Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists

Pau, D., Workman, A.J. , Kane, K.A. and Rankin, A.C. (2005) Electrophysiological effects of prucalopride, a novel enterokinetic agent, on isolated atrial myocytes from patients treated with beta-adrenoceptor antagonists. Journal of Pharmacology and Experimental Therapeutics, 313, pp. 146-153. (doi: 10.1124/jpet.104.076869)

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Publisher's URL: http://dx.doi.org/10.1124/jpet.104.076869

Abstract

Prucalopride is a selective 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 pro-arrhythmic 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 (10-9-10-4 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-dependency. 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% repolarisation (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 ERP were unaffected by prucalopride or 5-HT. Furthermore, 5-HT induced abnormal depolarisations 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 repolarisation or refractory period, and was devoid of arrhythmic activity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rankin, Professor Andrew and Workman, Dr Antony and Pau, Dr Davide
Authors: Pau, D., Workman, A.J., Kane, K.A., and Rankin, A.C.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
Journal Name:Journal of Pharmacology and Experimental Therapeutics
ISSN:0022-3565

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