Inhibitory effects of coronary vasodilator papaverine on heterologously-expressed HERG currents in Xenopus oocytes
Abstract
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 ventricular myocytes. It blocked heterologously-expressed HERG currents in a concentration-dependent manner (IC50 71.03±4.75μmol/L, NH 0.80,n=6), whereas another phosphodiesterase inhibitor, theophylline (500μmol/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±4.25μS 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.
Keywords:
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 ventricular myocytes. It blocked heterologously-expressed HERG currents in a concentration-dependent manner (IC50 71.03±4.75μmol/L, NH 0.80,n=6), whereas another phosphodiesterase inhibitor, theophylline (500μmol/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±4.25μS 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.