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Protective effects of metoprolol and ascorbic acid during the development of diabetic cardiomyopathy

University of British Columbia

The existence of a heart muscle disorder specific to Diabetes Mellitus (DM) has been proposed, termed, Diabetic Cardiomyopathy (DCM). DCM is defined as the presence of an early asymptomatic diastolic dysfunction that eventually progresses to overt systolic dysfunction in the absence of ischemic or valvular heart disease. Metabolic impairment and increased oxidative stress have been highlighted as causes. The β-blocker metoprolol is known to improve function in diabetic rat hearts, possibly through amelioration of the sequelae associated with oxidative stress, without lowering oxidative stress. It is unclear if lowering oxidative stress in concert with metoprolol treatment would improve function further. Ascorbic Acid (AA) is a potent antioxidant and has been shown to improve function in the diabetic rat heart. Hypothesis: We propose that metabolic changes that occur during diabetes elevate oxidative stress, leading to protein damage, signaling changes, cell death and other sequelea; the eventual sum of these changes is an impairment of function. Treatment of either the sequelae of oxidative stress or oxidative stress directly will be beneficial but treatment of both will improve function further. To accomplish our study we induced DM in male Wistar rats using 60 mg/kg streptozotocin and treated them with metoprolol at 15 mg/kg/day via osmotic pump and/or AA at 1000 mg/kg/day via drinking water. In order to study the effect of treatment on the development of dysfunction we studied a time point before and after development of dysfunction (5 and 7 weeks, respectively). Blood was collected to assess the severity of diabetes and echocardiography performed to assess in vivo heart function. At termination, ex vivo heart function and substrate use were measured by working heart perfusion. Tissue was collected for measurements of metabolite levels and oxidative protein damage. Function significantly worsened in association with metabolism and oxidative damage. Both drugs improved function, while only AA reduced oxidative damage. Combined treatment led to improvement in function more pronounced then single treatment. Our β-blocker and antioxidant treatment strategy focuses on oxidative stress, and not on diabetes specifically, thus it may prove useful in other disease where oxidative stress contributes to pathology.

Text

2012-04-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42141

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/