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1 ; Pediatrics, NYU School of Medicine, New York, NY, USA
2 ; inGenious Targeting Labs. Inc, New York, NY, USA
3 ; GlaxoSmithKline, Harlow, United Kingdom
4 ; Cardiovascular Medicine, Kyoto University, Kyoto, Japan
5 ; Pediatrics, University of Iowa, Iowa City, IA, USA
6 ; Medicine, NYU School of Medicine, New York, NY, USA
7 ; Pediatrics, NYU School of Medicine, New York, NY, USA; Pharmacology and Physiology & Neurosciences, NYU School of Medicine, New York, NY, USA
* To whom correspondence should be addressed. E-mail: william.coetzee{at}med.nyu.edu.
Cardiac KATP channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice which 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 wild-type mice, but an increased mortality was noted after the age of 4-5 months. Transgenic mice lacked cardiac KATP 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 early afterdepolarizations following 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 pro-arrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggests that these features are intrinsic to the myocardium and that KATP channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations.
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