Long-chain acylcarnitines (LCACs) increase rapidly within minutes after the onset of
ischemia in vivo or
hypoxia in vitro and produce a time-dependent reversible reduction in gap junctional conductance in isolated myocyte pairs. The present study was performed to assess whether LCACs contribute to cellular uncoupling in response to
ischemia in isolated blood-perfused rabbit papillary muscles by use of simultaneous measurements of transmembrane action potentials, extracellular electrograms, extracellular K+, and tissue LCACs and
ATP. LCACs increased threefold in response to 20 minutes of no-flow
ischemia from 127 +/- 5 to 397 +/- 113 pmol/mg
protein (P < .01), concomitant with the onset of cellular uncoupling, extracellular K+ accumulation, and a marked reduction in conduction velocity and action potential duration. To assess whether inhibition of the accumulation of LCACs modified the electrophysiological alterations during
ischemia, muscles were pretreated with either
sodium 2-(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate (
POCA, 10 mumol/L) or
oxfenicine (100 mumol/L), inhibitors of
carnitine acyltransferase I. Both
POCA and
oxfenicine completely prevented the increase in LCACs even with 40 minutes of
ischemia (138 +/- 37 and 56 +/- 4 pmol/mg
protein, respectively), associated with a marked delay in the onset and progression of cellular uncoupling and
ischemic contracture. Although
POCA and
oxfenicine did not affect either the initial early rise in extracellular K+ or the initial fall in conduction velocity, both agents markedly delayed the secondary rise in extracellular K+ as well as the secondary fall in conduction velocity, independent of the level of tissue
ATP. Thus, LCACs accumulate during
myocardial ischemia and contribute substantially to the initiation of cell-to-cell uncoupling. Inhibition of
carnitine acyltransferase I and prevention of the increase in LCACs markedly delays cellular uncoupling and development of
ischemic contracture in response to
ischemia.