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 (I(K)) 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 (I(to)), and only showed significantly inhibitory effect at the highest concentration (300 μM). Changrolin also induced a concentration-dependent inhibition of sodium currents (I(Na)) with an IC(50) 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 (I(Ca)) was decreased by changrolin in a concentration-dependent manner with an estimated IC(50) of 74.73 μM (Hill coefficient=-0.9082, n=6). In conclusion, changrolin blocks Na(+) and Ca(2+) channels, and also blocks K(+) channels (I(to) and I(K)) 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.