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Aim:To characterize the effects of papaverine on HERG channels expressed inXenopus oocytes as well as cardiac action potential in rabbit ventricular myocytes.Methods:Conventional microelectrodes were used to record action potential inrabbit ventricular myocytes.HERG currents were recorded by 2-electrode voltageclamp technique in Xenopus oocytes injected with HERG cRNA.Results:Papa-verine increased the cardiac action potential duration in rabbit ventricular myocytes.It blocked heterologously-expressed HERG currents in a concentration-depen-dent manner (IC_(50)71.03±4.75 μmol/L,NH 0.80,n=6),whereas another phosphodi-esterase inhibitor,theophylline (500 μmol/L),did not.The blockade of papaverineon HERG currents was not voltage-dependent.The slope conductance measuredas a slope of the fully activated HERG current-voltage curves decreased from78.03±4.25 μS of the control to 56.84±5.33,36.06±6.53,and 27.09±5.50 μS (n=4) by30,100,and 300 μmol/L of papaverine,respectively.Papaverine (100 μmol/L)caused a 9 mV hyperpolarizing shift in the voltage-dependence of steady-stateinactivation,but there were no changes in the voltage-dependence of HERG cur-rent activation.Papaverine blocked HERG channels in the closed,open,andinactivated states.Conclusion:These results showed that papaverine blockedHERG channels in a voltage-and state-independent manner,which may mostlikely be the major mechanism of papaverine-induced cardiac arrhythmia reportedin humans.
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 technique technique in Xenopus oocytes injected with HERG cRNA. Results: Papa-verine increased the cardiac action potential duration in rabbit ventricular myocytes. It blocked heterologously-expressed HERG currents in a concentration-depen dent manner (IC 50 (50) 71.03 ± 4.75 μmol / L, NH 0.80, n = 6), another phosphodi-esterase inhibitor, theophylline (500 μmol / L), did not. The blockade of papaverine on HERG currents was not voltage-dependent. The slope conductance measuredas 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. (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 cur-rent activation. Papaverine blocked HERG channels in the closed, open, and inactivated states.Conclusion: These results showed that papaverine blockedHERG channels in a voltage-and state-independent manner, which may mostly be the major mechanism of papaverine-induced cardiac arrhythmia reported in humans.