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±4.75 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.
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Kim, Cs., Lee, N., Son, Sj. et al. Inhibitory effects of coronary vasodilator papaverine on heterologously-expressed HERG currents in Xenopus oocytes. Acta Pharmacol Sin 28, 503–510 (2007). https://doi.org/10.1111/j.1745-7254.2007.00507.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00507.x
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