Atrial tachycardia induces remodelling of muscarinic receptors and their coupled potassium currents in canine left atrial and pulmonary vein cardiomyocytes.

BACKGROUND AND PURPOSE: Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M2, M3, M4) in atrial cardiomyocytes are coupled to distinct K+-currents (called IKM2, IKM3, IKM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+-currents in left-atrial (LA) and PV cardiomyocytes. EXPERIMENTAL APPROACH: Receptor expression was assayed by western blot. IKM2, IKM3 and IKM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm). KEY RESULTS: Current densities of IKM2, IKM3 and IKM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M2, M3 and M4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing. CONCLUSIONS AND IMPLICATIONS: AT downregulated all three mAChR-coupled K+-current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+-currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.

Beta-blockers as antiarrhythmic agents.

Drugs that suppress beta-adrenergic signaling by competitively inhibiting agonist binding to beta-adrenergic receptors ("beta-blockers") have important antiarrhythmic properties. They differ from most other antiarrhythmic agents by not directly modifying ion channel function; rather, they prevent the arrhythmia-promoting actions of beta-adrenergic stimulation. beta-Blockers are particularly useful in preventing sudden death due to ventricular tachyarrhythmias associated with acute myocardial ischemia, congenital long QT syndrome, and congestive heart failure. They are also quite valuable in controlling the ventricular rate in patients with atrial fibrillation. This chapter reviews the properties of beta-adrenoceptor signaling, the basic mechanisms of cardiac arrhythmias on which beta-blockers act, the ion channel mediators of beta-adrenergic responses, the evidence for clinical antiarrhythmic indications for beta-blocker therapy and the specific pharmacodynamic and pharmacokinetic properties of beta-blockers that differentiate the various agents of this class.