title: Diminished Ca2+ and Ba2+ currents in myocytes surviving in the epicardial border zone of the 5-day infarcted canine heart.
abstract: Ventricular arrhythmias frequently occur in patients suffering from ischemic heart disease. In a canine model developed to understand the pathoelectrophysiological mechanisms of the ischemia-related arrhythmias, electrical stimulation can initiate and terminate reentrant ventricular tachyarrhythmias, which arise in surviving subepicardial muscle fibers (epicardial border zone [EBZ] fibers) of the left ventricle 5 days after coronary artery occlusion. Both the structural and electrical changes occurring in the EBZ provide the important substrate for generation of reentrant ventricular tachyarrhythmias. In this study, we tested the hypothesis that abnormalities exist in the electrophysiological properties of macroscopic Ca2+ currents in myocytes isolated from the EBZ of the 5-day infarcted canine heart (IZs). We recorded the T-type (ICa,T) and L-type (ICa,L) Ca2+ currents by using the whole-cell voltage-clamp technique with either Ca2+ or Ba2+ (5 mmol/L) as the charge carrier and under experimental conditions (Na(+)- and K(+)-free solutions, 10 mmol/L intracellular EGTA) that eliminated contamination by other currents. When Ca2+ served as the charge carrier, the density of peak ICa,T in IZs (0.89 +/- 0.5 pA/pF, n = 28) was similar to that in myocytes from normal noninfarcted hearts (NZs) (1.1 +/- 0.5 pA/pF, n = 32). Although no changes existed in the properties of ICa,T, dramatic changes occurred in the density and function of ICa.L in IZs compared with NZs. Density of peak ICa,L at a holding potential of -40 mV (8-second clamp-step interval) was significantly reduced in IZs (4.6 +/- 1.5 pA/pF, n = 40) compared with NZs (7.2 +/- 1.6 pA/pF, n = 53). The reduction in peak ICa,L density was not attributable to altered steady state inactivation relations or a delay in recovery of ICa,L from inactivation. The time course of decay of peak ICa,: was described by a biexponential function in both cell types, with the fast and slow time constants (tau 1 and tau 2, respectively) of decay being significantly faster in IZs (tau 1 12.3 +/- 3.6 ms; tau 2, 55.1 +/- 31.1 ms) than in NZs (tau 1, 16.1 +/- 4.1 ms; tau 2, 85.2 +/- 51.7 ms). In addition, rapid clamp stimulation (at 1-s intervals) of cells produced a larger frequency-dependent decrease of peak ICa,L density in IZs than NZs, suggesting that at more physiologically relevant rates, little ICA.L may be activated. Finally, a significant reduction and acceleration of decay of the ICa,L persisted even when Ca2+ was substituted by equimolar Ba2+ as the charge carrier.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pharmacology, Columbia College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: R
authors.initials: R
authors.lastname: Aggarwal
authors.forename: P A
authors.initials: PA
authors.lastname: Boyden
mesh_terms: D000818:Animals; D001464:Barium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D004285:Dogs; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology* / Q000503:physiopathology*; D066298:In Vitro Techniques; D009203:Myocardial Infarction / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D001464:Barium