A MECHANISM FOR THE PROARRHYTHMIC EFFECTS OF CISAPRIDE (PROPULSID) - HIGH-AFFINITY BLOCKADE OF THE HUMAN CARDIAC POTASSIUM CHANNEL HERG

Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to treat nocturnal heartburn as well as a variety of other gastro intestinal disorders, The use of cisapride has been associated with ac quired long QT syndrome and ventricular arrhythmias such as torsades d e pointes which produces sudden cardiac death, These cardiotoxic effec ts can be due to blockade of one or more types of K+ channel currents in the human heart, For this reason we compared the effects of cisapri de on two cloned human cardiac K+ channels, Kv1.5 and the human ether- a-go-go-related gene (HERG) stably transfected into mammalian cells, U sing patch clamp electrophysiology, we found that cisapride was a pote nt inhibitor of HERG displaying an IC50 value of 44.5 nmol/l when tail currents at -40 mV were measured following a 2 s test depolarization to +20 mV, When HERG currents were measured at the end of prolonged (2 0 s) depolarizing steps to +20 mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/l, The main effect of cisapride w as to enhance the rate of HERG current decay thereby reducing current at the end of the voltage clamp pulse, Furthermore, the potency of cis apride for the HERG channel was similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/l) and the nons edating antihistamine terfenadine (IC50 = 56.0 nmol/l). In contrast to its effects on HERG, cisapride inhibited Kv1.5 channel currents weakl y displaying an IC50 value of 21.2 mu mol/l. It is concluded that cisa pride displays specific, high affinity block of the human cardiac K+ c hannel HERG, It is likely that this interaction underlies the proarrhy thmic effects of the drug observed under certain clinical settings. (C ) 1997 Federation of European Biochemical Societies.