RT Journal Article
SR Electronic
T1 Electrophysiological Effects of Prucalopride, a Novel Enterokinetic Agent, on Isolated Atrial Myocytes from Patients Treated with β-Adrenoceptor Antagonists
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 146
OP 153
DO 10.1124/jpet.104.076869
VO 313
IS 1
A1 Davide Pau
A1 Antony J. Workman
A1 Kathleen A. Kane
A1 Andrew C. Rankin
YR 2005
UL http://jpet.aspetjournals.org/content/313/1/146.abstract
AB Prucalopride is a selective 5-hydroxytryptamine type 4 (5-HT4) receptor agonist developed for the treatment of gastrointestinal disorders. The endogenous agonist 5-HT acting via 5-HT4 receptors increases the L-type Ca2+ current (ICaL) with potentially proarrhythmic consequences (Pau et al., 2003). The aims of this study were to investigate the effects of prucalopride on ICaL, 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 ICaL amplitude, with a maximum response at 10 μM, from –5.3 ± 0.6 to –10.9 ± 1.5 pA/pF (p < 0.05; n = 22 cells, 10 patients), without affecting its voltage-dependence. Subsequent application of 10 μM 5-HT further increased ICaL to –17.7 ± 2.8 pA/pF (p < 0.05; n = 16 cells, 9 patients). The increase in ICaL by prucalopride, 98 ± 15%, was significantly smaller than that by 5-HT, 233 ± 26% (p < 0.05). Prucalopride (10 μM) significantly increased the action potential duration at 50% repolarization (APD50) from 12 ± 2 to 17 ± 3 ms (p < 0.05; n = 22 cells, 9 patients). Following washout of prucalopride, 5-HT (10 μM) increased APD50, to a greater extent, from 14 ± 3 to 32 ± 7 ms (p < 0.05; n = 11 cells; 8 patients). The APD75, APD90, 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 ICaL and APD50, with no effect on late repolarization or refractory period, and was devoid of arrhythmic activity. The American Society for Pharmacology and Experimental Therapeutics