Prevention of adenosine A(2A) receptor activation diminishes beat-to-beat alternation in human atrial myocytes
Por:
Molina, CE, Llach, A, Herraiz-Martinez, A, Tarifa, C, Barriga, M, Wiegerinck, RF, Fernandes, J, Cabello, N, Vallmitjana, A, Benitez, R, Montiel, J, Cinca, J, Hove-Madsen, L
Publicada:
1 ene 2016
Resumen:
Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A(2A) receptor (A(2A)R) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs-protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 +/- 0.1 to 0.6 +/- 0.1 Hz; p < 0.01 for beta-adrenergic receptors and from 1.4 +/- 0.1 to 0.5 +/- 0.1 Hz; p < 0.05 for A(2A)Rs. The latter was linked to increased spontaneous calcium release and after-depolarizations. Moreover, A(2A)R activation increased the fraction of non-uniformly responding cells in HL-1 myocyte cultures from 19 +/- 3 to 51 +/- 9 %; p < 0.02, and electrical mapping in perfused porcine atria revealed that adenosine induced electrical alternans at longer cycle lengths, doubled the fraction of electrodes showing alternation, and increased the amplitude of alternations. Importantly, protein kinase A inhibition increased the highest frequency where uniform responses could be maintained from 0.84 +/- 0.12 to 1.86 +/- 0.11 Hz; p < 0.001 and prevention of A(2A)R-activation with exogenous adenosine deaminase selectively increased the threshold from 0.8 +/- 0.1 to 1.2 +/- 0.1 Hz; p = 0.001 in myocytes from patients with AF. In conclusion, A(2A)R-activation promotes beat-to-beat irregularities in the calcium transient in human atrial myocytes, and prevention of A(2A)R activation may be a novel means to maintain uniform beat-to-beat responses at higher beating frequencies in patients with atrial fibrillation.
Filiaciones:
Molina, CE:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Univ Duisburg Essen, Fac Med, Inst Pharmacol, D-45122 Essen, Germany
Llach, A:
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona 08025, Spain
Herraiz-Martinez, A:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Tarifa, C:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Barriga, M:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Wiegerinck, RF:
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona 08025, Spain
Fernandes, J:
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona 08025, Spain
Cabello, N:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
Montiel, J:
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiac Surg, Barcelona 08025, Spain
Cinca, J:
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona 08025, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, CSIC ICCC, Cardiovasc Res Ctr, Cardiac Rhythm & Contract, St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, St Antoni Ma Claret 167, Barcelona 08025, Spain
Green Published
|