Consequences of cardiac myocyte-specific ablation of K<sub>ATP</sub>channels in transgenic mice expressing dominant negative Kir6 subunits

Tong, Xiaoyong; Porter, Lisa M.; Liu, Gong-Xin; Dhar-Chowdhury, Piyali; Srivastava, S. K.; Pountney, David; Yoshida, Haruhiko; Artman, Michael; Fishman, Glenn I.; Yu, Cindy; Iyer, Ramesh S.; Morley, Gregory E.; Gutstein, David E.; Coetzee, William A.

doi:10.1152/ajpheart.00051.2006

Cited by 69 publications

(89 citation statements)

References 46 publications

(44 reference statements)

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“…It is possible that these opposing actions resulted in the neutral effect of thiazolidinedione treatment on ventricular fibrillation observed during low-flow ischaemia, but that predominance of the latter action accounts for the promotion of ventricular fibrillation by rosiglitazone (and HMR-1098) observed during complete coronary occlusion. Consistent with the current observations, mice with genetic ablation of cardiac K ATP channels demonstrate increased susceptibility to lethal ventricular arrhythmias [8,11], while pharmacological K ATP openers have been shown to extend time to ventricular fibrillation and decrease incidence of ventricular fibrillation during coronary occlusion in pigs and dogs [5,6]. However, we cannot exclude the possibility that unmeasured effects of thiazolidinediones on ion channels other than K ATP [38][39][40][41] also influenced the development of ischaemic arrhythmias in the present study.…”

Section: Discussionsupporting

confidence: 86%

“…Opening of cardiac K ATP channels in ischaemia also stabilises resting membrane potential and may therefore have anti-arrhythmic effects [4][5][6]. Conversely, pharmacological blockade or genetic ablation of K ATP channels may be harmful, promoting ischaemic and catecholamine-induced arrhythmias and abolishing ischaemic preconditioning [7][8][9][10][11]. However, findings are divided in this regard.…”

Section: Introductionmentioning

confidence: 99%

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Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Reiter

et al. 2008

Diabetologia

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Aims/hypothesis Opening of ATP-sensitive potassium (K ATP ) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K ATP channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K ATP channels in vivo. Methods Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K ATP channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K ATP blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. Results With vehicle, epicardial MAP shortened by 44±9 ms during ischaemia. This effect was attenuated to 12±8 ms with troglitazone and 6±6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K ATP blockade. Intracoronary levcromakalim shortened MAP by 38±10 ms, an effect attenuated to 12±8, 13±4 and 9±5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K ATP blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K ATP blockade promotes ischaemic ventricular fibrillation in this model. Conclusions/interpretation Thiazolidinedione drugs block cardiac K ATP channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Reiter

et al. 2008

Diabetologia

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“…In Langendorff-based ischemia experiments, hearts isolated from Kir6.2 null animals exhibited reduced cardiac function compared to control hearts [17]. In addition, cardiac overexpression of mutant Kir6.1 or Kir6.2 subunits resulted in increased mortality, decreased performance on treadmill stress tests, and isoproterenol induced arrhythmias in isolated myocytes [24]. Similar experiments now conducted in SUR2 null animals yielded entirely opposite results; in all experiments, SUR2 null animals better handled acute cardiac stress.…”

Section: Discussionmentioning

confidence: 68%

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Stoller

Kakkar

Smelley

et al. 2007

Journal of Molecular and Cellular Cardiology

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Adenosine triphosphate sensitive potassium (K ATP ) channels are thought to mediate stress response by sensing intracellular ATP concentration. Cardiomyocyte K ATP channels are composed of the poreforming Kir6.2 subunit and the regulatory sulfonylurea receptor 2 (SUR2). We studied the response to acute isoproterenol in SUR2 null mice as a model of acute adrenergic stress and found that the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated. Similar results were observed following administration of a nitric oxide donor consistent with a vasodilatory role. Langendorff-perfused hearts were subjected to global ischemia, and hearts from SUR2 null mice exhibited significantly reduced infarct size (54±4 vs 30±3%) and improved cardiac function compared to control mice. SUR2 null mice have hypertension and develop cardiac hypertrophy. However, despite longstanding hypertension, fibrosis was absent in SUR2 null mice. SUR2 null mice were administered nifedipine to block baseline coronary vasospasm, and hearts from nifedipinetreated SUR2 null mice exhibited increased infarct size compared to untreated SUR2 null mice (42 ±3 % vs 54±3%). We conclude that conventional sarcolemmal cardiomyocyte K ATP channels containing full length SUR2 are not required for mediating the response to acute cardiovascular stress.

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“…When activated by a reduced ATP/ ADP ratio, reflecting either increased cellular metabolic demand or reduced cellular ATP generation, K ATP channel-dependent potassium efflux shortens cardiac action potential duration, allowing for a longer diastolic interval that supports myocardial relaxation and restoration of ion gradients and energetic resources as well as limits sodium and calcium entry into the cell and thus reduces energy requirements for ion transport/exchange and contraction (1,9,10,(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

Sierra

Zhu

Sapay

et al. 2013

Journal of Biological Chemistry

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Background: Surface expression of cardiac ATP-sensitive potassium (K ATP ) channels impacts cellular energy homeostasis. Results: Activation of calcium/calmodulin-dependent protein kinase II (CaMKII) results in K ATP channel internalization, requiring specific motifs on the Kir6.2 channel subunit. Conclusion: CaMKII phosphorylation of Kir6.2 promotes endocytosis of cardiac K ATP channels. Significance: This mechanism reveals new targets to improve cardiac energy efficiency and stress resistance.

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

Abstract: Coetzee. Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits.

Cited by 69 publications

References 46 publications

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

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

Abstract: Coetzee. Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits.

Cited by 69 publications

References 46 publications

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

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