Electrophysiological Effects of Prucalopride,a Novel Enterokinetic Agent,on Isolated Atrial Myocytes from Patients Treated with beta-Adrenoceptor Antagonists

摘要

Prucalopride is a selective 5-hydroxytryptamine type 4 (5-HT_4) receptor agonist developed for the treatment of gastrointestinal disorders.The endogenous agonist 5-HT acting via 5-HT_4 receptors increases the L-type Ca~(2+) current (I_(CaL)) with potentially proarrhythmic consequences (Pau et al.,2003).The aims of this study were to investigate the effects of prucalopride on I_(CaL),action potentials,refractory period,and arrhythmic activity in human atrial myocytes,and to compare these with the effects of 5-HT,using the whole-cell perforated patch-clamp technique.Prucalopride (10~(-9) to 10~(-4) M) produced a concentration-dependent increase in I_(CaL) amplitude,with a maximum response at 10muM,from -5.3+-0.6 to -10.9+-1.5pA/pF (p < 0.05;n=22 cells,10 patients),without affecting its voltage-dependence.Subsequent application of 10muM 5-HT further increased I_(CaL) to -17.7 +- 2.8 pA/pF (p < 0.05;n=16 cells,9 patients).The increase in I_(CaL) by prucalopride,98+-15%,was significantly smaller than that by 5-HT,233+-26% (p < 0.05).Prucalopride (10muM) significantly increased the action potential duration at 50% repolarization (APD_(50)) from 12+-2 to 17+-3 ms (p < 0.05;n=22 cells,9 patients).Following washout of prucalopride,5-HT (10muM) increased APD_(50),to a greater extent,from 14 +- 3 to 32+-7 ms (p < 0.05;n=11 cells;8 patients).The APD_(75),APD_(90),and effective refractory period were unaffected by prucalopride or 5-HT.Furthermore,5-HT induced abnormal depolarizations in 27% of the cells studied,whereas prucalopride induced none (p < 0.05).In conclusion,in human atrial cells,prucalopride,at concentrations markedly above those used therapeutically,acted as partial agonist on I_(CaL) and APD_(50),with no effect on late repolarization or refractory period,and was devoid of arrhythmic activity.