Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia.
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 microg 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 micromol 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.
Chandler
Margaret P
MP
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA. mpc10@po.cwru.edu
Chavez
Pedro N
PN
McElfresh
Tracy A
TA
Huang
Hazel
H
Harmon
Charles S
CS
Stanley
William C
WC
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D019344:Lactic Acid / Q000097:blood; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D013552:Swine
D001786:Blood Glucose; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D019344:Lactic Acid; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D005998:Glycine