Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart.
Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 infarcted heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca2+ and K+ currents in cells isolated from the 14-day (IZ14d) and 2-mo (IZ2m) EBZ and compared them with those occurring in cells from the same hearts but remote (Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca2+ and K+ currents in cells from the different groups. Ca2+ current densities remain reduced in cells of the 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin to, but do not recover to, cells from noninfarcted epicardium (NZ) values. Importantly, I(Ca,L) in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca2+ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in beta-adrenergic responsiveness of I(Ca,L) exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ14d, the transient outward K+ current (Ito) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, Ito and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast Ito but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering I(Ca,L) of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I(Ca,L) "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.
Dun
Wen
W
Department of Pharmacology, Center of Molecular Therapeutics, Columbia University, New York, New York 10032, USA.
Baba
Shigeo
S
Yagi
Takuya
T
Boyden
Penelope A
PA
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002470:Cell Survival; D004285:Dogs; D004553:Electric Conductivity; D005424:Flecainide / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D014945:Wound Healing
D015220:Calcium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019789:Tetraethylammonium; D005424:Flecainide