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Genetic knockout of KATP channels predisposes to catecholamine‐induced proarrhythmogenesis
Author(s) -
Liu X.,
Yamada S.,
O'Coclain F.,
Kane G.,
Hodgson D.,
Alexeev A.,
Jahangir A.,
Miki T.,
Seino S.,
Terzic A.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.181
Subject(s) - repolarization , afterdepolarization , medicine , cardiac action potential , herg , catecholamine , long qt syndrome , endocrinology , cardiac electrophysiology , electrophysiology , cardiology , sulfonylurea receptor , pharmacology , potassium channel , chemistry , qt interval , glibenclamide , diabetes mellitus
Cardiac K‐ATP channels have been recently been implicated to serve a homeostatic function under catecholamine stress. Since the use of drugs that modulate K‐ATP channels is common in clinical practice, the implications of channel function on cardiac electrophysiology warrant further investigation. Here, using simultaneous monophasic action potential and ECG recordings, we examined the arrhythmogenic consequences of genetic deletion of the pore‐forming K‐ATP channel subunit Kir6.2. Infusion of the sympathomimetic isoproterenol (1muM) readily induced early afterdepolarizations in Kir6.2 knockout (KO) but not in the wildtype (WT) hearts (incidence: 96.8% versus 1%, p<0.01). This translated into an order of 10 magnitude higher incidence of triggered activity and associated premature ventricular contraction in the KO hearts. Although there was no significant difference in perfusion flow between KO and WT hearts before or after isoproterenol infusion, the shortening of the action potential duration at 90% repolarization under sympathomimetic challenge observed in the WT (from 82 to 74 ms, p<0.01) was absent in the KO (79 to 80 ms, p>0.05). We conclude that cardiac K‐ATP channels are required to secure proper repolarization reserve and prevent afterdepolarization‐associated arrhythmia under sympathetic stress. Therefore, clinical conditions that are associated with reduced K‐ATP channel activity, such as use of sulfonylurea drugs, may predispose to arrhythmic events. Clinical Pharmacology & Therapeutics (2004) 75 , P48–P48; doi: 10.1016/j.clpt.2003.11.181