Effects of the fatty acid blocking agents, oxfenicine and 4-bromocrotonic acid, on performance in aerobic and ischemic myocardium.
Two fatty acid blocking agents, oxfenicine (33 mg/kg) and 4-bromocrotonic acid (0.34 mg/kg/min for 70 min), were used to selectively adjust levels of long-chain acyl CoA and carnitine in aerobic and ischemic myocardium. The purpose of the study was to test whether the shift in these amphiphiles was associated with alterations of mechanical function in intact myocardium. The extracorporeally perfused swine heart preparation was used. Hearts were perfused at aerobic levels for 40 min following which flow to the anterior descending (LAD) circulation was reduced by 50% for the final 30 min of perfusion. All hearts were perfused with excess fatty acids to raise serum levels to 1.37 +/- 0.16 mumol/mol throughout the studies. Oxfenicine and 4-bromocrotonic acid affected a 20% (P less than 0.05 and P less than 0.05, respectively) further decline in 14CO2 production from labelled palmitate as compared with placebo hearts during regional ischemia. Accompanying this were downward shifts in acyl carnitine (-27 delta %, NS in aerobic tissue; -70 delta %, P less than 0.001 in ischemic tissue) and acyl CoA (-13 delta %, NS in aerobic tissue; -33 delta %, P less than 0.01 in ischemic tissue) for oxfenicine and upward shifts of acyl carnitine (+212 delta %, P less than 0.001 in aerobic tissue; -9 delta %, NS in ischemic tissue) and acyl CoA (+78 delta %, P less than 0.001 in aerobic tissue; +29 delta %, P less than 0.025 in ischemic tissue) for 4-bromocrotonic acid. These adjustments in amphiphiles were further associated with improved function (+55 delta % increase in max LV dP/dt, P less than 0.05) in oxfenicine-treated hearts and depressed function (+87 delta % increase in LVEDP, P less than 0.05) in 4-bromocrotonic acid-treated hearts. Thus, at comparable conditions of coronary flow, left ventricular pressure, and fatty acid availability and oxidation between treatments, depletion or build-up of CoA and carnitine esters as affected by selective inhibitors of fatty acid metabolism were causally linked to improved or impaired cardiac performance in intact hearts.
D000332:Aerobiosis; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D002331:Carnitine / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D003327:Coronary Disease / Q000378:metabolism*; D003437:Crotonates / Q000494:pharmacology*; D005227:Fatty Acids / Q000037:antagonists & inhibitors*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000378:metabolism; D010477:Perfusion; D013552:Swine
D002087:Butyrates; D003437:Crotonates; D005227:Fatty Acids; D010168:Palmitates; C034444:4-bromocrotonic acid; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine; D005998:Glycine