This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kovoor, P. Articles by Clapham, D. E. Search for Related Content PubMed PubMed Citation Articles by Kovoor, P. Articles by Clapham, D. E.

EXPERIMENTAL STUDY

Evaluation of the role of I_KACh in atrial fibrillation using a mouse knockout model

Pramesh Kovoor, MD, PhD^*, Kevin Wickman, PhD, Colin T. Maguire, William Pu, MD, Josef Gehrmann, MD, Charles I. Berul, MD and David E. Clapham, MD, PhD

^* Department of Cardiology, Westmead Hospital, Sydney, Australia
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

Manuscript received June 22, 2000; revised manuscript received February 27, 2001, accepted March 22, 2001.

Reprint requests and correspondence: Dr. David E. Clapham, Howard Hughes Medical Institute, Director of Cardiovascular Research, Children’s Hospital and Harvard Medical School, Enders 1309, 320 Longwood Avenue, Boston, Massachusetts 02115
clapham{at}rascal.med.harvard.edu

OBJECTIVES

We sought to study the role of I_KACh in atrial fibrillation (AF) and the potential electrophysiologic effects of a specific I_KACh antagonist.

BACKGROUND

I_KACh mediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of I_KACh in the generation of AF and the electrophysiologic effects of specific I_KACh blockade have not been studied.

METHODS

Adult wild-type (WT) and I_KACh-deficient knockout (KO) mice were studied in the absence and presence of the muscarinic receptor agonist carbachol. The electrophysiologic features of KO mice were compared with those of WT mice to assess the potential effects of a specific I_KACh antagonist.

RESULTS

Atrial fibrillation lasting for a mean of 5.7 ± 11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol. Atrial arrhythmia could not be induced in KO mice. Ventricular tachyarrhythmia could not be induced in either type of mouse. Sinus node recovery times after carbachol and sinus cycle lengths were shorter and ventricular effective refractory periods were greater in KO mice than in WT mice. There was no significant difference between KO and WT mice in AV node function.

CONCLUSIONS

Activation of I_KACh predisposed to AF and lack of I_KACh prevented AF. It is likely that I_KACh plays a crucial role in the generation of AF in mice. Specific I_KACh blockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.

Abbreviations and Acronyms   AF = atrial fibrillation   AV = atrioventricular   ECG = electrocardiogram or electrocardiographic   KO = IKACh-deficient knockout (mice)   MLC = myosin light chain   PCR = polymerase chain reaction   RNA = ribonucleic acid   SA = sinoatrial   WT = wild-type (mice)

This article has been cited by other articles:

				B. F. McBride The Emerging Role of Antiarrhythmic Compounds With Atrial Selectivity in the Management of Atrial Fibrillation J. Clin. Pharmacol., March 1, 2009; 49(3): 258 - 267. [Abstract] [Full Text] [PDF]

				N. Li, V. Timofeyev, D. Tuteja, D. Xu, L. Lu, Q. Zhang, Z. Zhang, A. Singapuri, T. R. Albert, A. V. Rajagopal, et al. Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation J. Physiol., March 1, 2009; 587(5): 1087 - 1100. [Abstract] [Full Text] [PDF]

				Y. Etzion, M. Mor, A. Shalev, S. Dror, O. Etzion, A. Dagan, O. Beharier, A. Moran, and A. Katz New insights into the atrial electrophysiology of rodents using a novel modality: the miniature-bipolar hook electrode Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1460 - H1469. [Abstract] [Full Text] [PDF]

				R. R. Neubig And the Winner Is ... RGS4! Circ. Res., August 29, 2008; 103(5): 444 - 446. [Full Text] [PDF]

				C. Cifelli, R. A. Rose, H. Zhang, J. Voigtlaender-Bolz, S.-S. Bolz, P. H. Backx, and S. P. Heximer RGS4 Regulates Parasympathetic Signaling and Heart Rate Control in the Sinoatrial Node Circ. Res., August 29, 2008; 103(5): 527 - 535. [Abstract] [Full Text] [PDF]

				C.-Y. Chen, D. Chow, N. Chiamvimonvat, K. A. Glatter, N. Li, Y. He, K. E. Pinkerton, and A. C. Bonham Short-term secondhand smoke exposure decreases heart rate variability and increases arrhythmia susceptibility in mice Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H632 - H639. [Abstract] [Full Text] [PDF]

				R. Ochi, Y. Momose, K. Oyama, and W. R. Giles Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents Cardiovasc Res, April 1, 2006; 70(1): 88 - 96. [Abstract] [Full Text] [PDF]

				Y. Fu, X. Huang, H. Zhong, R. M. Mortensen, L. G. D'Alecy, and R. R. Neubig Endogenous RGS Proteins and G{alpha} Subtypes Differentially Control Muscarinic and Adenosine-Mediated Chronotropic Effects Circ. Res., March 17, 2006; 98(5): 659 - 666. [Abstract] [Full Text] [PDF]

				D. Dobrev, A. Friedrich, N. Voigt, N. Jost, E. Wettwer, T. Christ, M. Knaut, and U. Ravens The G Protein-Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation Circulation, December 13, 2005; 112(24): 3697 - 3706. [Abstract] [Full Text] [PDF]

				J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]

