Activation of β₃-Adrenoceptor Promotes Rapid Pacing-Induced Atrial Electrical Remodeling in Rabbits

Abstract

Cardiac electrophysiological function is under the regulatory control of the sympathetic nervous system. In addition to classical β-adrenoceptors (β-AR, including β₁- and β₂- subtypes), β₃-AR is also expressed in human heart and shows its distinctive functions. This study is aimed to elucidate the role of β₃-AR in the regulation of atrial fibrillation (AF), especially its role in rapid pacing-induced atrial electrical remodeling in rabbits. The rapid atrial pacing model was established by embedding electrodes in the right atrium pacing at a speed of 600 beats per minute. The protein level of β₃-AR in the atria was found significantly upregulated by western blot. The atrial effective refractory period (AERP) and its rate adaptation were decreased after pacing which were further shortened by BRL37344, a selective β₃-AR agonist, leading to the increase of AF inducibility and duration. Similarly, β₃-AR activation induced time-dependent shortening of action potential duration (APD), together with decrease of L-type calcium current (I_Ca,L) and increase of inward rectifier potassium current (I_K1) and transient outward potassium current (I_to) in rapid pacing atrial myocytes. Meanwhile, all the effects were abolished by specific β₃-AR antagonist, SR59230A. In summary, our study represents that activation of β₃-AR promotes the atrial electrical remodeling process by altering the balance of ion channels in atrial myocytes, which provides new insights into the pharmacological role of β₃-AR in heart diseases.

β3-Adrenoceptor Mediates Metabolic Protein Remodeling in a Rabbit Model of Tachypacing-Induced Atrial Fibrillation

“…Inhibition of β3-AR suppresses AF-induced metabolism-related protein disruption via regulating PPARα/PGC-1α pathway. All of these results, together with our previous reports that β3-AR inhibition could block structural [11] and electrical [10] remodeling and partially alleviate metabolism-related protein remodeling in rodent models, suggest that the β3-AR might be a potential novel target for AF therapy.…”

“…We also previously reported that β3-AR activation increases I to in rapidly paced atrial myocytes [10] and reduced AERP. In this study, β3-AR inhibition reversed the AF-induced decrease of AERP also suggests that the PPARα/PGC-1α signaling pathway contributes to the β3-AR-mediated metabolism remodeling.…”

“…The AF animal model was previously established by Yu et al [10]. Briefly, New Zealand white rabbits (2.0 - 2.5 kg) were anesthetized with ketamine (35 mg/kg; Sigma Aldrich, St. Louis, MO, USA) and xylazine (5 mg/kg, i.m., Sigma Aldrich).…”

“…All experiments were carried out in the presence of 10-μM nadolol (an antagonist for β1- and β2-ARs) 30 min before antagonist or agonist infusion. At 25 min after pacing was started, BRL37344 (9 μg/kg) or SR59230A (0.5 mg/kg) was initially administered by pump infusion for at least 30 min, followed by infusion twice a day throughout the study period [10,12,19]. The control group was given the vehicle solvent of the β3-AR agonist and antagonist.…”

“…It has been classically thought that β3-AR mediates metabolic processes (e.g., lipolysis) in adipocytes [9]. A recent report from Yu et al showed that activation of β3-AR promoted atrial electrical remodeling, possibly by altering the calcium and potassium current, in rapidly paced atrial myocytes [10]. Additionally, Sheng et al also found that in the canine model of pacing-induced AF, upregulation of the β3-AR contributed to oxidative stress, and exacerbated atrial structural remodeling [11].…”