Circulation Research, Vol 58, 230-240, Copyright © 1986 by American Heart Association

ARTICLES

The dependence of electrophysiological derangements on accumulation of endogenous long-chain acyl carnitine in hypoxic neonatal rat myocytes

MT Knabb, JE Saffitz, PB Corr and BE Sobel

To determine whether accumulation of long-chain acyl carnitine contributes to electrophysiological abnormalities induced by hypoxia, we characterized effects of normoxic and hypoxic perfusion on the subcellular distribution of endogenous long-chain acyl carnitine and transmembrane potentials of cultured rat neonatal myocytes. Hypoxia increased long-chain acyl carnitine more than 5-fold. Sodium 2-[5-(4- chlorophenyl)-pentyl]-oxirane-2-carboxylate (10 microM), a carnitine acyltransferase inhibitor, precluded accumulation of long-chain acyl carnitine induced by hypoxia. Tissue was processed for electron microscopy by a procedure specifically developed for selective extraction of endogenous short-chain and free carnitine but retention of endogenous long-chain acyl carnitine. In normoxic-perfused cells, long-chain acyl carnitine was concentrated in mitochondria and cytoplasmic membranous components. Only small amounts were present in sarcolemma. Hypoxia increased mitochondrial long-chain acyl carnitine by 10-fold and sarcolemmal long-chain acyl carnitine by 70-fold. After 60 minutes of hypoxia, sarcolemma contained 1.4 X 10(7) long-chain acyl carnitine molecules/micron 3 of membrane volume, a value corresponding to approximately 3.5% of total sarcolemmal phospholipid. Hypoxia also significantly decreased maximum diastolic potential, action potential amplitude and maximum upstroke velocity of phase 0. Sodium 2-[5-(4- chlorophenyl)-pentyl]-oxirane-2-carboxylate inhibited accumulation of long-chain acyl carnitine in each subcellular compartment and prevented the depression of electrophysiological function induced by hypoxia. These results strongly implicate endogenous long-chain acyl carnitine as a mediator of electrophysiological alterations induced by hypoxia.

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