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

Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, New York

Submitted 22 February 2005 ; accepted in final form 1 April 2005

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). -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 µM isoproterenol on I_Ks in IZs and NZs. Under our recording conditions, 10 µM 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 -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.

epicardial border zone; delayed rectifier; tetraethylammonium; C-9356; isoproterenol

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