The general goal of this project is to understand the factors which control the force of cardiac muscle contraction. More specifically the goals are to elucidate mechanisms of excitation-contraction (E-C) coupling and to gain insight into the interrelationships involved in the regulation of intracellular Ca, Na, pH and K. The relative roles of Ca influx and SR Ca release in the beat to beat control of cardiac contractility is an important and controversial question. The planned studies will provide direct information bearing on this issue. Experiments will be done using double barreled Ca selective microelectrodes to measure transient depletions of Cao which occur during individual beats reflecting phasic Ca influx and cumulative depletions of Cao which occur over several beats reflecting changes in Ca content. Studies of the regulation, interaction and compartmentalization of intracellular Ca, Na and H ions will also be undertaken using ion selective microelectrodes to continuously and directly monitor the intracellular activities of these ions (in normal, physiologically altered and ischemic conditions). Aspects of how these cations interact at sarcolemmal sites will be studied in isolated cardiac sarcolemmal vesicles. These will allow assessment of sidedness, symmetry, Na-Ca exchange, the Na-H exchange and Ca binding in the sarcolemmal vesicles and the role these properties may have in the control of cardiac contractility. Biophysical models will be developed to describe how Ca, Na and H interact with sarcolemma bearing fixed negative charges and to describe the effects of electrodiffusive forces acting on Ca as it converges on a Ca channel. There is also much insight to be gained in technically simple experiments taking advantage of pharmacological agents, physiological manipulations and cardiac tissues with apparently differing E-C coupling mechanisms. The results of the studies planned should increase our understanding of the regulation of basic cardiac muscle function in normal as well as pharmacologically and pathologically altered states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001526-03
Application #
3073852
Study Section
Physiology Study Section (PHY)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Type
Overall Medical
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521
Bers, D M; Peskoff, A (1991) Diffusion around a cardiac calcium channel and the role of surface bound calcium. Biophys J 59:703-21
Bers, D M; Christensen, D M (1990) Functional interconversion of rest decay and ryanodine effects in rabbit and rat ventricle depends on Na/Ca exchange. J Mol Cell Cardiol 22:715-23
Harrison, S M; Bers, D M (1990) Temperature dependence of myofilament Ca sensitivity of rat, guinea pig, and frog ventricular muscle. Am J Physiol 258:C274-81
Harrison, S M; Bers, D M (1990) Modification of temperature dependence of myofilament Ca sensitivity by troponin C replacement. Am J Physiol 258:C282-8
Wernli, R Y; Strauss, R G; Cordle, D G (1990) A patient with transient autoanti-Jka. Acta Haematol 84:190-2
Hryshko, L V; Stiffel, V; Bers, D M (1989) Rapid cooling contractures as an index of sarcoplasmic reticulum calcium content in rabbit ventricular myocytes. Am J Physiol 257:H1369-77
Bers, D M; Bridge, J H (1989) Relaxation of rabbit ventricular muscle by Na-Ca exchange and sarcoplasmic reticulum calcium pump. Ryanodine and voltage sensitivity. Circ Res 65:334-42
Harrison, S M; Bers, D M (1989) Influence of temperature on the calcium sensitivity of the myofilaments of skinned ventricular muscle from the rabbit. J Gen Physiol 93:411-28
Bers, D M (1989) SR Ca loading in cardiac muscle preparations based on rapid-cooling contractures. Am J Physiol 256:C109-20
Harrison, S M; Bers, D M (1989) Correction of proton and Ca association constants of EGTA for temperature and ionic strength. Am J Physiol 256:C1250-6

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