Effect of N-acetylcysteine on cardiovascular function in two rat models of diabetes

JYT Leung, CCY Pang. University of British Columbia, Department of Anesthesiology, Pharmacology & Therapeutics, V6T1Z3, Canada

Objective: Diabetes is associated with increased oxidative stress, which plays a major role in the development of cardiovascular complications. This study investigated if reducing oxidative stress with N-acetylcysteine (NAC) restores in vivo cardiac and vascular contractile functions to dobutamine and noradrenaline, respectively, in two rat models of diabetes, induced through i.v. injection of streptozotocin (STZ), or a combination of high fructose (FRU) feeding and subsequent injection of STZ (FRU-STZ).

Methods: Male Wistar rats (200-250 g) were divided into six groups: control, NAC-treated control, STZ, NAC-treated STZ, FRU-STZ, and NAC-treated FRU-STZ. Control and STZ rats were fed a normal diet, while FRU-STZ rats were fed a diet high in FRU (60% of caloric intake) starting on day 0 until the end of the study at week 6. STZ (50 mg/kg i.v. bolus) was given at week 2 and NAC (1.5 g/kg/day p.o.) administration started at week 3 until the end of the study. Following 6 weeks of feeding, the effects of dobutamine (0.3-30 µg/kg/min i.v.) on cardiac contractility, and of noradrenaline (3 and 8 nmol/kg/min i.v.) on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP, index of body venous tone) were determined in the six groups of conscious rats (n = 7-9 per group).

Results: All diabetic rats injected with STZ had lower body weight and higher blood glucose than control rats. Those fed with a high FRU diet also had markedly elevated plasma triglyceride levels. Dobutamine dose-dependently increased left ventricular contractility; however, the responses were significantly (P<0.05) less in both the STZ and FRU-STZ groups. These two groups also exhibited significantly reduced MAP and MCFP responses to noradrenaline relative to the control group. NAC did not affect cardiac and vascular responses in the control rats, but significantly increased cardiac contractility to dobutamine and the MAP and MCFP responses to noradrenaline in both diabetic groups.

Conclusion: In vivo cardiac contraction to dobutamine, as well as arterial and venous constrictions to noradrenaline were attenuated in rats with STZ- and those with FRU-STZ-induced diabetes. Chronic treatment with the antioxidant NAC partially restored cardiac and vascular contractile functions in these rats.