The major aim of the project is to evaluate voltage-gated Ca2+ currents (ICa) and Na+-Ca2+ exchange currents (I Na-Ca) as sources of the Ca2+ influx required for tension generation in developing cardiac cells. In mature myocardium, Ca2+ influx via ICa induces the release of large quantities of Ca2+ stored in the sarcoplasmic reticulum (SR). INa- ca and other Ca2+ pumps act largely to remove Ca2+ from the sarcoplasma which induces cellular relaxation. The precise role of these mechanisms in Ca2+ influx and cell contraction in immature myocardium is not know. The precise role of these mechanisms in Ca2+ influx and cell contraction in immature myocardium is not known. However, previous studies have documented fundamental differences in cell structure, contractile function and dependence on external Ca2+ between immature and mature heart. This proposal examines the hypothesis that INa-Ca plays a significant role in Ca2+ influx and activation of cell contraction in immature myocardium. During the initial stage of the project, the whole-cell voltage clamp technique will be used to distinguish and extensively characterize ICa and I-Na-Ca in single cardiac myocytes isolated from rabbits at various stages of development (fetal through adult). Since ICa and INa-Ca may contribute in a synergistic fashion to net Ca2+ influx, the relative contribution of each will then be determined by simultaneous measurements of the magnitude and time course of each current as compared to the magnitude of the associated cell contraction. While the project examines basic issues in cellular electrophysiology and excitation-contraction coupling, it also has immediate clinical significance. It directly addresses the possibility that there are fundamental differences in the mode of action of Ca2+ channel blockers at various stages of development.
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