Abstract 5347: Alpha-Adrenergic-Regulation of IK1 and Acetylcholine-gated IK,ACh is Impaired in Patients with Atrial Fibrillation
In chronic atrial fibrillation (cAF) the major effector of vagal excitation IK,ACh develops arrhythmogenic ACh-independent constitutive activity with limited additional activation via muscarinic receptors. Since the sympathetic nervous system prevents excessive vagal nerve activation we tested whether modulation of IK,ACh by adrenoceptors (ARs) is affected in cAF. IK,ACh was measured with whole-cell voltage-clamp in isolated right atrial myocytes from 29 sinus rhythm (SR) and 17 cAF patients. Compared to SR basal current was higher in cAF whereas carbachol (CCh, 2 μM)-activated IK,ACh was smaller (Figure⇓). Activation of beta-ARs with isoproterenol (ISO, 1 μM) increased CCh-activated IK,ACh by ~25% and ~20% in SR and cAF, respectively, whereas activation of adenylyl cyclase with forskolin (FSK, 1 μM) was without effect suggesting channel activation by G-beta/gamma-binding rather than PKA. Stimulation of alpha-1-ARs with phenylephrine (PE, 100 μM) reduced CCh-activated IK,ACh in SR by ~80%, but was ineffective in cAF. Neomycin (NEO, 500 μM), a blocker of phospholipase-C (PLC), prevented the PE effect suggesting that PE blunts IK,ACh activation via PLC-induced depletion of membrane PIP2 content required for IK,ACh stimulation. PE, but not ISO or FSK, reduced basal current in SR by ~50%, suggesting inhibition of IK1, but was ineffective on basal current in cAF which consists of IK1 and constitutively active IK,ACh. Inhibition of CCh-activated IK,ACh and suppression of IK1 by alpha-1-ARs are impaired in cAF. These changes may shift the balance to stronger beta-AR-mediated IK,ACh activation promoting the maintenance of AF.