BLOCKAGE OF THE HERG HUMAN CARDIAC K+ CHANNEL BY THE GASTROINTESTINALPROKINETIC AGENT CISAPRIDE

Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is n ot known. The human ether-a-go-go-related gene (HERG), which encodes t he rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisap ride. We tested the hypothesis that cisapride blocks HERG. The whole c ell patch-clamp recording technique was used to study HERG channels st ably expressed heterologously in HEK293 cells. Under voltage-clamp con ditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Cu rrents rapidly recovered with drug washout. The onset of block by cisa pride required channel activation indicative of open or inactivated st ate blockage. Block of HERG with cisapride after channel activation wa s voltage dependent. At -20 mV, 10 nM cisapride reduced HERG tail-curr ent amplitude by 5%, whereas, at +20 mV, the tail-current amplitude wa s reduced by 45% (n = 4 cells). At -20 and +20 mV, 100 nM cisapride re duced tail-current amplitude by 66 and 90%, respectively. We conclude that cisapride is a potent blocker of HERG channels expressed in HEK29 3 cells. This effect may account for the clinical occurrence of Q-T pr olongation and ventricular arrhythmias observed with cisapride.