sr-59230a and Atrial-Fibrillation

The beta 3-adrenoceptor (β3-AR) is closely associated with energy metabolism. This study aimed to explore the role of β3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF).. Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1) the pacing group, 2) the β3-AR agonist (BRL37344)-treated group, and 3) the β3-AR antagonist (SR59230A)-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP). RT-PCR and western blot (WB) were used to show alterations in β3-AR and metabolic-related protein.. RT-PCR and WB results showed that β3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of β3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS) and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4) and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1), a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα) and PPAR co-activator (PGC-1α) can be regulated by pharmacological intervention of the β3-AR.. β3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway might be the relevant down-stream molecular machinery in response to AF-induced activation of β3-AR. β3-AR might be a novel target in AF treatment.

Topics: Adenosine Triphosphate; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; CD36 Antigens; Disease Models, Animal; Down-Regulation; Electrocardiography; Fatty Acids; Glucose Transporter Type 4; Myocytes, Cardiac; PPAR alpha; Propanolamines; Rabbits; Receptors, Adrenergic, beta-3; Signal Transduction; Transcription Factors; Up-Regulation

Cardiac electrophysiological function is under the regulatory control of the sympathetic nervous system. In addition to classical β-adrenoceptors (β-AR, including β(1)- and β(2)- subtypes), β(3)-AR is also expressed in human heart and shows its distinctive functions. This study is aimed to elucidate the role of β(3)-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 β(3)-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 β(3)-AR agonist, leading to the increase of AF inducibility and duration. Similarly, β(3)-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 β(3)-AR antagonist, SR59230A. In summary, our study represents that activation of β(3)-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 β(3)-AR in heart diseases.

Topics: Action Potentials; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Atrial Fibrillation; Atrial Function; Calcium Channels, L-Type; Cardiac Pacing, Artificial; Electrocardiography; Electrodes; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying; Propanolamines; Rabbits; Receptors, Adrenergic, beta-3; Refractory Period, Electrophysiological