Conduction of cardiac action potentials is thought to occur via local circuit currents flowing through low resistance junctions to adjacent cardiac cells. Alterations in the conductance of these junctions may be related to the slowing of conduction velocity present in disease states with a high incidence of arrhythmias. Many substances are known to alter junctional conductance but the ionic mechanism is not fully understood. Therefore, this proposal attempts to determine the relatinoship between junctional conductance and intracellular ions (Ca and H) in cardiac Purkinje fibers using cable analysis and ion-selective microelectrodes. The intrinsic differences between resting and active preparations in their response to 'substances' that alter junctional conductance (e.g. Ca, CO2, NH4Cl) also will be explored. The accuracy of Cai measurements will be improved by the determination of critical stability constants (for EGTA & HEDTA) in solutions resembling the intracellular milieu. Tests of the following hypotheses will be undertaken: 1) Changes in free [Ca]i and pHi are directly related to changes in junctional conductance of cardiac cells. 2) Alterations in free [Ca]i and pHi interact to modify junctional conductance but changes in Cai predominate with regard to net change in conductance. 3) Activity-dependent events (e.g. Ca influx via the slow inward current, Ca flux via Na/Ca exchange, Ca release and reuptake by sarcoplasmic reticulum, and perhaps Na influx during stimulation) affect the process by which Cai and pHi are maintained and thereby modify junctional conductance. 4) Alterations in the extracellular milieu (e.g. by CO2, NH4Cl, Ca) change free [Ca]i and pHi. The amount of change depends on cellular activity. The long term objective of these studies is to increase the understanding of cardiac cell-to-cell transmission so as to promote further insights into the genesis and treatment of cardiac arrhythmias.
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