Cellular electrophysiological effects of changrolin in isolated rat cardiac myocytes

Changrolin (2, 6-bis[pyrrolidin-1-ylmethyl]-4-[quinazolin-4-ylamino] phenol) is an anti-arrhythmic drug derived from β-dichroine, an active component of the Chinese medicinal herb, Dichroa febrifuga Lour. To elucidate the mechanism underlying the anti-arrhythmic effect of changrolin, we used the whole-cell patch-clamp technique to characterize the electrophysiological actions of changrolin in isolated rat cardiomyocytes. In this study, changrolin inhibited delayed rectified K+ currents (IK) in a concentration-dependent manner with inhibiting the current by 11.9% ± 4.7%, 27.8% ± 3.4%, 31.5% ± 3.6% and 40.8% ± 3.7% at 10, 30, 100 and 300 μM, respectively (n = 7–8). Changrolin was less effective against transient outward K+ currents (Ito), and only showed significantly inhibitory effect at the highest concentration (300 μM). Changrolin also induced a concentration-dependent inhibition of sodium currents (INa) with an IC50 of 10.19 μM (Hill coefficient = −1.727, n = 6–7). In addition, changrolin exerted a holding potential-dependent block on Na+ channels, produced a hyperpolarizing shift in the steady-state inactivation curve, as well as exhibited a marked frequency-dependent component to the blockade of Na+ channels. Finally, calcium currents (ICa) was decreased by changrolin in a concentration-dependent manner with an estimated IC50 of 74.73 μM (Hill coefficient = −0.9082, n = 6). In conclusion, changrolin blocks Na+ and Ca2+ channels, and also blocks K+ channels (Ito and IK) to some extent. Notably, changrolin preferentially blocks the inactivated state of Na+ channels. These effects lead to a modification of electromechanical function and likely contribute to the termination of arrhythmia.