Celecoxib Blocks Cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) Channels. Effects on Cardiac Action Potentials

Macías, Álvaro; Moreno, Cristina; Moral-Sanz, Javier; Cogolludo, Ángel; David, Miren; Alemanni, Matteo; Pérez‐Vizcaíno, Francisco; Zaza, Antonio; Valenzuela, Carmen; González, Teresa

doi:10.1016/j.bpj.2010.12.2536

Cited by 9 publications

(12 citation statements)

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“…It is devoid of adverse effects of routinely used analgesic drugs but is equally efficacious in reducing pain sensation (Harish et al, 2012). Moreover, the selective cyclooxygenase inhibitor, celecoxib, was found to enhance K v 7.2-7.4, K v 7.2/7.3, and K v 7.3/7.5 currents, but it inhibits K v 7.1 and K v 7.1/KCNE1 currents (Macías et al, 2010). Retigabine, another opener of K V 7 channels, is used for treatment of refractory partial-onset seizures (Harris and Murphy, 2011) but differs from flupirtine because retigabine at high concentrations (approximately 10-100 mM) also block other voltage-gated K channels (Rundfeldt, 1997;Brown and Passmore, 2009).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Hedegaard

Johnsen

Povlsen

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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The voltage-gated K V 7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of K V 7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of K V 7.1, K V 7.4, and K V 7.5 in the left anterior descending rat coronary artery and all K V 7 subtypes (K V 7.1-K V 7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of K V 7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 mM) and linopirdine (10 mM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of K V 7 channels, flupirtine (10 mM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 mM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. K V 7 channels are expressed in rat coronary arteries and myocardium. Inhibition of K V 7 channels exerts cardioprotection and opening of K V 7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for K V 7 blockers in the treatment of ischemiareperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Hedegaard

Johnsen

Povlsen

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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“…Currents were recorded from transiently transfected COS7 cells using the perforated amphotericin B-patch-clamp technique with an Axopatch 200B amplifier (Axon Instruments) as described [19,20].…”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence

Moreno

Oliveras

Bartolucci

et al. 2017

Journal of Molecular and Cellular Cardiology

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Words: 5891Moreno et al., D242N mutation in KV7.1 causes long QT syndrome 1 Abstract KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of more than 500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7.1 channel, disrupting the conserved charge balance of this region. Perforated patch-clamp experiments show that, unexpectedly, the mutation did not disrupt the voltage-dependent activation but it removed the inactivation and slowed the activation kinetics of D242N KV7.1 channels. Biotinylation of cell-surface protein and co-immunoprecipitation experiments revealed that neither plasma membrane targeting nor co-assembly between KV7.1 and KCNE1 was altered by the mutation. However, the association of D242N KV7.1 with KCNE1 strongly shifted the voltage dependence of activation to more depolarized potentials (+50mV), hindering IKs current at physiologically relevant membrane potentials. Both functional and computational analysis suggest that the clinical phenotype of the LQTS patients carrying the D242N mutation is due to impaired action potential adaptation to exercise and, in particular, to increase in heart rate. Moreover, our data identify D242 aminoacidic position as a potential residue involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel.

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“…They include several voltage‐activated ion channels, which are modulated by celecoxib. For example, Na + currents (Park et al , ; Frolov et al , ), L‐type calcium channels (Zhang et al , ; Brueggemann et al , ), Kv2.1 (Frolov et al , ), Kv1.5, Kv4.3 and Kv7.1 (Macias et al , ) and human eag‐related gene potassium channels (Frolov et al , ) are all inhibited by celecoxib. In contrast, celecoxib increases Kv7.2‐5 currents (Brueggemann et al , ; Du et al , ).…”

Section: Discussionmentioning

confidence: 99%

COX‐2‐selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels

Spyra

Meisner

Schaefer

et al. 2017

British J Pharmacology

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Celecoxib Blocks Cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) Channels. Effects on Cardiac Action Potentials

Cited by 9 publications

References 0 publications

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence

COX‐2‐selective inhibitors celecoxib and deracoxib modulate transient receptor potential vanilloid 3 channels

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