guanosine-triphosphate and Atrial-Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic ACh receptors (M2R, M3R) are involved in vagally induced AF. M2R and M3R activate the heterotrimeric G proteins, G(i) and G(q), respectively, by promoting GTP binding, and these in turn activate distinct K(+) channels. Signaling is terminated by GTP hydrolysis, a process accelerated by regulator of G protein signaling (RGS) proteins. RGS2 is selective for G(q) and thus may regulate atrial M3R signaling. We hypothesized that knockout of RGS2 (RGS2(-/-)) would render the atria more susceptible to electrically induced AF. One-month-old male RGS2(-/-) and C57BL/6 wild-type (WT) mice were instrumented for intracardiac electrophysiology. Atrial effective refractory periods (AERPs) were also determined in the absence and presence of carbachol, atropine, and/or the selective M3R antagonist darifenacin. Susceptibility to electrically induced AF used burst pacing and programmed electrical stimulation with one extrastimulus. Real-time RT-PCR measured atrial and ventricular content of RGS2, RGS4, M2R, M3R, and M4R mRNA. AERP was lower in RGS2(-/-) compared with WT mice in both the high right atrium (HRA) (30 +/- 1 vs. 34 +/- 1 ms, P < 0.05) and mid right atrium (MRA) (21 +/- 1 vs. 24 +/- 1 ms, P < 0.05). Darifenacin eliminated this difference (HRA: 37 +/- 2 vs. 39 +/- 2 ms, and MRA: 30 +/- 2 vs. 30 +/- 1, P > 0.4). RGS2(-/-) were more susceptible than WT mice to atrial tachycardia/fibrillation (AT/F) induction (11/22 vs. 1/25, respectively, P < 0.05). Muscarinic receptor expression did not differ between strains, whereas M2R expression was 70-fold higher than M3R (P < 0.01). These results suggest that RGS2 is an important cholinergic regulator in the atrium and that RGS2(-/-) mice have enhanced susceptibility to AT/F via enhanced M3 muscarinic receptor activity.

Topics: Animals; Atrial Fibrillation; Body Temperature; Disease Models, Animal; Electrophysiologic Techniques, Cardiac; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; Guanosine Triphosphate; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Muscarinic M3; RGS Proteins; Risk Factors

Calcium channel blockers are among the most commonly used therapeutic drugs. Nevertheless, the utility of calcium channel blockers for heart disease is limited because of the potent vasodilatory effect that causes hypotension, and other side effects attributable to blockade of noncardiac channels. Therefore, focal calcium channel blockade by gene transfer is highly desirable. With a view to creating a focally applicable genetic calcium channel blocker, we overexpressed the ras-related small G-protein Gem in the heart by somatic gene transfer. Adenovirus-mediated delivery of Gem markedly decreased L-type calcium current density in ventricular myocytes, resulting in the abbreviation of action potential duration. Furthermore, transduction of Gem resulted in a significant shortening of the electrocardiographic QTc interval and reduction of left ventricular systolic function. Focal delivery of Gem to the atrioventricular (AV) node significantly slowed AV nodal conduction (prolongation of PR and AH intervals), which was effective in the reduction of heart rate during atrial fibrillation. Thus, these results indicate that gene transfer of Gem functions as a genetic calcium channel blocker, the local application of which can effectively modulate cardiac electrical and contractile function.

Topics: Action Potentials; Adenoviridae; Animals; Atrial Fibrillation; Atrioventricular Node; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Electrocardiography; Genetic Therapy; Genetic Vectors; Guanosine Triphosphate; Guinea Pigs; Heart Conduction System; Heart Ventricles; Immediate-Early Proteins; Injections; Ion Channel Gating; Monomeric GTP-Binding Proteins; Mutagenesis, Site-Directed; Mutation, Missense; Protein Subunits; Protein Transport; Recombinant Fusion Proteins; Sus scrofa

Topics: Adenoviridae; Animals; Atrial Fibrillation; Calcium Channel Blockers; Calcium Channels, L-Type; Drug Design; Genetic Therapy; Genetic Vectors; Guanosine Triphosphate; Guinea Pigs; Heart Conduction System; Immediate-Early Proteins; Ion Channel Gating; Models, Biological; Monomeric GTP-Binding Proteins; Multigene Family; Protein Subunits; Protein Transport; Recombinant Fusion Proteins; Sus scrofa