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

Abstract

1. 5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT 4 receptors. 2. The aims of this study were to examine the effects of 5-HT on the L-type Ca 2+ current (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. 3. 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 37°C. 4. 5-HT (1 nM-10 μM) caused a concentration-dependent increase in 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 EC 50: -7.09±0.07 vs -7.26±0.06) or Hill coefficient (n H: 1.5±0.6 vs 1.5±0.3) of the 5-HT concentration-response curve. 5. 5-HT (10 μM) produced a greater increase in the APD at 50% repolarisation (APD 50) in cells from β-blocked patients (of 37±10 ms, i.e. 589±197%) vs non-β-blocked patients (of 10±4ms, i.e. 157±54%; P< 0.05). Both the APD 90 and the ERP were unaffected by 5-HT. 6. 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). 7. 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.