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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Cellular uncoupling induced by accumulation of long-chain acylcarnitine during ischemia.

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.[1]

References

  1. Cellular uncoupling induced by accumulation of long-chain acylcarnitine during ischemia. Yamada, K.A., McHowat, J., Yan, G.X., Donahue, K., Peirick, J., Kléber, A.G., Corr, P.B. Circ. Res. (1994) [Pubmed]
 
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