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Cardiovascular Research 2003 59(1):143-151; doi:10.1016/S0008-6363(03)00327-4
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia

Margaret P. Chandlera,*, Pedro N. Chavezb, Tracy A. McElfresha, Hazel Huanga, Charles S. Harmonc and William C. Stanleya

aDepartment of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA
bDivision of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, Cleveland, OH, USA
cChugai Biopharmaceuticals Inc., San Diego, CA, USA

mpc10{at}po.cwru.edu

* Corresponding author. Tel.: +1-216-368-5585; fax: +1-216-368-3952.

Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 µg kg–1 min–1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l–1; n = 7) or vehicle (n = 7). Regional anterior wall power was assessed from the left ventricular pressure–anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 µmol min–1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.

KEYWORDS Angina; Dobutamine; Heart; Energy metabolism


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