Inhibitory effects of coronary vasodilator papaverine on heterologouslyexpressed HERG currents in Xenopus oocytes

Aim： To characterize the effects of papaverine on HERG channels expressed in Xenopus oocytes as well as cardiac action potential in rabbit ventricular myocytes. Methods： Conventional microelectrodes were used to record action potential in rabbit ventricular myocytes. HERG currents were recorded by 2-electrode voltage clamp technique in Xenopus oocytes injected with HERG cRNA. Results： Papaverine increased the cardiac action potential duration in rabbit ventficular myocytes. It blocked heterologously-expressed HERG currents in a concentration-depen- dent manner （IC50 71.03±4.75 μmol/L, NH 0.80, n=6）, whereas another phosphodiesterase inhibitor, theophylline （500 μmol/L）, did not. The blockade of papaverine on HERG currents was not voltage-dependent. The slope conductance measured as a slope of the fully activated HERG current-voltage curves decreased from 78.03±4.25 μS of the control to 56.84±5.33, 36.06±6.53, and 27.09±5.50 μS （n=4） by 30, 100, and 300 μmol/L of papaverine, respectively. Papaverine （100 μmol/L） caused a 9 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, but there were no changes in the voltage-dependence of HERG current activation. Papaverine blocked HERG channels in the closed, open, and inactivated states. Conclusion： These results showed that papaverine blocked HERG channels in a voltage- and state-independent manner, which may most likely be the major mechanism of papaverine-induced cardiac arrhythmia reported in humans.