Effects of (+)-octanoylcarnitine in intact myocardium.
Fatty acid metabolites (long-chain esters of CoA and carnitine) which collect in ischemic myocardium can form amphiphiles capable of disrupting subcellular performance. It is important to document the role of these amphiphiles in intact tissue. D-Octanoylcarnitine was chosen because of its previously described effects on inhibiting palmitoylcarnitine transferase (PCT-II) in in vitro and in vivo liver preparations. This inhibition will shift tissue levels of CoA and carnitine intermediates and thus alter amphiphile levels. The compound's actions in cardiac muscle are unknown. Dose response curves were developed in intact hearts to test the influence of D-octanoylcarnitine at pharmacological concentrations. Measurements were obtained in working, extracorporeally perfused, swine hearts. Drug was administered either systemically (IV) or via direct intracoronary (IC) infusions into the left anterior descending coronary circulation. Excess fatty acids were provided to ensure adequate fatty acid substrate for oxidation. Coronary flow was controlled at aerobic levels. Systemic administration of D-octanoylcarnitine (0.8-6.8 mM) resulted in transient peripheral hypotension which caused correlative decreases in 14CO2 production from labeled palmitate. Infusion of D-octanoylcarnitine (0.5-3.9 mM) IC did not cause appreciable hypotension and was not associated with suppression of fatty acid oxidation. No build-up of carnitine esters was noted in treated hearts but acyl CoA levels were reduced (p less than or equal to 0.002). This latter finding was modestly related to increasing dose schedule of the compound in the IC group. The lack of suppression in fatty acid oxidation argues against significant inhibition of PCT II and lessens the attractiveness of using D-octanoylcarnitine in intact myocardium to selectively block fatty acid utilization at this locus.
DeMaison
L
L
Section of Cardiology, University of Wisconsin, Madison.
Cohen
L M
LM
Liedtke
A J
AJ
Nellis
S H
SH
Whitesell
L F
LF
Eggleston
A
A
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000108:Acetylcarnitine / Q000378:metabolism; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010172:Palmitoylcarnitine / Q000378:metabolism; D013552:Swine; D013997:Time Factors
C002893:decanoylcarnitine; D010172:Palmitoylcarnitine; D000108:Acetylcarnitine; D000105:Acetyl Coenzyme A; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; C008698:octanoylcarnitine; D002331:Carnitine