Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles

Published:August 03, 2020DOI:


      Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong.


      The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline.


      We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes.


      ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former.


      ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.


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        • Antzelevitch C.
        • Yan G.X.
        • Ackerman M.J.
        • et al.
        J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge.
        Heart Rhythm. 2016; 13: e295-e324
        • Milman A.
        • Andorin A.
        • Postema P.G.
        • et al.
        Ethnic differences in patients with Brugada syndrome and arrhythmic events: new insights from SABRUS.
        Heart Rhythm. 2019; 16: 1468-1474
        • Nademanee K.
        • Hocini M.
        • Haissaguerre M.
        Epicardial substrate ablation for Brugada syndrome.
        Heart Rhythm. 2017; 14: 457-461
        • Rolf S.
        • Bruns H.J.
        • Wichter T.
        • et al.
        The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol.
        Eur Heart J. 2003; 24: 1104-1112
        • Xu Y.
        • Tuteja D.
        • Zhang Z.
        • et al.
        Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts.
        J Biol Chem. 2003; 278: 49085-49094
        • Chang P.C.
        • Chen P.S.
        SK channels and ventricular arrhythmias in heart failure.
        Trends Cardiovasc Med. 2015; 25: 508-514
        • Chen M.
        • Xu D.Z.
        • Wu A.Z.
        • et al.
        Concomitant SK current activation and sodium current inhibition cause J wave syndrome.
        JCI Insight. 2018; 3e122329
        • Chen M.
        • Yin D.
        • Guo S.
        • et al.
        Sex-specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles.
        J Physiol. 2018; 596: 4299-4322
        • Yan G.X.
        • Antzelevitch C.
        Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation.
        Circulation. 1999; 100: 1660-1666
        • Parks X.X.
        • Contini D.
        • Jordan P.M.
        • Holt J.C.
        Confirming a role for α9nAChRs and SK potassium channels in type II hair cells of the turtle posterior crista.
        Front Cell Neurosci. 2017; 11: 356
        • Dasari S.
        • Hill C.
        • Gulledge A.T.
        A unifying hypothesis for M1 muscarinic receptor signalling in pyramidal neurons.
        J Physiol. 2017; 595: 1711-1723
        • Shimeno K.
        • Takagi M.
        • Maeda K.
        • et al.
        A predictor of positive drug provocation testing in individuals with saddle-back type ST-segment elevation.
        Circ J. 2009; 73: 1836-1840
        • Fei Y.D.
        • Li W.
        • Hou J.W.
        • et al.
        Oxidative stress-induced afterdepolarizations and protein kinase C signaling.
        Int J Mol Sci. 2017; 18: 688
        • Bebarova M.
        • Matejovic P.
        • Pasek M.
        • Simurdova M.
        • Simurda J.
        Effect of ajmaline on action potential and ionic currents in rat ventricular myocytes.
        Gen Physiol Biophys. 2005; 24: 311-325
        • Chua S.K.
        • Chang P.C.
        • Maruyama M.
        • et al.
        Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.
        Circ Res. 2011; 108: 971-979
        • Fedida D.
        • Giles W.R.
        Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle.
        J Physiol. 1991; 442: 191-209
        • Yan G.X.
        • Antzelevitch C.
        Cellular basis for the electrocardiographic J wave.
        Circulation. 1996; 93: 372-379
        • Zang W.J.
        • Chen L.N.
        • Yu X.J.
        • et al.
        Comparison of effects of acetylcholine on electromechanical characteristics in guinea-pig atrium and ventricle.
        Exp Physiol. 2005; 90: 123-130
        • Liang B.
        • Nissen J.D.
        • Laursen M.
        • et al.
        G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization.
        Cardiovasc Res. 2014; 101: 175-184
        • Matsuda T.
        • Takeda K.
        • Ito M.
        • et al.
        Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium.
        J Pharmacol Sci. 2005; 98: 33-40
        • Litovsky S.H.
        • Antzelevitch C.
        Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol: a direct effect of acetylcholine in ventricular myocardium.
        Circ Res. 1990; 67: 615-627
        • Calloe K.
        • Goodrow R.
        • Olesen S.P.
        • Antzelevitch C.
        • Cordeiro J.M.
        Tissue-specific effects of acetylcholine in the canine heart.
        Am J Physiol Heart Circ Physiol. 2013; 305: H66-H75
        • Roberge F.A.
        • Nadeau R.A.
        • James T.N.
        The nature of the PR interval.
        Cardiovasc Res. 1968; 2: 19-30
        • Batchvarov V.N.
        • Govindan M.
        • Camm A.J.
        • Behr E.R.
        Significance of QRS prolongation during diagnostic ajmaline test in patients with suspected Brugada syndrome.
        Heart Rhythm. 2009; 6: 625-631
        • Bestetti R.B.
        • Ramos C.P.
        • Figueredo-Silva J.
        • Sales-Neto V.N.
        • Oliveira J.S.
        Ability of the electrocardiogram to detect myocardial lesions in isoproterenol induced rat cardiomyopathy.
        Cardiovasc Res. 1987; 21: 916-921
        • Mantravadi R.
        • Gabris B.
        • Liu T.
        • et al.
        Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts.
        Circ Res. 2007; 100: e72-e80
        • Kawano H.
        • Okada R.
        • Yano K.
        Histological study on the distribution of autonomic nerves in the human heart.
        Heart Vessels. 2003; 18: 32-39
        • Antzelevitch C.
        • Yan G.X.
        J-wave syndromes: Brugada and early repolarization syndromes.
        Heart Rhythm. 2015; 12: 1852-1866
        • Di Diego J.M.
        • Cordeiro J.M.
        • Goodrow R.J.
        • et al.
        Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males.
        Circulation. 2002; 106: 2004-2011
        • Lu L.
        • Zhang Q.
        • Timofeyev V.
        • et al.
        Molecular coupling of a Ca2+-activated K+ channel to L-type Ca2+ channels via α-actinin 2.
        Circ Res. 2007; 100: 112-120
        • Ko J.S.
        • Guo S.
        • Hassel J.
        • et al.
        Ondansetron blocks wildtype and p.F503L variant small conductance calcium activated potassium channels.
        Am J Physiol Heart Circ Physiol. 2018; 315: H375-H388
        • Panfilov A.V.
        Is heart size a factor in ventricular fibrillation? Or how close are rabbit and human hearts?.
        Heart Rhythm. 2006; 3: 862-864