Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl CoA levels.
OBJECTIVE
Malonyl CoA is an important regulator of fatty acid oxidation in the heart secondary to its ability to inhibit carnitine palmitoyltransferase 1 (CPT 1). Malonyl CoA is produced from acetyl CoA in a reaction catalyzed by acetyl CoA carboxylase (ACC). In this study we determined if alterations in malonyl CoA regulation of fatty acid metabolism are involved in the increase in energy transduction seen following an increase in cardiac work.


METHODS
Anesthetized, open-chest, domestic swine were subjected to a 30 min control period followed by a 30 min treatment period with either dobutamine (15 micrograms.kg-1. min-1 i.v.) (n = 6) or saline (n = 6).


RESULTS
Heart rate, left ventricular peak dp/dt, and MVO2, were significantly increased in the dobutamine group compared to the saline group during the treatment period. Free fatty acid and glucose uptake were increased 210 and 248%, respectively, in the dobutamine group during the treatment period. Malonyl CoA content was decreased by 55% (from 0.40 +/- 0.05 to 0.18 +/- 0.12 nmol/g wet wt; P < 0.05) with dobutamine treatment, but was not affected by saline treatment. ACC activity was not significantly different between groups (0.31 +/- 0.02 vs. 0.30 +/- 0.04 nmol. min-1. mg protein-1, respectively). The activity of AMP-dependent protein kinase (AMPK), which phosphorylates and inactivates ACC, was also not significantly different in the dobutamine hearts compared to the saline hearts (322 +/- 26 vs. 338 +/- 39 pmol. min-1. mg protein-1, respectively).


CONCLUSIONS
The increased cardiac work following dobutamine infusion is accompanied by a decrease in malonyl CoA levels and an increase in fatty acid uptake. However, the decrease in malonyl CoA cannot be explained by a decrease in ACC activity.
Hall
J L
JL
Section of Cardiovascular Pharmacology, Syntex Discovery Research, PaloAlto, CA 94304, USA.
Lopaschuk
G D
GD
Barr
A
A
Bringas
J
J
Pizzurro
R D
RD
Stanley
W C
WC
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D019344:Lactic Acid; D004280:Dobutamine; D008316:Malonyl Coenzyme A; D005947:Glucose; D010100:Oxygen