Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart

Abstract

We have shown reduced density and altered kinetics in slowly activating K+ currents (I(Ks)) in epicardial border zone (EBZ) cells (IZs) of the 5-day-infarcted canine heart (Jiang M, Cabo, C, Yao J-A, Boyden PA, and Tseng G-N. Cardiovasc Res 48: 34-43, 2000). beta-Adrenergic stimulation with isoproterenol increases I(Ks) in normal cells (NZs). In this study, we used a voltage-clamp protocol with an external solution to isolate I(Ks) from contaminating currents to determine the effects of 1 muM isoproterenol on I(Ks) in IZs and NZs. Under our recording conditions, 10 microM azimilide-sensitive currents were stimulated with isoproterenol to compare responsiveness of I(Ks) to isoproterenol in the two cell groups. I(Ks) tail density was reduced 67% in IZs (group I, n = 26) compared with NZs (n = 24, P < 0.05). Isoproterenol-stimulated azimilide-sensitive tail currents were increased 1.72 +/- 0.2-fold in NZs and 2.2 +/- 0.3-fold in IZs (P > 0.05). In 33% of IZs (group II, n = 13), native currents showed no tail currents; however, isoproterenol-stimulated azimilide-sensitive currents were voltage dependent, fast activating, and large in amplitude compared with group I IZs, similar to "lone" KCNQ1 currents. Using short clamp pulses, we also found an increase in sustained currents sensitive to tetraethylammonium chloride (TEA) and no change in C-9356-sensitive currents in IZs with little or no transient outward current. In some IZs where I(Ks) is downregulated, the effect of isoproterenol on I(Ks) was similar to that on I(Ks) in NZs. In others, the existence of lone KCNQ1-type currents, which are sensitive to beta-adrenergic stimulation, is consistent with our findings of an increased KCNQ1-to-KCNE1 mRNA ratio (Jiang et al.). Accompanying altered I(Ks) in IZs are an enhanced TEA-sensitive current and a normal C-9356-sensitive current.