Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade

Pau, D., Workman, A.J., Kane, K.A. and Rankin, A.C. (2003) Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade. British Journal of Pharmacology, 140, pp. 1434-1441. (doi: 10.1038/sj.bjp.0705553)

Abstract

<b>1.</b> 5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT₄ receptors. <b>2.</b> The aims of this study were to examine the effects of 5-HT on the L-type Ca²⁺ current (<i>I</i>_CaL) action potential duration (APD), the effective refractory period (ERP) and arrhythmic activity in human atrial cells, and to assess the effects of prior treatment with β-adrenoceptor antagonists. <b>3.</b> Isolated myocytes, from the right atrial appendage of 27 consenting patients undergoing cardiac surgery who were in sinus rhythm, were studied using the whole-cell perforated patch-clamp technique at 37ºC. <b>4.</b> 5-HT (1 n-10 μM) caused a concentration-dependent increase in <i>I</i>_CaL, which was potentiated in cells from β-blocked (maximum response to 5-HT, E_max=299±12% increase above control) compared to non-β-blocked patients (E_max=220±6%, P<0.05), but with no change in either the potency (log EC₅₀: -7.09±0.07 vs -7.26±0.06) or Hill coefficient (<i>n</i>_H: 1.5±0.6 vs 1.5±0.3) of the 5-HT concentration-response curve. <b>5.</b> 5-HT (10 μM) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from β-blocked patients (of 37±10 ms, i.e. 589±197%) vs non-β-blocked patients (of 10±4 ms, i.e. 157±54%; P<0.05). Both the APD₉₀ and the ERP were unaffected by 5-HT. <b>6.</b> Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from β-blocked, compared to zero of 16 cells from the non-β-blocked patients (P<0.05). <b>7.</b> In summary, the 5-HT-induced increase in calcium current was associated with a prolonged early plateau phase of repolarisation, but not late repolarisation or refractoriness, and the enhancement of these effects by chronic β-adrenoceptor blockade was associated with arrhythmic potential.

• Item Type: Articles
• Keywords: Human atrium, isolated myocytes, 5-HT4 receptors, calcium current, action potential, refractory period beta-adrenergic antagonists, arrhythmias (mechanisms)
• 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: Q Science > QP Physiology
• 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: British Journal of Pharmacology
• Publisher: Nature
• ISSN: 1476-5381
• Copyright Holders: Copyright © 2003 Nature
• First Published: First published in British Journal of Pharmacology 140:1434-1441
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher