Coronary hyperemia and cardiac hypertrophy following inhibition of fatty acid oxidation. Evidence of a regulatory role for cytosolic phosphorylation potential.
Oxfenicine (S-4-hydroxyphenylglycine) is a cardioselective inhibitor of long-chain fatty acid oxidation. In anesthetized dogs, oxfenicine (3.3 mg/kg, i.v.) increased myocardial blood flow by 33% under normal conditions and by 71% during isoprenaline infusion, but produced no other hemodynamic changes. Similar results were obtained with two other inhibitors of fatty acid oxidation, 2-bromopalmitate and 2-tetradecylglycidate. Chronic administration of oxfenicine to dogs for 1 year produced dose-related, nonpathological increases in relative heart weight (up to 85% at 750 mg/kg per day). Smaller effects (up to 30% at 900 mg/kg per day) were observed in a similar study in rats. Cardiac hypertrophy has previously been reported in rodents treated with 2-tetradecylglycidate. Moreover, cardiomegaly is frequently observed in cases of carnitine deficiency. We therefore suggest that coronary hyperemia and cardiac hypertrophy following either inhibition of fatty acid oxidation or an increase in cardiac work load may be adaptive changes triggered by a common mechanism-namely, a fall in cytosolic phosphorylation potential. In support of this, oxfenicine decreased the phosphocreatine/creatine ratio in rat hearts perfused in the presence of oleate. These findings suggest the possibility that metabolic abnormalities may provide the key to many idiopathic cardiomyopathies of uncertain origin.
Higgins
A J
AJ
Faccini
J M
JM
Greaves
P
P
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced*; D003326:Coronary Circulation / Q000187:drug effects*; D003401:Creatine / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects*; D004285:Dogs; D005227:Fatty Acids / Q000037:antagonists & inhibitors*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology; D010725:Phosphocreatine / Q000378:metabolism*; D010766:Phosphorylation
D005227:Fatty Acids; D010168:Palmitates; D010725:Phosphocreatine; C022776:2-bromopalmitate; D000244:Adenosine Diphosphate; C023010:4-hydroxyphenylglycine; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D003401:Creatine; D005998:Glycine