Effects of pent-4-enoate on cellular redox state, glycolysis and fatty acid oxidation in isolated perfused rat heart

Abstract

The metabolic effects of pent-4-enoate were studied in beating and potassium-arrested perfused rat hearts. The addition of 0.8imM-pent-4-enoate to the fluid used to perfuse a potassium-arrested heart resulted in a 70 % increase in the 02 consumption and a 66 % decrease in the glycolytic flux as measured in terms of the de-tritiation of [3-3H]glucose, although the proportion of the 02 consumption attributable to glucose oxidation decreased from an initial 30 % to 10 %. The pent-4-enoate-induced increase in 02 consumption was only 15 % in the beating heart. In the potassium-arrested heart, pent-4-enoate stimulated palmitate oxidation by more than 100% when measured in terms of the production of "4CO2 from [1-14C]palmitate, but in the beating heart palmitate oxidation was inhibited. Perfusion of the heart with pent-4-enoate had no effect on the proportion of pyruvate dehydrogenase found in the active form, in spite of large changes in the CoASH and acetyl-CoA concentrations and changes in their concentration ratios. The effects of pent-4-enoate on the cellular redox state were dependent on the ATP consumption of the heart. In the beating heart, pent-4-enoate caused a rapid mitochondrial NAD+ reduction that subsequently faded out, so that the final state was more oxidized than the initial state. The arrested heart, however, remained in a more reduced state than initially, even after the partial re-oxidation that followed the initial rapid NAD+ reduction. The ability of pent-4-enoate to increase or decrease fatty acid oxidation can be explained on the basis of the differential effects of pent-4-enoate on the concentration of citric acid-cycle intermediates under conditions of high or low ATP consumption of the myocardial cell. The proportion of the fatty acids in the fuel consumed by the heart is probably primarily determined by the regulatory mechanisms of glycolysis. When pent-4-enoate causes an increase in the citric acid-cycle intermediates, feedback inhibition of glycolysis results in an increase in the oxidation of fatty acids.

Effects of 5-hydroxydecanoate and ischemic preconditioning on the ischemic-reperfused heart of fed and fasted rats

“…These findings appear rather similar to recent observations concerning 5-HD metabolism which besides its inhibitory effect on the K-ATPmito is a substrate for enzymes of the 13-oxidative pathway (8). Taken together, these evidences suggest that the inhibitory effect of 5-HD on lactate production might be ascribed to a slowed glycolytic rate through the inhibition 6-phosphofructokinase due to an increase of citrate (9) or to the accumulation of its own oxidative metabolites (25). On the other hand, these metabolic effects of 5-HD do not seem to be the consequence of the blockade of K-ATPmito since it has been previously found that diazoxide exerted an inhibitory effect on lactate production (10).…”

Elimination and replenishment of tricarboxylic acid-cycle intermediates in myocardium

“…We have previously demonstrated that the metabolism of pent-4-enoate and pentanoate in the isolated perfused rat heart is rapid and leads to an accumulation of tricarboxylic acid-cycle intermediates (Hiltunen, 1978;Hiltunen et al, 1978), accompanied by incorporation of H'4CO3-into these intermediates . Moreover, the rate of CO2 fixation was appreciable even in the absence of odd-carbon fatty acids.…”

Isolated rat heart mitochondria are able to metabolize pent-4-enoate to tricarboxylic acid-cycle intermediates

“…In earlier experiments performed in our laboratory, pent-4-enoate caused a considerable increase in the concentration of tricarboxylic acid-cycle intermediates in perfused hearts, especially in that of malate, and pentanoate caused a similar metabolic change. These results suggested that acryloyl-CoA formed during the fl-oxidation of pent-4-enoate could undergo reduction in cardiac muscle, after which the C3 compound is metabolized to tricarboxylic acid-cycle intermediates (Hiltunen, 1978;Hiltunen et al, 1978). The enzyme system which reduces acryloyl-CoA in mammalian tissue is not known, and the possibility that pent-4-enoyl-CoA is reduced to pentanoyl-CoA cannot be excluded.…”

“…The metabolic fate of the acryloyl group is still uncertain. Perfused liver is able to oxidize pent-4-enoate continuously provided that its concentration in the perfusion medium is not too high (Williamson et al, , 1970), and we have suggested previously, on the basis of experiments say whether the compound reduced is with pent-4-enoate and perfused rat hearts, that cardiac muscle is able to metabolize it by a mechanism in which the carbon skeleton of the acryloyl part of pent-4-enoate is transformed to tricarboxylic acid-cycle intermediates via the propionate pathway (Hiltunen, 1978;Hiltunen et al, 1978). The aim of the present work was to ascertain whether isolated heart mitochondria can metabolize pent-4-enoate.…”

“…The rapidity of this pathway leading to physiological compounds explains the short half-life (20min) of blood pent-4-enoate (Sherratt, 1978;Osmundsen & Sherratt, 1978), the high concentrations (1 mM) needed for inhibiting fatty acid oxidation and gluconeogenesis in bicarbonate-containing systems (Hiltunen et al, 1978;Williamson et al, 1970) and high doses (250mg/kg body wt.) needed for the hypoglycaemic effect of pent-4-enoate in animals (Corredor et al, 1967).…”