Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia.

Electrophysiological and biochemical sequelae of myocardial ischemia occur within minutes of the onset of myocardial ischemia in vivo. Both conduction delay and conduction block occur rapidly within the same time interval as the accumulation of long-chain acylcarnitines. In the present study, double whole-cell voltage-clamp procedures were used to assess the influence of long-chain acylcarnitines on gap junctional conductance in isolated pairs of canine ventricular myocytes. Long-chain acylcarnitine (5 microM) decreased gap junctional conductance from 153 to 48 nS in a time-dependent and reversible manner. Although the amplitude of junctional current was reduced by 68%, the current continued to demonstrate a linear current-voltage relation. The extent of endogenous accumulation of long-chain acylcarnitines in junctional regions of the sarcolemma was assessed in isolated myocytes in which endogenous free, short-chain, and long-chain acylcarnitine pools had been equilibrated with [3H]carnitine. Under normoxic conditions, long-chain acylcarnitines were not detectable in junctional sarcolemma of myocytes as assessed using electron microscopic autoradiography. Exposure of myocytes to hypoxia (PO2, < 15 mm Hg) for 10 minutes resulted in the preferential accumulation of endogenous long-chain acylcarnitines in junctional sarcolemma (173 +/- 5 x 10(5) molecules/microns 3), a concentration that was sevenfold greater than that found in nonjunctional sarcolemma. Therefore, endogenous long-chain acylcarnitines accumulate preferentially in junctional regions of the sarcolemma during short intervals of hypoxia. Exogenously supplied long-chain acylcarnitines can markedly decrease cellular coupling in a reversible manner, suggesting that this amphiphile may contribute to the marked slowing in conduction velocity in the ischemic heart in vivo, not only by suppressing the rapid Na+ inward current directly, as has been shown previously, but also by decreasing cellular coupling.