Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat.
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. beta-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 after chronic metoprolol treatment and acute metoprolol perfusion. Chronic metoprolol treatment attenuated the development of cardiac dysfunction in streptozotocin (STZ)-diabetic rats. After 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 acetyl-CoA carboxylase phosphorylation or AMP-activated protein kinase activity were observed. Both acute metoprolol perfusion and chronic in vivo metoprolol treatment led to decreased maximum activity and decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA. Metoprolol also increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression and prevented the reexpression of atrial natriuretic peptide in diabetic hearts. These data demonstrate that metoprolol ameliorates diabetic cardiomyopathy and inhibits fatty acid oxidation in streptozotocin-induced diabetes. Since malonyl-CoA levels are not increased, the reduction in total carnitine palmitoyltransferase I 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.
Sharma
Vijay
V
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Univ. of British Columbia, Vancouver, Canada.
Dhillon
Pavan
P
Wambolt
Richard
R
Parsons
Hannah
H
Brownsey
Roger
R
Allard
Michael F
MF
McNeill
John H
JH
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology* / Q000627:therapeutic use; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011768:Pyruvate Dehydrogenase Complex; D019308:Palmitic Acid; D008316:Malonyl Coenzyme A; D009320:Atrial Natriuretic Factor; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000103:Acetyl-CoA Carboxylase; D008790:Metoprolol; D005947:Glucose