Inhibitory effects of coronary vasodilator papaverine on heterologously-expressed HERG currents in Xenopus oocytes.
OBJECTIVE
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 micromol/L, NH 0.80, n=6), whereas another phosphodiesterase inhibitor, theophylline (500 micromol/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 muS of the control to 56.84+/-5.33, 36.06+/-6.53, and 27.09+/-5.50 microS (n=4) by 30, 100, and 300 micromol/L of papaverine, respectively. Papaverine (100 micromol/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.


CONCLUSIONS
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.
Kim
Cuk-seong
CS
Department of Physiology, College of Medicine, Chungnam National University, Daejeon 301131, Korea.
Lee
Nam
N
Son
Sook-jin
SJ
Lee
Kyu-seung
KS
Kim
Hyo-shin
HS
Kwak
Yong-geun
YG
Chae
Soo-wan
SW
Lee
Sang-do
SD
Jeon
Byeong-hwa
BH
Park
Jin-bong
JB
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*; D014981:Xenopus
D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D010208:Papaverine