Inhibitory effects of berberine on ATP-sensitive K+ channels in cardiac myocytes

The effects of berberine on cardiac action potentials were measured in isolated guinea-pig papillary muscles exposed to hypoxia and cromakalim using the standard microelectrode technique. In addition, the patch clamp technique was used to determine the effects of berberine on cromakalim-induced outward currents in isolated ventricular myocytes and on ATP-sensitive K+ (KATP) channels in inside-out membrane patches. Berberine, at 3 microM significantly inhibited, while at 100 microM completely blocked the shortening of action potential duration and effective refractory period induced by hypoxia or cromakalim (100 microM). Under the whole-cell voltage clamp conditions, berberine (3-100 microM) attenuated or even abolished the cromakalim-elicited outward K+ currents. Berberine (3-100 microM) inhibited KATP channel activity in a concentration-dependent fashion in inside-out membrane patches exposed to 0.1 mM ATP. This inhibition appeared to be mainly due to a decrease in the open channel probability without affecting unitary conductance or the time constants for open and closed channel times. Glibenclamide (10 microM) partially blocked the hypoxia-evoked but fully reversed the cromakalim-evoked abbreviation of action potential duration and effective refractory period. Both the whole-cell outward K+ currents induced by cromakalim and the opening of single KATP channels induced by the low intracellular ATP concentration were also completely abolished by 10 microM glibenclamide. We conclude that berberine is a blocker of the cardiac KATP channel. The reported beneficial effect of berberine on ischemia-induced arrhythmias is likely attributed to its inhibition of KATP channel activation and subsequent shortening of action potential duration and effective refractory period during ischemia.