RESUMEN
Background: Previous studies have associated slowed ventricular conduction with the arrhythmogenesis mediated by the gap junction and sodium channel inhibitor heptanol in mouse hearts. However, they did not study the propagation patterns that might contribute to the arrhythmic substrate. This study used a multi-electrode array mapping technique to further investigate different conduction abnormalities in Langendorff-perfused mouse hearts exposed to 0.1 or 2 mM heptanol. Methods: Recordings were made from the left ventricular epicardium using multi-electrode arrays in spontaneously beating hearts during right ventricular 8 Hz pacing or S1S2 pacing. Results: In spontaneously beating hearts, heptanol at 0.1 and 2 mM significantly reduced the heart rate from 314 ± 25 to 189 ± 24 and 157 ± 7 bpm, respectively (ANOVA, p < 0.05 and p < 0.001). During regular 8 Hz pacing, the mean LATs were increased by 0.1 and 2 mM heptanol from 7.1 ± 2.2 ms to 19.9 ± 5.0 ms (p < 0.05) and 18.4 ± 5.7 ms (p < 0.05). The standard deviation of the mean LATs was increased from 2.5 ± 0.8 ms to 10.3 ± 4.0 ms and 8.0 ± 2.5 ms (p < 0.05), and the median of phase differences was increased from 1.7 ± 1.1 ms to 13.9 ± 7.8 ms and 12.1 ± 5.0 ms by 0.1 and 2 mM heptanol (p < 0.05). P5 took a value of 0.2 ± 0.1 ms and was not significantly altered by heptanol at 0.1 or 2 mM (1.1 ± 0.9 ms and 0.9 ± 0.5 ms, p > 0.05). P50 was increased from 7.3 ± 2.7 ms to 24.0 ± 12.0 ms by 0.1 mM heptanol and then to 22.5 ± 7.5 ms by 2 mM heptanol (p < 0.05). P95 was increased from 1.7 ± 1.1 ms to 13.9 ± 7.8 ms by 0.1 mM heptanol and to 12.1 ± 5.0 ms by 2 mM heptanol (p < 0.05). These changes led to increases in the absolute inhomogeneity in conduction (P5−95) from 7.1 ± 2.6 ms to 31.4 ± 11.3 ms, 2 mM: 21.6 ± 7.2 ms, respectively (p < 0.05). The inhomogeneity index (P5−95/P50) was significantly reduced from 3.7 ± 1.2 to 3.1 ± 0.8 by 0.1 mM and then to 3.3 ± 0.9 by 2 mM heptanol (p < 0.05). Conclusion: Increased activation latencies, reduced CVs, and the increased inhomogeneity index of conduction were associated with both spontaneous and induced ventricular arrhythmias.
RESUMEN
The human ether-a-go-go-related gene (hERG) encodes the K+ channel that carries the rapid component of the delayed rectifier current in the human heart. Reduction of hERG activity induced by gene mutations or pharmacological inhibition is responsible for the type 2 form of long QT syndrome in patients which can develop into ventricular arrhythmia and sudden cardiac death. Therefore, pharmacological activation of hERG may lead to therapeutic potential for cardiac arrhythmias. In this study we characterized a small and novel compound, N-(2-(tert-butyl)phenyl)-6-(4-chlorophenyl)-4-(trifluoromethyl) nicotinamide, HW-0168, that exhibits potent activation of hERG channel with an EC50 of 0.41 ± 0.2 µM. Using whole-cell patch clamp recording of HEK293 cells stably expressed hERG channels, we found that HW-0168 dramatically increased current amplitude about 2.5 folds and slowed down current inactivation about 4 folds. HW-0168 shifted the voltage-dependent channel activation to hyperpolarizing direction about 3.7 mV and the voltage-dependent channel inactivation to depolarizing direction about 9.4 mV. In addition, recording of guinea-pig ventricular cells confirmed that HW-0168 shortened the action potential duration. In conclusion, we identified a novel hERG channel activator HW-0168 that can be used for studying the physiological role of hERG in cardiac myocytes and may be beneficial for treating long QT syndrome.