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© 1995 American Heart Association, Inc.
Articles |
Diminished Ca2+ and Ba2+ Currents in Myocytes Surviving in the Epicardial Border Zone of the 5-Day Infarcted Canine Heart
From the Department of Pharmacology, Columbia College of Physicians and Surgeons, New York, NY.
Correspondence to Dr Penelope A. Boyden, Department of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th St, New York, NY 10032.
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,L was described by a biexponential function in both
cell types, with the fast and slow time constants (
1 and
2, respectively) of decay being significantly
faster in IZs (1, 12.3±3.6 ms;
2, 55.1±31.1 ms) than in NZs
(1, 16.1±4.1 ms; 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. These latter findings
suggest that the reduced peak ICa,L density in IZs may be
due to a decrease in the number of functional channels, which also show
an alteration in the voltage-dependent inactivation process. In
summary, we have shown that chronic changes exist in the
electrophysiological properties of
ICa,L in cells that survive in the infarcted heart. Such
changes could contribute to the altered repolarization of action
potentials of myocytes from EBZs of the 5-day infarcted canine heart.
Key Words: L-type Ca2+ current • myocardial infarction • ion channels • ventricular myocytes • T-type Ca2+ current
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