Impact of R-Carvedilol on beta 2-Adrenergic Receptor-Mediated Spontaneous Calcium Release in Human Atrial Myocytes
Por:
Casabella-Ramon, S, Jimenez-Sabado, V, Tarifa, C, Casellas, S, Lu, TT, Izquierdo-Castro, P, Gich, I, Jimenez, M, Ginel, A, Guerra, JM, Chen, SRW, Benítez R and Hove-Madsen, L
Publicada:
1 jul 2022
Resumen:
A hallmark of atrial fibrillation is an excess of spontaneous calcium release events, which can be mimicked by beta 1- or beta 2-adrenergic stimulation. Because beta 1-adrenergic receptor blockers (beta 1-blockers) are primarily used in clinical practice, we here examined the impact of beta 2-adrenergic stimulation on spontaneous calcium release and assessed whether the R- and S-enantiomers of the non-selective beta- blocker carvedilol could reverse these effects. For this purpose, human atrial myocytes were isolated from patients undergoing cardiovascular surgery and subjected to confocal calcium imaging or immunofluorescent labeling of the ryanodine receptor (RyR2). Interestingly, the beta 2-adrenergic agonist fenoterol increased the incidence of calcium sparks and waves to levels observed with the non-specific beta-adrenergic agonist isoproterenol. Moreover, fenoterol increased both the amplitude and duration of the sparks, facilitating their fusion into calcium waves. Subsequent application of the non beta-blocking R-Carvedilol enantiomer reversed these effects of fenoterol in a dose-dependent manner. R-Carvedilol also reversed the fenoterol-induced phosphorylation of the RyR2 at Ser-2808 dose-dependently, and 1 mu M of either R- or S-Carvedilol fully reversed the effect of fenoterol. Together, these findings demonstrate that beta 2-adrenergic stimulation alone stimulates RyR2 phosphorylation at Ser-2808 and spontaneous calcium release maximally, and points to carvedilol as a tool to attenuate the pathological activation of beta 2-receptors.
Filiaciones:
Casabella-Ramon, S:
CSIC, Inst Invest Biomed Barcelona, Barcelona 08036, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Barcelona 08193, Spain
Univ Autonoma Barcelona, Neurosci Inst, Barcelona 08193, Spain
Jimenez-Sabado, V:
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc CIBERCV, Madrid 28029, Spain
Tarifa, C:
CSIC, Inst Invest Biomed Barcelona, Barcelona 08036, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Casellas, S:
Hosp Santa Creu & Sant Pau, Serv Cirugia Cardiaca, Barcelona 08025, Spain
Lu, TT:
Univ British Columbia, Fac Med, Vancouver, BC V6T 1Z4, Canada
Izquierdo-Castro, P:
CSIC, Inst Invest Biomed Barcelona, Barcelona 08036, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Gich, I:
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Inst Salud Carlos III, CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain
Jimenez, M:
Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Barcelona 08193, Spain
Univ Autonoma Barcelona, Neurosci Inst, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Enfermedades Hepat & Digest CIBEREHD, Madrid 28029, Spain
Ginel, A:
Hosp Santa Creu & Sant Pau, Serv Cirugia Cardiaca, Barcelona 08025, Spain
Guerra, JM:
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc CIBERCV, Madrid 28029, Spain
Univ Autonoma Barcelona, Serv Cardiol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Chen, SRW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 2T9, Canada
Benítez R:
Univ Politecn Cataluna, Dept Engn Sistemes Automat & Informat Ind, Barcelona 08034, Spain
Hove-Madsen, L:
CSIC, Inst Invest Biomed Barcelona, Barcelona 08036, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08041, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc CIBERCV, Madrid 28029, Spain
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