Submitted on August 15, 2007
Accepted on January 17, 2008
Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin (STZ) diabetic rat
VIJAY SHARMA1, PAVAN DHILLON, Richard B Wambolt2, Hannah L Parsons3, Roger Brownsey4, Michael F. Allard5, and John Hugh McNeill6*
1 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada; , Canada
2 Pathology and Laboratory Medicine, UBC / St Paul's Hospital, Vancouver, Canada
3 Pathology, UBC, Vancouver, Canada
4 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
5 McDonald Research Laboratories/iCAPTURE Centre, University of British Columbia, Vancouver,, Canada
6 Division of Pharmacology and Toxicology, University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed. E-mail: jmcneill{at}interchange.ubc.ca.
The effects of diabetes on heart function may be initiated or compounded by the exaggerated reliance of the diabetic heart on fatty acids and ketones as metabolic fuels. b-blocking agents such as metoprolol have been proposed to inhibit fatty acid oxidation. We hypothesized that metoprolol would improve cardiac function by inhibiting fatty acid oxidation and promoting a compensatory increase in glucose utilization. We measured ex vivo cardiac function and substrate utilization following chronic metoprolol treatment and acute metoprolol perfusion. Chronic metoprolol treatment attenuated the development of cardiac dysfunction in the STZ-diabetic rats. Following chronic treatment with metoprolol, palmitate oxidation was increased in control hearts but decreased in diabetic hearts without affecting myocardial energetics. Acute treatment with metoprolol during heart perfusions led to reduced rates of palmitate oxidation, stimulation of glucose oxidation and increased tissue ATP levels. Metoprolol lowered malonyl CoA levels in control hearts only, but no changes in ACC phosphorylation or AMPK activity were observed. Both acute metoprolol perfusion and chronic in vivo metoprolol treatment led to decreased maximum activity and decreased sensitivity of CPT-1 to malonyl CoA. Metoprolol also increased SERCA expression and prevented the re-expression of ANP in diabetic hearts. These data demonstrate that metoprolol ameliorates diabetic cardiomyopathy and inhibits fatty acid oxidation in STZ-induced diabetes. Since malonyl CoA levels are not increased, the reduction in total CPT-1 activity is the most likely factor to explain the decrease in fatty acid oxidation. The metabolism changes occur in parallel with changes in gene expression.
