Mirabegron, a beta 3-adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently

Mirabegron increases atrial fibrillation (AF) risk. The left atrium (LA) is the most critical 'substrate' for AF and has higher arrhythmogenesis compared with the right atrium (RA). The present study aimed to investigate the electrophysiological and arrhythmogenic effects of mirabegron on the LA and RA and clarify the potential underlying mechanisms. Conventional microelectrodes, a whole-cell patch clamp and a confocal microscope were used in rabbit LA and RA preparations or single LA and RA myocytes before and after mirabegron administration with or without cotreatment with KT5823 [a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor]. The baseline action potential duration at repolarization extents of 20 and 50% (but not 90%) were shorter in the LA than in the RA. Mirabegron at 0.1 and 1 mu M (but not 0.01 mu M) reduced the action potential duration at repolarization extents of 20 and 50% in the LA and RA. Mirabegron (0.1 mu M) increased the occurrence of tachypacing-induced burst firing in the LA but not in the RA, where it was suppressed by KT5823 (1 mu M). Mirabegron (0.1 mu M) increased the L-type Ca2+ current (ICa-L), ultrarapid component of delayed rectifier K+ current (I-Kur), Ca2+ transients and sarcoplasmic reticulum Ca2+ content but reduced transient outward K+ current (I-to) in the LA myocytes. However, mirabegron did not change the Na+ current and delayed rectifier K+ current in the LA myocytes. Moreover, pretreatment with KT5823 (1 mu M) inhibited the effects of mirabegron on ICa-L, I-to and I-Kur in the LA myocytes. Furthermore, in the RA myocytes, mirabegron reduced ICa-L but did not change I-to. In conclusion, mirabegron differentially regulates electrophysiological characteristics in the LA and RA. Through the activation of the cAMP-dependent protein kinase pathway and induction of Ca2+ dysregulation, mirabegron may increase LA arrhythmogenesis, leading to increased AF risk.