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Consequences of cardiac myocyte-specific ablation of K_ATP channels in transgenic mice expressing dominant negative Kir6 subunits

¹Pediatric Cardiology, ⁶Department of Medicine, and ⁷Pharmacology and Physiology and Neurosciences, New York University School of Medicine, New York, New York; ²inGenious Targeting Laboratories, Stony Brook, New York; ³GlaxoSmithKline, Harlow, United Kingdom; ⁴Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan; and ⁵Department of Pediatrics, University of Iowa, Iowa City, Iowa

Submitted 10 January 2006 ; accepted in final form 20 February 2006

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 -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.

potassium channels; ATP-sensitive K⁺ channel; heart; ventricle; stress responses

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