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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042357-04
Application #
3360511
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Su, Z; Bridge, J H; Philipson, K D et al. (1999) Quantitation of Na/Ca exchanger function in single ventricular myocytes. J Mol Cell Cardiol 31:1125-35
Huelsing, D J; Spitzer, K W; Cordeiro, J M et al. (1999) Modulation of repolarization in rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol 276:H572-81
Yao, A; Su, Z; Nonaka, A et al. (1998) Effects of overexpression of the Na+-Ca2+ exchanger on [Ca2+]i transients in murine ventricular myocytes. Circ Res 82:657-65
Litwin, S E; Li, J; Bridge, J H (1998) Na-Ca exchange and the trigger for sarcoplasmic reticulum Ca release: studies in adult rabbit ventricular myocytes. Biophys J 75:359-71
Huelsing, D J; Spitzer, K W; Cordeiro, J M et al. (1998) Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol 274:H1163-73
Spitzer, K W; Sato, N; Tanaka, H et al. (1997) Electrotonic modulation of electrical activity in rabbit atrioventricular node myocytes. Am J Physiol 273:H767-76
Litwin, S E; Bridge, J H (1997) Enhanced Na(+)-Ca2+ exchange in the infarcted heart. Implications for excitation-contraction coupling. Circ Res 81:1083-93
Litwin, S; Kohmoto, O; Levi, A J et al. (1996) Evidence that reverse Na-Ca exchange can trigger SR calcium release. Ann N Y Acad Sci 779:451-63
Levi, A J; Li, J; Spitzer, K W et al. (1996) Effect on the indo-1 transient of applying Ca2+ channel blocker for a single beat in voltage-clamped guinea-pig cardiac myocytes. J Physiol 494 ( Pt 3):653-73
Matsui, H; Barry, W H; Livsey, C et al. (1995) Angiotensin II stimulates sodium-hydrogen exchange in adult rabbit ventricular myocytes. Cardiovasc Res 29:215-21

Showing the most recent 10 out of 19 publications