The objective of this project is to ascertain the mechanism(s) for the actions of l-palmitoylcarnitine (l-PC) on the electrophysiological properties of isolated myocytes. In particular, our objective is to learn how l-PC can be arrhythmogenic. Because l-PC accumulates within, and can be released from ischemic heart cells, this amphiphile has been implicated as one of the agents that induces arrhythmias. However, the mechanism(s) by which l-PC induces arrhythmias are not known. Two experimental paradigms will be used, namely, the currently clamp and voltage clamp technique with single ventricular myocytes and the cellular electrophoresis technique with erythrocytes and myocytes. With the former method, experiments will be done to measure the modifications of sarcolemmal ion transport that are induced by l-PC and quantitative reconstructions of altered ionic currents will be used to determine mechanism(s) for the arrhythmogenic effect of this amphiphile. With the cellular electrophoresis method, experiments will be done to evaluate a surface charge hypothesis for the effects of l- PC. From preliminary work, it has been concluded that l-PC acts like elevated extracellular calcium to shift the voltage-dependence of sodium and calcium currents in heart muscle cells by reducing surface negative charge. The validity of the surface charge hypothesis can be tested in electrophoresis experiments and then re-evaluated in isolated myocytes. In this way, the predictions of the surface charge hypothesis will be subjected to careful and systematic evaluations with the quantitative precision available with the voltage clamp method. With these experimental approaches, there will result not only a test of a specific hypothesis for l-PC action, but also a mechanistic description of the altered ion transport processes that are responsible for its arrhythmogenic action. The model for these experiments is one in which a normal (non-ischemic) myocyte is exposed to an abnormally high l-PC concentration arising from a damaged and abnormal (ischemic) heart cell. Eventually, it will be possible to test a myocyte model in which the cell in question is dialyzed with a solution containing l-PC. In this way, one can mimic the condition that obtains in an abnormal cell which is made ischemic and has its intracellular l-PC concentration elevated to an abnormal level.
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| Gruver, C; Pappano, A J (1993) Effect of membrane incorporation of 1-palmitoylcarnitine on surface charge of human erythrocytes. J Mol Cell Cardiol 25:1275-84 |
| Tanaka, M; Gilbert, J; Pappano, A J (1992) Inhibition of sodium pump by l-palmitoylcarnitine in single guinea-pig ventricular myocytes. J Mol Cell Cardiol 24:711-9 |
