Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade.
5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT4 receptors. The aims of this study were to examine the effects of 5-HT on the L-type Ca2+ current (ICaL) 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 beta-adrenoceptor antagonists. 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 degrees C. 5-HT (1 nm-10 microm) caused a concentration-dependent increase in ICaL, which was potentiated in cells from beta-blocked (maximum response to 5-HT, Emax=299+/-12% increase above control) compared to non-beta-blocked patients (Emax=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 (nH: 1.5+/-0.6 vs 1.5+/-0.3) of the 5-HT concentration-response curve. 5-HT (10 microm) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from beta-blocked patients (of 37+/-10 ms, i.e. 589+/-197%) vs non-beta-blocked patients (of 10+/-4 ms, i.e. 157+/-54%; P<0.05). Both the APD90 and the ERP were unaffected by 5-HT. Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from beta-blocked, compared to zero of 16 cells from the non-beta-blocked patients (P<0.05). 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 beta-adrenoceptor blockade was associated with arrhythmic potential.
Pau
Davide
D
Section of Cardiology, Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER. dp39d@clinmed.gla.ac.uk
Workman
Antony J
AJ
Kane
Kathleen A
KA
Rankin
Andrew C
AC
D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin