Control of Oxidative Metabolism in Volume-Overloaded Rat Hearts
Chronic mechanic overloading of the heart has been shown to lead to a significant depletion of tissue carnitine (1,2) that is possibly related to impaired carnitine transport to the myocardium (3, 4). At the same time, the ability of chronically overloaded hearts to oxidize exogenous palmitate is diminished (5, 6). This decrease of long-chain fatty acid utilization is accompanied by reduced myocardial oxygen consumption (MVO2) and gives rise to an impaired mechanical activity during in vitro perfusions (6, 7). Most of the above quoted alterations disappear when exogenous palmitate is replaced by octanoate, a short-chain fatty acid that has free access to mitochondrial matrix (8). This suggests that the respiratory chain of volume-overloaded rat hearts perfused in presence of long-chain fatty acids may be actually substrate limited (7). In this work, we tried to improve NADH delivery to respiratory chain by a prolonged treatment of volume-overloaded rats with millimolar concentrations of propionyl-L-carnitine (9). It has been shown that the administration of this compound significantly increases both blood plasma concentrations and myocardial tissue levels of L-carnitine (10, 11). This, in turn, may improve long chain fatty acid utilization (5) and glucose oxidation (12) via a decreased acetyl-CoA/CoA ratio (13, 14). The control and volume-overloaded hearts were perfused with 11 mM glucose and 1.2 mM palmitate (2.4 mM octanoate) over a range of left ventricular work loads, leading to a progressive increase in the myocardial V02 (7). The respective relationships between the rates of oxidative phosphorylation and different intracellular energy parameters ((cytosolic phosphorylation potential (ATP/ADPf.Pi), ADPf, and mitochondrial NAD+/NADH ratio)) as obtained in control and volume-overloaded hearts were compared for each metabolic condition examined. The effects of the pretreatment with propionyl-L-carnitine on the kinetics of oxidative phosphorylation were tested under conditions of a high work load (heart ejecting against an increased aortic resistance related to the clamp of the aortic outflow line) as described previously (6, 7).
KeywordsGlucose Oxidation Myocardial Oxygen Consumption Control Heart Fatty Acid Utilization Palmitate Oxidation
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