This is an application for a Fogarty International Research Collaboration Award. The proposal represents an expansion of our currently funded grant P01-HL 39707. The studies proposed in this grant application are directed to the understanding of the electrophysiological bases of normal and abnormal impulse propagation in cardiac muscle. Our overall objective is to provide insight into the cellular and subcellular mechanisms responsible for AV nodal conduction disturbances. Rate-dependent patterns of propagation failure in the AV node (such as Wenckebach periodicity) have been previously characterized in our laboratory as resulting from diastolic changes in the excitability of those cells that are distal to an area of conduction impairment. The demonstration of rate-dependent excitation patterns in a single cell has allowed us to characterize the specific ionic currents that are responsible for such phenomena. As the first specific aim of this application, we will use the """"""""action potential clamp"""""""" (APC) technique in single, quiescent AV nodal myocytes to investigate the dynamic behavior of the calcium inward current (ICa.L) during the Wenckebach patterns of single AV nodal cells. The second specific aim deals with the effects of metabolic inhibition (i.e., pharmacological interruption of aerobic respiration) on the membrane conductance and cell excitability of single AV nodal myocytes. Recent studies from this and other laboratories have shown that pharmacological inhibition of aerobic metabolism leads to opening of ATP-sensitive potassium channels in the sarcolemma, with a consequent increase in membrane conductance. As our second specific aim, we will study the effects of metabolic inhibition ont he responsiveness of AV nodal myocytes to stimulation at various frequencies. It is our hypothesis that metabolic inhibition will impair cell excitability and displace the dynamic range of cycle lengths at which various Wenckebach patterns will be found. The new dynamic range should be mathematically predicted by the effects of metabolic inhibition on action potential duration, refractory period and the time course of the recovery of excitability curve. The overall project should improve our understanding of the factors modulating excitability of AV nodal myocytes, particularly under conditions related to anoxia in the heart.
| Ek, J F; Delmar, M; Perzova, R et al. (1994) Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43. Circ Res 74:1058-64 |
