Previous investigations from our laboratory have shown that heart rate-dependent and intermittent block processes, such as during Wenckebach periodicity in AV transmission, cannot be explained merely on the basis of slow conduction, and are not compatible with the behavior expected from an homogeneous system of electrically coupled cells. It is our hypothesis that, in a nonhomogeneous system that involves an area of conduction impairment separating two fully excitable zones, the success or failure of propagation at a given rate is determined by the recovery of excitability of the cells beyond the impairment zone. Our goal is to investigate in single cells the cellular and subcellular mechanisms of time-dependent changes in excitability that are responsible for cyclic conduction block patterns. We will study the role of current source properties and intercellular communication between cell pairs in determining success or failure of impulse propagation, as a function of driving frequency. We will use current and voltage clamp techniques in enzymatically dissociated guinea pig ventricular myocytes, as well as computer simulations toward the following Specific Aims: 1) Study the passive membrane properties of single cells and characterize the changes in their excitability during diastole. 2) Study the ionic mechanisms responsible for post-repolarization refractoriness and rate-dependent failure of activation. 3) Investigate the roles of action potential amplitude and maximum upstroke velocity as source properties in determining action potential propagation. 4) Correlate junctional resistance with action potential propagation between pairs of coupled myocytes. 5) Study the development of newly-formed intercellular communications between single heart cells. These studies should improve our understanding of the factors involved in the property of excitability of cardiac myocytes and their ability to conduct electrical impulses. The results should give also precise and direct answers about the ionic bases of conduction block processes with alternation or with Wenckebach periodicity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040923-03
Application #
3358292
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Morley, G E; Anumonwo, J M; Delmar, M (1992) Effects of 2,4-dinitrophenol or low [ATP]i on cell excitability and action potential propagation in guinea pig ventricular myocytes. Circ Res 71:821-30
Lorente, P; Delgado, C; Delmar, M et al. (1992) Analytical modeling of the hysteresis phenomenon in guinea pig ventricular myocytes. Acta Biotheor 40:177-93
Lorente, P; Delgado, C; Delmar, M et al. (1991) Hysteresis in the excitability of isolated guinea pig ventricular myocytes. Circ Res 69:1301-15
Delmar, M; Ibarra, J; Davidenko, J et al. (1991) Dynamics of the background outward current of single guinea pig ventricular myocytes. Ionic mechanisms of hysteresis in cardiac cells. Circ Res 69:1316-26
Anumonwo, J M; Delmar, M; Vinet, A et al. (1991) Phase resetting and entrainment of pacemaker activity in single sinus nodal cells. Circ Res 68:1138-53
Ibarra, J; Morley, G E; Delmar, M (1991) Dynamics of the inward rectifier K+ current during the action potential of guinea pig ventricular myocytes. Biophys J 60:1534-9
Delmar, M; Jalife, J (1990) Analysis of rate-dependent activation in single atrioventricular nodal cells. Ann N Y Acad Sci 591:23-37
Hoshino, K; Anumonwo, J; Delmar, M et al. (1990) Wenckebach periodicity in single atrioventricular nodal cells from the rabbit heart. Circulation 82:2201-16
Delmar, M; Glass, L; Michaels, D C et al. (1989) Ionic basis and analytical solution of the wenckebach phenomenon in guinea pig ventricular myocytes. Circ Res 65:775-88
Delmar, M; Michaels, D C; Jalife, J (1989) Slow recovery of excitability and the Wenckebach phenomenon in the single guinea pig ventricular myocyte. Circ Res 65:761-74