				Z. Zhang, Y. He, D. Tuteja, D. Xu, V. Timofeyev, Q. Zhang, K. A. Glatter, Y. Xu, H.-S. Shin, R. Low, et al. Functional Roles of Cav1.3({alpha}1D) Calcium Channels in Atria: Insights Gained From Gene-Targeted Null Mutant Mice Circulation, September 27, 2005; 112(13): 1936 - 1944. [Abstract] [Full Text] [PDF]

				D. J. Milan and C. A. MacRae Animal models for arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 426 - 437. [Abstract] [Full Text] [PDF]

				A. Royer, S. Demolombe, A. El Harchi, K. Le Quang, J. Piron, G. Toumaniantz, D. Mazurais, C. Bellocq, G. Lande, C. Terrenoire, et al. Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity Cardiovasc Res, January 1, 2005; 65(1): 128 - 137. [Abstract] [Full Text] [PDF]

				A. Nygren, A. E. Lomax, and W. R. Giles Heterogeneity of action potential durations in isolated mouse left and right atria recorded using voltage-sensitive dye mapping Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2634 - H2643. [Abstract] [Full Text] [PDF]

				M. D. Richardson, J. D. Kilts, and M. M. Kwatra Increased Expression of Gi-Coupled Muscarinic Acetylcholine Receptor and Gi in Atrium of Elderly Diabetic Subjects Diabetes, September 1, 2004; 53(9): 2392 - 2396. [Abstract] [Full Text] [PDF]

				D. Dobrev, T. Christ, and U. Ravens Muscarinic subtype-2 receptor autoantibodies: actors or bystanders in human atrial fibrillation? Eur. Heart J., July 1, 2004; 25(13): 1091 - 1092. [Full Text] [PDF]

				A. Baba, T. Yoshikawa, Y. Fukuda, T. Sugiyama, M. Shimada, M. Akaishi, K. Tsuchimoto, S. Ogawa, and M. Fu Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy Eur. Heart J., July 1, 2004; 25(13): 1108 - 1115. [Abstract] [Full Text] [PDF]

				S. Verheule, T. Sato, T. Everett IV, S. K. Engle, D. Otten, M. Rubart-von der Lohe, H. O. Nakajima, H. Nakajima, L. J. Field, and J. E. Olgin Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-{beta}1 Circ. Res., June 11, 2004; 94(11): 1458 - 1465. [Abstract] [Full Text] [PDF]

				A. E. Lomax, C. S. Kondo, and W. R. Giles Comparison of time- and voltage-dependent K+ currents in myocytes from left and right atria of adult mice Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1837 - H1848. [Abstract] [Full Text] [PDF]

				F. Sarmast, A. Kolli, A. Zaitsev, K. Parisian, A. S Dhamoon, P. K Guha, M. Warren, J. M.B Anumonwo, S. M Taffet, O. Berenfeld, et al. Cholinergic atrial fibrillation: IK,ACh gradients determine unequal left/right atrial frequencies and rotor dynamics Cardiovasc Res, October 1, 2003; 59(4): 863 - 873. [Abstract] [Full Text] [PDF]

				V. V. Patel, M. Arad, I. P. G. Moskowitz, C. T. Maguire, D. Branco, J. G. Seidman, C. E. Seidman, and C. I. Berul Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiachypertrophy and Wolff-Parkinson-White syndrome J. Am. Coll. Cardiol., September 3, 2003; 42(5): 942 - 951. [Abstract] [Full Text] [PDF]

				P. Kirchhof, L. Fabritz, L. Fortmuller, G. P. Matherne, A. Lankford, H. A. Baba, W. Schmitz, G. Breithardt, J. Neumann, and P. Boknik Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H145 - H153. [Abstract] [Full Text] [PDF]

				C. I. Berul Electrophysiological phenotyping in genetically engineered mice Physiol Genomics, May 13, 2003; 13(3): 207 - 216. [Abstract] [Full Text] [PDF]

				Y.-M. Cha, P. P. Dzeja, W. K. Shen, A. Jahangir, C. Y. T. Hart, A. Terzic, and M. M. Redfield Failing atrial myocardium: energetic deficits accompany structural remodeling and electrical instability Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1313 - H1320. [Abstract] [Full Text] [PDF]

				I. Bettahi, C. L. Marker, M. I. Roman, and K. Wickman Contribution of the Kir3.1 Subunit to the Muscarinic-gated Atrial Potassium Channel IKACh J. Biol. Chem., December 6, 2002; 277(50): 48282 - 48288. [Abstract] [Full Text] [PDF]

				S. N. Hardouin, K. N. Richmond, A. Zimmerman, S. E. Hamilton, E. O. Feigl, and N. M. Nathanson Altered Cardiovascular Responses in Mice Lacking the M1 Muscarinic Acetylcholine Receptor J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 129 - 137. [Abstract] [Full Text] [PDF]

				J. Gehrmann, M. Meister, C. T. Maguire, D. C. Martins, P. E. Hammer, E. J. Neer, C. I. Berul, and U. Mende Impaired parasympathetic heart rate control in mice with a reduction of functional G protein beta gamma -subunits Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H445 - H456. [Abstract] [Full Text] [PDF]

				J. M. Nerbonne, C. G. Nichols, T. L. Schwarz, and D. Escande Genetic Manipulation of Cardiac K+ Channel Function in Mice: What Have We Learned, and Where Do We Go From Here? Circ. Res., November 23, 2001; 89(11): 944 - 956. [Abstract] [Full Text] [PDF]