The potential role of Ca2+ for electrical cell-to-cell uncoupling and conduction block in myocardial tissue

Ca2+ ions are often invoked as potential initiators of cardiac arrhythmias in pathophysiological situations which are associated with an increase of free [Ca2+]i. It is well documented that elevated [Ca2+]i may produce SR release of Ca2+ and oscillations of membrane potential, thereby leading to triggered or spontaneous ectopic activity. The relation among elevated free [Ca2+]i, electrical cell-to-cell coupling, conduction slowing, and reentrant arrhythmias is more speculative. If Ca2+ (e.g. in mechanically injured cells) has direct access to the cellular interconnections (gap junctions), rapid uncoupling occurs at [Ca2+]i which is even within the range of a normal contractile cycle. If cellular integrity is preserved and changes of [Ca2+]i are imposed by extracellular interventions, the effect of [Ca2+]i is critically dependent on pHi. At normal pHi, transcellular conductance remains normal even if [Ca2+]i is increased to bring the cells into a hypercontractile state (> 1-2 microM). At decreased pHi, rapid uncoupling develops at low [Ca2+]i. Comparison of the conduction delay between two cells (or conduction velocity in a simulated conducting medium) with the [Ca2+]i-mediated increase in coupling resistance suggests that the transition from normal conduction velocity to conduction block (a key event in re-entrant arrhythmias) occurs within a relatively narrow range of [Ca2+]i or pHi, almost like a threshold phenomenon. Major efforts have been made in recent years to assess the changes of electrical cell-to-cell coupling and [Ca2+]i in myocardial ischemia. Therefore, the discussion of the role of [Ca2+]i as a modulator of electrical coupling is made in this pathophysiological setting. Comparison of several studies indicate that cell-to-cell resistance and [Ca2+]i in ischemia increase at the same time (10-15 min after perfusional arrest). Since other potential uncoupling processes (delta ATP, delta Mg2+, amphiphilic metabolites, delta pHi) show a similar time-course, it is difficult to attribute cell-to-cell uncoupling in ischemia solely to an increase in [Ca2+]i. Both an initial decrease of membrane excitability and subsequent electrical cell-to-cell uncoupling characterize the early phase of ischemia. The first mechanism is assumed to be more important for the generation of conduction block and re-entry. However, Ca(2+)-induced cell-to-cell uncoupling may partially contribute to the second phase of the early ischemic arrhythmias and mark the transition from reversible to irreversible ischemic damage.