title: Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits.
abstract: Cardiac ATP-sensitive K+ (K(ATP)) channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice that express dominant negative Kir6.x pore-forming subunits (Kir6.1-AAA or Kir6.2-AAA) in cardiac myocytes by driving their expression with the alpha-myosin heavy chain promoter. Weight gain and development after birth of these mice were similar to nontransgenic mice, but an increased mortality was noted after the age of 4-5 mo. Transgenic mice lacked cardiac K(ATP) channel activity as assessed with patch clamp techniques. Consistent with a decreased current density observed at positive voltages, the action potential duration was increased in these mice. Some myocytes developed EADs after isoproterenol treatment. Hemodynamic measurements revealed no significant effects on ventricular function (apart from a slightly elevated heart rate), whereas in vivo electrophysiological recordings revealed a prolonged ventricular effective refractory period in transgenic mice. The transgenic mice tolerated stress less well as evident from treadmill stress tests. The proarrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggest that these features are intrinsic to the myocardium and that K(ATP) channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations.
authors.affiliation: Pediatric Cardiology, NYU School of Medicine, 560 First Ave., TCH-521, New York, NY 10016, USA.
authors.forename: XiaoYong
authors.initials: X
authors.lastname: Tong
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Porter
authors.forename: GongXin
authors.initials: G
authors.lastname: Liu
authors.forename: Piyali
authors.initials: P
authors.lastname: Dhar-Chowdhury
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.forename: David J
authors.initials: DJ
authors.lastname: Pountney
authors.forename: Hidetada
authors.initials: H
authors.lastname: Yoshida
authors.forename: Michael
authors.initials: M
authors.lastname: Artman
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.forename: Cindy
authors.initials: C
authors.lastname: Yu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Iyer
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Morley
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D004562:Electrocardiography; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology; D006439:Hemodynamics / Q000502:physiology; D054086:KATP Channels; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D010496:Pericardium / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012032:Refractory Period, Electrophysiological / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D012313:RNA; D018995:Myosin Heavy Chains