Following occlusion of the left anterior descending canine coronary artery, some myocardial and Purkinje fibers survive in the infarcting region, but undergo electrophysiological changes during the subsequent hours and days. These changes can cause arrhythmias. Of particular interest is the pronounced membrane depolarization seen in the subendocardial Purkinje fibers at 24 hours after ligation, and the role played by the resulting abnormal automaticity of these fibers in generating the subacute arrhythmias. A broad objective of the project is to determine to what extent changes in intracellular ion activity induce these electrical normalities, and to develop specific pharmacologic interventions which counter the progression of these ionic and electrical abnormalities. Only when the mechanisms causing the arrhythmias are understood at this most basic level can more effective means to treat them be developed. One approach is to use isolated preparations from infarcted canine hearts. The arrhythmias which are caused by experimental myocardial infarction in the dog resemble in many ways arrhythmias which occur in humans in terms of mechanisms and response to drugs, making this a sound approach. The experimental design uses double barreled ion selective microelectrodes to measure both ion activity and membrane potential in the cell impaled. During previous experiments with this techniques, marked abnormalities in the intracellular K+ and Na+ activity were found 24 hours after ligation. These abnormalities implicate membrane conductance changes as well as Na/K pump suppression. Quantitative and qualitative differences in the behavior of both ions as early as 1 hour after ligation indicate that the development of ionic abnormalities during the first day after ligation is a slow and complex process. Having identified various stages in the ionic responses during ischemic progression, we will apply whole cell patch clamp and cable analysis to identify underlying membrane mechanisms. This will increase our understanding of the cellular mechanisms involved in these slowly developing arrhythmogenic ionic alterations and hopefully lead to development of clinical interventions which can block them.
| Lasker, S M; Han, D; Kline, R P (1997) Zatebradine slows ectopic ventricular rhythms in canine heart 24 hours after coronary artery ligation. J Cardiovasc Pharmacol 29:662-9 |
| Cui, J; Kline, R P; Pennefather, P et al. (1994) Gating of IsK expressed in Xenopus oocytes depends on the amount of mRNA injected. J Gen Physiol 104:87-105 |
| Binah, O; Kline, R; Berke, G et al. (1993) Mechanisms whereby lytic granules from cytotoxic T lymphocytes damage guinea pig ventricular myocytes. Scand J Immunol 37:53-7 |
| Kline, R P; Sorota, S; Dresdner, K P et al. (1993) Spontaneous activity in transgenic mouse heart: comparison of primary atrial tumor with cultured AT-1 atrial myocytes. J Cardiovasc Electrophysiol 4:642-60 |
| Kline, R P; Hanna, M S; Dresdner Jr, K P et al. (1992) Time course of changes in intracellular K+, Na+, and pH of subendocardial Purkinje cells during the first 24 hours after coronary occlusion. Circ Res 70:566-75 |
