DIMINISHED CA2-DAY INFARCTED CANINE HEART( AND BA2+ CURRENTS IN MYOCYTES SURVIVING IN THE EPICARDIAL BORDER ZONE OF THE 5)

Ventricular arrhythmias frequently occur in patients suffering from is chemic heart disease. In a canine model developed to understand the pa thoelectrophysiological mechanisms of the ischemia-related arrhythmias , electrical stimulation can initiate and terminate reentrant ventricu lar tachyarrhythmias, which arise in surviving subepicardial muscle fi bers (epicardial border zone [EBZ] fibers) of the left ventricle 5 day s after coronary artery occlusion. Both the structural and electrical changes occurring in the EBZ provide the important substrate for gener ation of reentrant ventricular tachyarrhythmias. In this study, we tes ted the hypothesis that abnormalities exist in the electrophysiologica l properties of macroscopic Ca2+ currents in myocytes isolated from th e EBZ of the 5-day infarcted canine heart (IZs). We recorded the T-typ e (I-Ca,I-T) and L-type (I-Ca,I-L) Ca2+ currents by using the whole-ce ll voltage-clamp technique with either Ca2+ or Ba2+ (5 mmol/L) as the charge carrier and under experimental conditions (Na+- and K+-free sol utions, 10 mmol/L intracellular EGTA) that eliminated contamination by other currents. When Ca2+ served as the charge carrier, the density o f peak I-Ca,I-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 I-Ca,I-T, dramatic changes occurred in the density and function of I-Ca,I-L in IZs compa red with NZs. Density of peak I-Ca,I-L at a holding potential of -40 m V (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 red uction in peak I-Ca,I-L density was not attributable to altered steady state inactivation relations or a delay in recovery of I-Ca,I-L from inactivation. The time course of decay of peak I-Ca,I-L 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 signi ficantly 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 addit ion, rapid clamp stimulation (at 1-s intervals) of cells produced a la rger frequency-dependent decrease of peak I-Ca,I-L density in IZs than NZs, suggesting that at more physiologically relevant rates, little I -Ca,I-L may be activated. Finally, a significant reduction and acceler ation of decay of the I-Ca,I-L persisted even when Ca2+ was substitute d by equimolar Ba2+ as the charge carrier. These latter findings sugge st that the reduced peak Ic,, 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 I -Ca,I-L in cells that survive in the infarcted heart. Such changes cou ld contribute to the altered rt polarization of action potentials of m yocytes from EBZs of the 5-day infarcted canine heart.