Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice

Abstract

BackgroundAtrial fibrillation (AF) is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.ObjectivesOur aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR) subtypes, which may be involved in the onset and duration of AF.Methods and ResultsTrans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0±8.1 sec). We found that adrenergic activation by intraperitoneal norepinephrine (NE) injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2±104.8 sec; P<0.001). In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors’ effects on AF, we assessed the SR Ca2+ leak, a major trigger of AF, and consequent spontaneous SR Ca2+ release (SCR) in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.ConclusionsWe have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

“…Thereby, the blockade of α 1 -adrenoceptors may lead to the stabilization of Ca 2+ level producing antiarrhythmic effect in arrhythmias induced by catecholamines e.g., catecholaminergic polymorphic ventricular tachycardia. The above hypothesis was supported by Suita et al ( 2015 ), who demonstrated that prazosin not only shortened norepinephrine-induced elongation of atrial fibrillation in mice, but also attenuated norepinephrine-induced SR Ca 2+ leak and spontaneous SR Ca 2+ release in cultured atrium cardiomyocytes. This proves that α 1 -adrenoceptors may have role in preventing cardiac arrhythmias.…”

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

“…We previously demonstrated that the sympathetic activation by intraperitoneal administration of norepinephrine (NE) (1.5 mg/kg) strikingly elongated the duration of AF in mice. 23 The sympathetic activation-induced elongated AF was also shorter in Epac1-KO mice (WT vs. Epac1-KO: 716.49± 174.20 s vs. 215.19±70.94 s, P<0.05) ( Figure 1D). These findings indicate that Epac1 plays an important role in the development of AF in mice.…”

“…Simple and minimally invasive AF was induced in mice by transesophageal burst pacing, and the duration of AF (AFD) was measured, as previously reported. 23 Briefly, the mice were anesthetized under isoflurane (1.5%) inhalation. For 10 s, the transesophageal atrial burst pacing was conducted at a stimulation of 1.5 mA with 10-ms cycle lengths and a pulse width of 3 mA.…”

Low heart deceleration capacity imply higher atrial fibrillation-free rate after ablation

“…In our report, 85 (55.2%), 26 (16.9%) and 74 (48.1%) subjects were treated with amiodarone,propafenone and metoprolol, respectively. As we know, amiodarone slows conduction rate and prolongs the refractory period of the SA and AV nodes; 23 propafenone slows the influx of sodium ions into the cardiac muscle cells, causing a decrease in excitability of the cells; 24 and metoprolol blocks β1 adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential and prolonging repolarization of phase 3 25 . In general, these medicines are mainly to control arrhythmia by affecting the action potential of cardiac myocytes.…”