parameters in normal animals. Results from the present investigation demonstrated that rutin has a cardioprotective activity, and we conclude that the observed cardioprotection with rutin may be due to its aldose reductase inhibitory activity, as the enhanced aldose reductase pathway is implicated in the development of left ventricle dysfunction by several studies.