The applicant proposes to learn and apply the techniques of cellular electrophysiology to study the calcium currents in coronary smooth muscle. During the first phase of will learn the techniques of voltage clamping using the patch clamp method and the technique of measuring intracellular calcium concentration with the fluorescent dye, Fura-2. then apply these methods to study calcium currents coronary smooth muscle cells, specifically examining the time- and voltage-dependence the various calcium currents in these cells as well as the relationship between these currents, intracellular calcium concentrations, and the contractile state of the cells. We will also study the mechanism of action of calcium channel blocking drugs on smooth muscle cells. Finally, we will attempt to model the effect of these agents on calcium currents using a model similar to that of the Modulated Receptor Hypothesis, to explain the action of sodium channel blockers. The proposed area of research is an important area from both a clinical and a basic science standpoint. The understanding of the interaction between calcium currents, intracellular calcium concentrations, and smooth muscle contraction is important for the understanding and treatment of ischemic heart disease. Calcium channel blockers are widely used for the treatment of angina, hypertension, arrhythmias, and other diseases, and yet many aspects of their mechanisms of action are not yet understood. It is hoped that this proposed research will enhance the understanding of these important areas.
| Johns, J A; Anno, T; Bennett, P B et al. (1989) Temperature and voltage dependence of sodium channel blocking and unblocking by O-demethyl encainide in isolated guinea pig myocytes. J Cardiovasc Pharmacol 13:826-35 |
