bm-42304 and octanoic-acid

Myocardial fatty acid oxidation has been reported to be accompanied by an elevated O2 consumption compared with carbohydrate oxidation. The exact amount of this additional O2 consumption is controversial. Different investigators have observed an O2 wasting effect that is too large to be explained by the different ATP-to-O2 ratios of these substrates. With the use of isolated perfused rat hearts, O2 consumption and hemodynamic measurements were computer analyzed to provide on-line estimates of the ratio between O2 consumption and demand (EQ). Increasing palmitate or octanoate concentrations decreased the respiratory quotient, which was accompanied by a disproportionate increase of EQ. Inhibition of fatty acid oxidation by an inhibitor of acylcarnitine transferase or a blockade of mitochondrial thiolase caused a drastic reduction of fatty acid oxidation. The fatty acid-induced enhancement of O2 consumption was decreased to a much smaller extent, indicating that there are two different mechanisms responsible for the O2-wasting effect, one that depends on mitochondrial fatty acid oxidation and another that is not affected by an inhibition of this pathway.

Topics: Animals; Caprylates; Cinnamates; Crotonates; Energy Metabolism; Fatty Acids, Nonesterified; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxygen Consumption; Palmitates; Perfusion; Rats; Time Factors

A new hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate MCHP (BM 42.304) was shown to be an inhibitor of the transfer of long-chain fatty acids across the mitochondrial inner membrane. The following data support this conclusion: the drug, at already 5 microM, inhibited ketogenesis from oleate but not from octanoate in the perfused guinea-pig liver; likewise, ketogenesis from L-(-)-palmitoylcarnitine and palmitoyl-CoA + L-(-)-carnitine, but not from octanoate, was depressed in isolated guinea-pig liver mitochondria. Oxigraphic measurements of the oxygen uptake by isolated mitochondria showed that the drug impaired oxygen uptake with the long-chain fatty acid derivatives but not with octanoate. Finally, in vivo effects of the drug such as hypoketonemia and an increased concentration of free fatty acids in blood are in agreement with the above formulated mechanism of action. A comment is given on the relationships between fatty acid oxidation and gluconeogenesis in the guinea-pig liver.

Topics: Animals; Caprylates; Cinnamates; Female; Gluconeogenesis; Guinea Pigs; Hypoglycemic Agents; Ketone Bodies; Liver; Male; Mitochondria, Liver; Oleic Acid; Oleic Acids; Oxygen Consumption; Phosphoenolpyruvate