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

Abstract

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 + (K ATP) channels in inside-out membrane patches. Berberine, at 3 μM significantly inhibited, while at 100 μM completely blocked the shortening of action potential duration and effective refractory period induced by hypoxia or cromakalim (100 μM). Under the whole-cell voltage clamp conditions, berberine (3–100 μM) attenuated or even abolished the cromakalim-elicited outward K + currents. Berberine (3–100 μM) inhibited K ATP 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 μM) 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 K ATP channels induced by the low intracellular ATP concentration were also completely abolished by 10 μM glibenclamide. We conclude that berberine is a blocker of the cardiac K ATP channel. The reported beneficial effect of berberine on ischemia-induced arrhythmias is likely attributed to its inhibition of K ATP channel activation and subsequent shortening of action potential duration and effective refractory period during ischemia.