Effects of bepridil on stretch-activated BKca channels and stretch-induced extrasystoles in isolated chick hearts.

Abstract

Various types of mechanosensitive ion channels, including cationic stretch-activated channels (SAC(NS)) and stretch-activated BKca (SAKca) channels, modulate heart rhythm. Bepridil has been used as an antiarrhythmic drug with multiple pharmacological effects; however, whether it is effective for mechanically induced arrhythmia has not been well investigated. To test the effects of Bepridil on SAKca channels activity, cultured chick embryonic ventricular myocytes were used for single-channel recordings. Bepridil significantly reduced the open probability of the SAKca channel (P(O)). Next, to test the effects of bepridil on stretch-induced extrasystoles (SIE), we used an isolated 2-week-old Langendorff-perfused chick heart. The left ventricle (LV) volume was rapidly changed, and the probability of SIE was calculated in the presence and absence of bepridil, and the effect of the drug was compared with that of Gadolinium (Gd(3+)). Bepridil decreased the probability of SIE despite its suppressive effects on SAKca channel activity. The effects of Gd(3+), which blocks both SAKca and SAC(NS), on the probability of SIE were the same as those of bepridil. Our results suggest that bepridil blocks not only SAKca channels but possible also blocks SAC(NS), and thus decreases the stretch-induced cation influx (stabilizing membrane potential) to compensate and override the effects of the decrease in outward SAKca current (destabilizing membrane potential).