The long-term objectives are to continue the study mechanisms of both contractile regulation and excitation contraction coupling in the heart. Clinicians have become increasingly aware that patients with congestive heart failure have completely normal myocardial contractile function. For this reason investigators are beginning to turn their attention to mechanisms of diastolic relaxation in an effort to understand their function and to assess their involvement in diastolic heart failure. Advances in this area of cardiac physiology should provide a rational basis for drug therapy in cardiac disease and ischemic injury. Here we propose to the contributions of sarcoplasmic reticular (SR) Ca sequestration and Na+-Ca2+ exchange to diastolic relaxation. We will compare the relative rates of voltage sensitive Na -dependent (Na+-Ca2+ exchange mediated) and voltage insensitive Na independent (SR mediated) relaxation. We propose a novel approach to the isolation and measurement of the Na+-Ca2+ exchange current. We will show that this current underlies voltage dependent relaxation in the heart. We will examine the effect of pH and catecholamines on this current and on Na -dependent (voltage dependent) relaxation. We will proceed to study the way that transmembranous Ca flux (Isi. and catecholamines influence relaxation that is Nao-independent exchanged mediated by the SR. We will then investigate the way that SR Ca pumping and Na+-Ca2+ exchange interact to regulate diastolic relaxation and diastolic filling of the SR. The methods include voltage clamp of isolated cardiomyocytes, measurement of cell shortening, extremely rapid solution changes, rapid cooling of isolated cardiomyocytes and measurement of Cai and pHi with Ca and pH indicators.
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