Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine.

Abstract

Fatty acids are known to increase the severity of injury during acute myocardial ischemia. In this study, we determined the effects of a carnitine palmitoyltransferase I inhibitor, ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir) on reperfusion recovery of fatty acid perfused hearts. Following a 25-minute period of global ischemia, isolated working hearts reperfused with 1.2 mM palmitate, 11 mM glucose exhibited depressed function compared to hearts perfused with 11 mM glucose alone. A low dose of Etomoxir (10~9 M) decreased long chain acylcamitine and long chain acyl-coenzyme A (CoA) levels but did not prevent depressed function. In contrast, a high dose of Etomoxir (10~6 M) prevented the palmitate-induced depression of function but did not decrease myocardial long chain acylcamitine or long chain acyl-CoA levels. At this high dose of Etomoxir, oxygen consumption per unit work was decreased during reperfusion recovery, and ATP and creatine-phosphate levels were significantly higher after reperfusion. In aerobic hearts not subjected to ischemia, Etomoxir (10~6 M) increased glucose oxidation both in the presence and absence of palmitate, while 10"' M Etomoxir had no effect. In these aerobic hearts, only the low dose of Etomoxir decreased long chain acylcamitine and long chain acyl-CoA levels. These data demonstrate that Etomoxir (10"' M) increases functional recovery of fatty acid perfused ischemic hearts. This protection is unrelated to changes in levels of long chain acylcamitines but may be due to increased glucose use by the reperfused heart, resulting in decreased oxygen consumption per unit work.

Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia

“…In contrast to these data, previous studies have shown that decreased fatty acid oxidation during reperfusion is actually beneficial to functional recovery of the heart. 32 Normally, acetyl-CoA derived from fatty acid oxidation stimulates pyruvate dehydrogenase kinase, inactivates the pyruvate dehydrogenase complex, and decreases the rate of glucose oxidation. Therefore, if fatty acid oxidation is decreased during reperfusion, glucose oxidation would increase, leading to improved functional recovery.…”

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

“…Accordingly, the current findings do not necessarily contraindicate the strategic use of CPT-1 inhibitors in certain clinical situations. For example, such agents might still prove useful in the acute reversal of diabetic ketoacidosis (63), in the prevention of myocardial injury or arrhythmia during reperfusion of the heart after ischemia (64), or in the treatment of congestive heart failure (65).…”

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

“…However, in the previous experiment [7] when were administered a single dose (5 mmol/kg) of acetyl-DL-aminocarnitine in starved mice it was found seriously liver and kidney triglyceride levels very markedly elevated for up to 3 days. Another potent inhibitor of CPT1 was then applied in experimental condition to correct glycaemia: etomoxir, ethyl (2[6(4-chloro-phenoxy)hexyl]oxirane-2-carboxylate) [8].…”