Inhibition of fatty acid metabolism alters myocardial high-energy phosphates in vivo.
We previously observed that isoproterenol (ISO) stimulation of the in situ porcine right ventricle (RV) increases the ratio of phosphocreatine (PCr) to ATP, accompanied by marked augmentation of myocardial free fatty acid (FFA) uptake. We hypothesized that increased FFA uptake and utilization cause the increase in PCr/ATP and that inhibition of FFA metabolism during ISO would prevent such an increase. In open-chest pigs, myocardial oxygen consumption (MVO2) of the RV free wall was increased with ISO (0.15 microgram.kg-1.min-1 iv) in the absence (n = 6) and presence (n = 6) of oxfenicine (65 mg/kg iv), an inhibitor of carnitine palmitoyltransferase I. ISO caused twofold increases in MVO2 and arterial FFA concentration. In the absence of oxfenicine, ISO increased RV FFA uptake from a control of 0.01 +/- 0.01 to 0.11 +/- 0.02 (SE) mumol.g-1.min-1. The PCr/ATP, measured by 31P-nuclear magnetic resonance spectroscopy, rose from 1.75 +/- 0.05 to 2.22 +/- 0.10 (P < 0.05). In the presence of oxfenicine, FFA uptake did not increase with ISO, despite elevated arterial FFA concentration. PCr/ATP fell from 1.65 +/- 0.05 to 1.53 +/- 0.07 (P < 0.01 vs. response without oxfenicine). In four additional pigs, arterial FFA concentration was increased in the absence of ISO by infusion of Intralipid and heparin sodium. PCr/ATP increased in each pig. When oxfenicine was administered with Intralipid, PCr/ATP decreased in each pig. We conclude that increased utilization of FFA raises the RV PCr/ATP ratio in vivo. Inhibition of FFA metabolism prevents the rise in PCr/ATP otherwise observed with ISO or with high arterial FFA.(ABSTRACT TRUNCATED AT 250 WORDS)
Schwartz
G G
GG
Cardiology Section, Department of Veterans Affairs Medical Center, San Francisco, California.
Greyson
C
C
Wisneski
J A
JA
Garcia
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors* / Q000097:blood; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006352:Heart Ventricles; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism*; D013552:Swine
D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D010725:Phosphocreatine; C023010:4-hydroxyphenylglycine; D000255:Adenosine Triphosphate; D006493:Heparin; D007545:Isoproterenol; D005998:Glycine