Control of oxidative metabolism in volume-overloaded rat hearts: effect of propionyl-L-carnitine.

Abstract

The objective of the present work was the assessment of metabolic events responsible for the improvement of hemodynamic function of volume-overloaded hearts from rats receiving propionyl-L-carnitine. A severe cardiac hypertrophy was induced in 2-mo-old rats by surgical opening of an aortocaval communication. Three months later, during in vitro perfusions with 1.2 mM palmitate, 11 mM glucose, and 10 IU/l insulin, the mechanical performance and overall energy turnover (myocardial O2 consumption) of hypertrophied rat hearts were significantly decreased under conditions of moderate and high workloads. These changes in cardiac energetics paralleled the decrease in total tissue carnitine content and alterations in exogenous palmitate oxidation. The oxidative utilization of glucose was also slightly depressed in volume-overloaded hearts while steady-state glycolysis rates increased, especially in hearts subjected to high mechanical loads. This slowing of metabolic pathways involved in acetyl-CoA generation resulted in decreased NADH availability and in an apparent substrate limitation of oxidative phosphorylation suggested by a failure of cytosolic unbound ADP to drive respiration. Long-term administration of propionyl-L-carnitine normalized the degree of reduction of mitochondrial pyridine nucleotides and improved the kinetics of mitochondrial ATP production in volume-overloaded hearts. The resulting acceleration of energy turnover was essentially related to improved oxidative utilization of glucose, but steady-state palmitate oxidation rates also increased in severely hypertrophied hearts. This concomitant acceleration of glucose and palmitate oxidation may be related to the particular experimental conditions (high exogenous palmitate concentrations, elevated workloads) used in this study. We assume that the increase in intracellular carnitine, together with a stimulation of acetyl-CoA demands related to high workloads, creates conditions that are compatible with the simultaneous relief of pyruvate dehydrogenase and carnitine palmitoyltransferase I. The resulting increase in the rate of steady-state ATP production improves, in turn, the mechanical activity of volume-overloaded hearts.