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Introduction: Stable high-frequency rotors sustain ventricular fibrillation (VF) in the guinea pig heart. We surmised that rotor stabilization in the left ventricle (LV) and fibrillatory conduction toward the right ventricle (RV) result from chamber-specific differences in functional expression of inward rectifier (Kir2.x) channels and unequal IK1 rectification in LV and RV myocytes. Accordingly, selective blockade of IK1 during VF should terminate VF., Methods and Results: Relative mRNA levels of Kir2.x channels were measured in LV and RV. In addition, LV (n = 21) and RV (n = 20) myocytes were superfused with BaCl2 (5-50 micromol/L) to study the effects on IK1. Potentiometric dye-fluorescence movies of VF were obtained in the presence of Ba2+ (0-50 micromol/L) in 23 Langendorff-perfused hearts. Dominant frequencies (DFs) were determined by spectral analysis, and singularity points were counted in phase maps to assess VF organization. mRNA levels for Kir2.1 and Kir2.3 were significantly larger in LV than RV. Concurrently, outward IK1 was significantly larger in LV than RV myocytes. Ba2+ decreased IK1 in a dose-dependent manner (LV change > RV change). In baseline control VF, the fastest DF domain (28-40 Hz) was located on the anterior LV wall and a sharp LV-to-RV frequency gradient of 21.2 +/- 4.3 Hz was present. Ba2+ significantly decreased both LV frequency and gradient, and it terminated VF in a dose-dependent manner. At 50 micromol/L, Ba2+ decreased the average number of wavebreaks (1.7 +/- 0.9 to 0.8 +/- 0.6 SP/sec x pixel, P < 0.05) and then terminated VF., Conclusion: The results strongly support the hypothesis that IK1 plays an important role in rotor stabilization and VF dynamics.

Introduction: A cardiac culture cell line (AT-1) recently has been generated from transgenic mice. Initial studies have yielded opposing results as to the nature of the major repolarizing current(s) in these cells. The present study describes the ion selectivity, voltage dependence, and E4031 sensitivity of the major time-dependent outward current present in AT-1 cells. In addition, we have determined whether an outward current with the characteristics we observed could be capable of modulating action potential duration in a frequency-dependent manner (for stimulation cycle lengths between 250 and 1000 msec)., Methods and Results: Action potentials and membrane currents were recorded from nonconfluent cultures of quiescent AT-1 cells using the "perforated patch" technique. AT-1 cells showed a round appearance 1 or 2 days after plating. An E4031-insensitive transient outward current seemed to be absent in these cells. The main time-dependent outward current was a rapidly activating and rectifying potassium current with properties similar to those of IKr. Most of the potassium current was sensitive to the benzenesulfonamide E4031 (5 microM). The same concentration of E4031 led to a 38% increase in action potential duration. Action potential parameters were independent of the stimulation cycle length within the range of 250 to 1000 msec, thus suggesting that the membrane currents involved in the action potential of AT-1 cells are completely reset within a diastolic interval of approximately 150 msec., Conclusion: AT-1 cells present a unique electrophysiologic phenotype, which is clearly different from that reported for freshly dissociated adult atrial or ventricular myocytes from other species. AT-1 cells may be a good model to study IKr, since there seems to be minimal contamination by other outward conductances (such as IKs). In addition, the feasibility of culturing AT-1 cells provides us with a system where electrophysiologic experiments on IKr currents could be combined with biochemical or molecular biological studies requiring significant periods of incubation in a cell culture system.