Contrasting effects of propionate and propionyl-L-carnitine on energy-linked processes in ischemic hearts

Abstract

Propionyl-L-carnitine, unlike L-carnitine, is known to improve myocardial function and metabolism altered during the course of ischemia-reperfusion. In this study, the effect of propionyl-L-carnitine has been compared with that of propionate and carnitine on the performance of rat hearts perfused with a glucose-containing medium either under normoxia, ischemia, or postischemic reperfusion. In the postischemic phase, contractile parameters were partially restored both in the control and in the propionate plus carnitine-treated hearts, were markedly impaired by propionate, and were fully recovered by propionyl-L-carnitine. In addition, propionyl-L-carnitine, but not propionate, reduced the functional decay of mitochondria prepared from the ischemic hearts. Even in normoxic conditions propionate, unlike propionyl-L-carnitine, caused a drastic reduction of free CoA and L-carnitine. The concomitant increase in lactate production and decrease in ATP content might be explained by the inhibition of pyruvate dehydrogenase caused by the accumulation of propionyl-CoA. Indeed, when pyruvate was the only oxidizable substrate, propionate induced a gradual decrease in developed pressure, which was largely prevented by L-carnitine. The protective effect of propionyl-L-carnitine may be a consequence of the anaplerotic utilization of propionate in the presence of an optimal amount of ATP and free L-carnitine.

Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the Heart

“…Freshly excised rat hearts were homogenized by Ultra-Turrax in a medium containing 0.18 M KCl, 10 mM EDTA, 0.5% fatty acid-poor bovine serum albumin, 10 mM Hepes, pH 7.4. To remove EDTA and albumin, mitochondrial pellets were washed twice with 0.18 M KCl, 10 mM Hepes, pH 7.4 (18). In a separate set of experiments aimed at characterizing the localization of the mitochondrial NAD ϩ glycohydrolase, mitochondria were isolated after the incubation of the whole tissue homogenate with Nagarse as previously described (20).…”

“…To achieve this, the hearts were freezeclamped with aluminum tongues cooled in liquid nitrogen, and 0.3 g of freeze-clamped tissue (stored at Ϫ70°C) was ground and mixed thoroughly with 2 ml of 14% (v/v) HClO 4 . After thawing at 4°C, this mixture was homogenized and centrifuged as previously described (18). In the case of isolated mitochondria, 0.1 ml of 21% (v/v) HClO 4 was added to 1 mg of protein/ml suspensions.…”

“…The maintenance of mitochondrial NAD ϩ is thus associated with a significant protection from myocyte death, indicating that the PTP plays a key role in this process. (18). Hearts were not stimulated, and the flow was maintained at 12 ml/min throughout all the perfusion protocols except during ischemia, which was induced by the complete abolition of coronary flow for periods ranging from 30 to 90 min.…”

The Effect of Diabetes on Acetoacetate Metabolism in Heart.

“…It seems that the defect in the catabolism of acetoacetate in diabetes can be corrected by introducing anaplerotic substance such as propionate which could enrich citric acid cycle with succinyl CoA (an essential metabolite for acetoacetate oxidation), but the inhibitory effect of propionate on D-3-HB utilization 9 preclude the use of propionate to ameliorate ketone bodies catabolism. It has been found that propionate caused a drastic reduction of free CoA and L-carnitine in the heart, Di Lisa et al 26 . L-Carnitine had no effect on acetoacetate utilization in heart from normal rats, whereas, the 16 % increase of acetoacetate utilization in diabetic state is compensated by the increase in the rate of D-3-HB production, since the rate limiting step of acetoacetate and D-3-HB oxidation, 3-oxoacid CoA-transferase [EC 2.8.3.5], is inhibited in diabetes.…”

Dipropionylcysteine Ethyl Ester Compensates for Loss of Citric Acid Cycle Intermediates During Post Ischemia Reperfusion in the Pig Heart

“…Previous studies found that treatment with propionate can improve cardiac metabolic and contractile function with ischemia and/or reperfusion [26, 27], an effect which may be attributed to increased anaplerosis. Our earlier work showed that propionate is readily converted to the CAC intermediate succinyl-CoA in pig myocardium and perfused rat hearts and thus is a very effective anaplerotic substrate in the heart [23, 28].…”