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 þ 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 b-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 371C. 4 5-HT (1 nM -10 mM) caused a concentration-dependent increase in I CaL , which was potentiated in cells from b-blocked (maximum response to 5-HT, E max ¼ 299712% increase above control) compared to non-b-blocked patients (E max ¼ 22076%, Po0.05), but with no change in either the potency (log EC 50 : À7.0970.07 vs À7.2670.06) or Hill coefficient (n H : 1.570.6 vs 1.570.3) of the 5-HT concentration -response curve. 5 5-HT (10 mM) produced a greater increase in the APD at 50% repolarisation (APD 50 ) in cells from b-blocked patients (of 37710 ms, i.e. 5897197%) vs non-b-blocked patients (of 1074 ms, i.e. 157754%; Po0.05). 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 b-blocked, compared to zero of 16 cells from the non-b-blocked patients (Po0.05). 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 b-adrenoceptor blockade was associated with arrhythmic potential.

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

“…4. This figure also shows the superimposed concentration-response curve of the effect of 5-HT on peak I CaL obtained previously in our lab in atrial cells from a similar group of patients (Pau et al, 2003). Prucalopride (from 1 nM to 100 M) elicited a concentrationdependent increase in the amplitude of peak I CaL (measured at ϩ10 mV), with a maximum response (E max ) equal to an increase of 93 Ϯ 14% above control (n ϭ 7-22 cells, 2-9 patients).…”

“…Concentration-response data for the effect of prucalopride on I CaL were fitted iteratively (Prism 3.0; GraphPad Software Inc., San Diego, CA) using a variable slope sigmoidal concentration-response curve (Hill equation). The curves were fitted to mean I CaL values, obtained at six concentrations of prucalopride between 1 nM and 100 M. The concentrationresponse curve for 5-HT was obtained previously in our lab (Pau et al, 2003). Curve-fit values were compared using a two-tailed unpaired Student's t test.…”

“…The whole-cell perforated patch-clamp technique was used to record action potentials and calcium currents, as described in detail by Pau et al (2003). Briefly, cells were superfused at 37°C with a physiological solution containing: 130.0 mM NaCl, 4.0 mM KCl, 2.0 mM CaCl 2 , 1.0 mM MgCl 2 , 10.0 mM glucose, and 10.0 mM HEPES, pH 7.4.…”

“…Proarrhythmic activity of 5-HT has been demonstrated previously in human atrial muscle (Kaumann and Sanders, 1994) and in human atrial myocytes (Pau et al, 2003), probably associated with the increased I CaL . Moreover, it has been postulated that the release of 5-HT from platelets may be involved in the origin and maintenance of atrial fibrillation (Kaumann, 1994).…”

Surprises from a cardiac 5-HT4 TG mouse: spontaneous atrial arrhythmias by endogenous 5-HT of atrial origin? Different mechanism of arrhythmias through 5-HT4 receptors and β-adrenoceptors?

“…5-HT increases the L-type Ca 2+ current (I Ca,L )in human atrial myocytes in a PKA-dependent manner (Ouadid et al 1992). Chronic treatment of patients with β-blockers potentiates the effects of 5-HT on I Ca,L and arrhythmic activity of atrial myocytes (Pau et al 2003). 5-HT causes also cardiostimulation in porcine heart (Kaumann 1990;Parker et al 1994;Brattelid et al 2004), but not in other non-primate species, at least under physiological conditions.…”