Effects of inhibition of fatty acid oxidation on myocardial kinetics of 11C-labeled palmitate.
The effects of glucose and lactate infusion on palmitate oxidation were compared with the effect of 2-tetradecylglycidic acid (TDGA), an irreversible inhibitor of the carnitine acyltransferase I, in normoxic canine myocardium. The initial capillary transit retention fraction of [1-11C]palmitate and its fractional distribution between oxidation and esterification in myocardium were measured by the residue detection method after intracoronary tracer injection, as well as by effluent measurements of 11CO2, the end product of palmitate oxidation. TDGA reduced the initial capillary transit retention fraction (from 56 +/- 13% to 37 +/- 6%; p less than 0.001) and oxidation of palmitate (n = 19), as also evidenced by the decrease in the fraction of tracer released as 11CO2 from 28 +/- 5% to 6 +/- 3% (p less than 0.001). Infusion of carbohydrate (glucose or lactate; n = 6) reduced 11CO2 production from 30 +/- 7% to 7 +/- 4% (p less than 0.05) but did not alter the initial capillary transit retention fraction of tracer (59 +/- 5% vs. 56 +/- 10%; NS). The latter was due to increased esterification into neutral lipids (41 +/- 11% of injected palmitate after carbohydrate infusion versus 21 +/- 12% in control conditions), as measured from multiexponential curve fittings. When carbohydrates were given after inhibition of palmitate oxidation by TDGA (n = 7), the 11C tissue clearance kinetics were strikingly similar to those observed after carbohydrate infusion alone. Thus, enhanced metabolic trapping of [1-11C]palmitate in myocardium resulted in initial capillary transit retention fractions that were not different from control conditions (41 +/- 5% vs. 48 +/- 12%; NS) despite inhibition of oxidation. The results show that the intracellular metabolism of palmitate contributes to the control of its uptake by myocardium. The findings are consistent with inhibition of palmitate oxidation by carbohydrates occurring at the same site as TDGA.
Wyns
W
W
Division of Nuclear Medicine and Biophysics, UCLA School of Medicine 90024.
Schwaiger
M
M
Huang
S C
SC
Buxton
D B
DB
Hansen
H
H
Selin
C
C
Keen
R
R
Phelps
M E
ME
Schelbert
H R
HR
D000818:Animals; D050260:Carbohydrate Metabolism; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors; D004285:Dogs; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism* / Q000493:pharmacokinetics
D004852:Epoxy Compounds; D005227:Fatty Acids; D007328:Insulin; D007773:Lactates; D010169:Palmitic Acids; D019308:Palmitic Acid; D002333:Carnitine Acyltransferases; D005947:Glucose; C021756:2-tetradecylglycidic acid