Contribution of Ca-Regulated Ion Currents to the Action Potential Morphology During Cardiac Alternans

Abstract

Cardiac alternans, described as periodic beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is recognized as high risk indicator for cardiac arrhythmias, stroke and sudden cardiac death.We investigated mechanisms of cardiac alternans in single rabbit atrial myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique, and revealed a strong correlation between CaT amplitude and AP duration (APD) during alternans. Investigation of [Ca]i-Vm interactions indicates that disturbances in Ca signaling are the primary events mediating activity of Ca-regulated ion channels and leading to the changes in AP morphology. Voltage-clamp in form of pre-recorded APs (AP clamp) was used to assess the contribution of Ca-regulated membrane currents by measuring the difference between currents recorded during large and small alternans CaTs. Ca-dependent currents exhibited a large outward component (2.9 ± 1.1 pA/pF in amplitude) during AP phases 1 and 2 that was followed by an inward current (0.5 ± 0.1 pA/pF in amplitude; n=7) during AP repolarization. We also investigated contributions of Na/Ca exchange (NCX), L-type Ca, Ca-activated Cl and small conductance Ca-activated K currents to the AP morphology during Ca alternans. ∼90 % of the initial outward current was blocked by substitution of Cl ions or application of Cl channel blocker (DIDS) indicating that this current is mainly carried by Ca-activated Cl channels. In summary, during Ca alternans the prominent prolongation of AP at APD10 to APD30 repolarization levels during the small CaT is due to reduced Ca-activated Cl current while the overall effect of other Ca-sensitive currents (NCX, L-type Ca, small conductance K) cause slight shortening of AP in the APD50 to APD90 range.