Abstract 2897: Enhanced M3 Receptor Activity and Susceptibility to Atrial Fibrillation in RGS2 Deficient Mice
Background & Objective Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic acetylcholine receptors (M2R, M3R), are involved in vagal-induced AF. M2R and M3R activate the heterotrimeric G proteins Gi and Gq respectively, by promoting GTP binding, and these in turn activate distinct K+channels. Signalling is terminated by GTP hydrolysis, a process accelerated by regulator of G protein signalling (RGS) proteins. RGS2 is selective for Gq, and thus may regulate atrial M3R signalling. We hypothesised that knockout of RGS2 (RGS2−/−) would render the atria more susceptible to electrically-induced AF.
Methods One month old male RGS2−/− and wild type (WT) mice were anaesthetized and instrumented for intracardiac electrophysiology. Atrial effective refractory periods (AERPs) were determined in the absence and presence of the selective M3R antagonist Darifenacin (1 mg/kg, iv). Susceptibility to electrically induced AF used programmed electrical stimulation with 1 extra stimulus. Real-time RT-PCR was used to measure atrial content of M2R and M3R mRNA.
Results AERP was lower in RGS2−/− compared to WT mice in both the high RA (HRA) (30.0±1.1 vs 33.5±1.1 ms, P<0.05) and mid RA (MRA) (20.9±0.7 vs 23.8±0.6 ms, P<0.05). Darifenacin eliminated these strain-related differences (HRA: 36.6±1.7 vs 38.6±1.9 ms, and MRA: 30.4±1.7 vs 29.7±1.0, N=5 & 6, respectively, P>0.4). RGS2−/− mice were also more susceptible to AF induction (10/24 vs 1/25, P<0.05). Unidirectional conduction block from the MRA to HRA was frequently observed during AF. In 2 mice, after AF onset, the HRA cycle length (27 ms) was longer than that of the His bundle region (22 ms), which regularized to 25 ms, 173 ms after induction. This pattern suggests a drifting rotor converting to a stationary rotor after anchoring. Atrial muscarinic receptor expression did not differ between RGS2−/− and WT mice suggesting that increased AF susceptibility was not due to increased receptor density. M2R expression in both strains was approximately 70 fold higher than M3R (P<0.01).
Conclusions These results suggest that RGS2 is an important regulator in the atrium and that RGS2−/− mice have enhanced susceptibility to re-entrant mechanisms of AF through enhanced M3 muscarinic receptor activity.