Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Voigt N ，Heijman J ，Trausch A ，Mintert-Jancke E ，Pott L ，Ravens U ，Dobrev D ... -  《-》

Muscarinic type-1 receptors contribute to I(K,ACh) in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.

Basal and acetylcholine-gated inward-rectifier K+-currents (IK1 and IK,ACh, respectively) are altered in atrial fibrillation (AF). Gi-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating IK,ACh. Although a role for Gq-coupled non-M2-receptor subtypes has been suggested, the precise regulation of IK,ACh by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M1-receptor-mediated IK,ACh regulation and its remodeling in chronic AF (cAF). M1-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, whereas M2-receptor levels were unchanged. The regulation of IK,ACh by M1-receptors was investigated in right-atrial cardiomyocytes using two applications of the M-receptor agonist carbachol (CCh, 2μM), with pharmacological interventions during the second application. CCh application produced a rapid current increase (Peak-IK,ACh), which declined to a quasi-steady-state level (Qss-IK,ACh). In sinus rhythm (Ctl) the selective M1-receptor antagonists pirenzepine (10nM) and muscarinic toxin-7 (MT-7, 10nM) significantly inhibited CCh-activated Peak-IK,ACh, whereas in cAF they significantly reduced both Peak- and Qss-IK,ACh, with no effects on basal inward-rectifier currents in either group. Conversely, the selective M1-receptor agonist McN-A-343 (100μM) induced a current similar to the CCh-activated current in Ctl atrial cardiomyocytes pretreated with pertussis toxin to inhibit M2-receptor-mediated Gi-protein signaling, which was abolished by MT-7. Computational modeling indicated that M1- and M2-receptors redundantly activate IK,ACh to abbreviate APD, albeit with predominant effects of M2-receptors. Our data suggest that Gq-coupled M1-receptors also regulate human atrial IK,ACh and that their relative contribution to IK,ACh activation is increased in cAF patients. We provide novel insights about the role of non-M2-receptors in human atrial cardiomyocytes, which may have important implications for understanding AF pathophysiology.

Heijman J ，Kirchner D ，Kunze F ，Chrétien EM ，Michel-Reher MB ，Voigt N ，Knaut M ，Michel MC ，Ravens U ，Dobrev D ... -  《-》

Inhibitory effects of aprindine on the delayed rectifier K+ current and the muscarinic acetylcholine receptor-operated K+ current in guinea-pig atrial cells.

Ohmoto-Sekine Y ，Uemura H ，Tamagawa M ，Nakaya H ... -  《BRITISH JOURNAL OF PHARMACOLOGY》

Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation.

Voigt N ，Rozmaritsa N ，Trausch A ，Zimniak T ，Christ T ，Wettwer E ，Matschke K ，Dobrev D ，Ravens U ... -  《-》

The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.

Dobrev D ，Friedrich A ，Voigt N ，Jost N ，Wettwer E ，Christ T ，Knaut M ，Ravens U ... -  《-》