Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels

Kiehn, Johann; Thomas, Dierk; Karle, Christoph A.; Schöls, Wolfgang; Kübler, W.

doi:10.1007/pl00005344

Cited by 100 publications

(61 citation statements)

References 29 publications

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“…In terms of class III antiarrhythmic drugs, sotalol, E-4031 and dofetilide selectively inhibited I Kr (Sanguinetti & Jurkiewicz, 1990;Jurkiewicz & Sanguinetti, 1993). Amiodarone was also shown to inhibit I Kr in rabbit ventricular cells (Varro et al, 1996) and in Xenopus oocytes expressing the human ether-a-go-gorelated gene (HERG) (Kiehn et al, 1999). In the present study JTV-519 prolonged APD in the absence and presence of muscarinic stimulation.…”

Section: Discussionsupporting

confidence: 53%

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Nakaya

Furusawa

Ogura

et al. 2000

British J Pharmacology

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We investigated the effects of JTV‐519 (4‐[3‐(4‐benzylpiperidin‐1‐yl)propionyl]‐7‐methoxy‐2,3,4,5‐tetrahydro‐1,4‐benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K+ currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of JTV‐519 on experimental atrial fibrillation (AF) in isolated guinea‐pig hearts. In atrial cells stimulated at 0.2 Hz, JTV‐519 in concentrations of 0.3 and 1 μM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration‐dependent manner. The muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 μM), adenosine (10 μM) or by the intracellular loading of GTPγS (100 μM). JTV‐519 inhibited the carbachol‐, adenosine‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.12, 2.29 and 2.42 μM, respectively, suggesting that the drug may inhibit IK.ACh mainly by blocking the muscarinic receptors. JTV‐519 (1 μM) inhibited the delayed rectifier K+ current (IK). Electrophysiological analyses indicated that the drug preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component). In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV‐519 (1 μM) inhibited the induction of AF by prolonging MAP and ERP. We conclude that JTV‐519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K+ currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease. British Journal of Pharmacology (2000) 131, 1363–1372; doi:10.1038/sj.bjp.0703713

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Section: Discussionsupporting

confidence: 53%

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Nakaya

Furusawa

Ogura

et al. 2000

British J Pharmacology

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“…ISO, as we have previously reported, stimulates not only the cAMP-PKA pathway [14] , but also pPKCε (hyperphosphorylation of PKCε) [15] which participates in cardiac remodeling, oxidative stress and arrhythmogenesis [16] . Furthermore, expression of ERG, which is the α-subunit of KCNH2, is considered as an important target for antiarrhythmic activity [17] . The relation of change in ERG expression to β-adrenoceptor stimulation and the ET system is interesting, and however, has not been clarified yet [18] .…”

Section: Introductionmentioning

confidence: 99%

Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

2009

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Aim: Spatial dispersion of bioactive substances in the myocardium could serve as pathological basis for arrhythmogenesis and cardiac impairment by β-adrenoceptor stimulation. We hypothesized that dispersed NADPH oxidase, protein kinase Cε (PKCε), early response gene (ERG), and matrix metalloproteinase 9(MMP-9) across the heart by isoproterenol (ISO) medication might be mediated by the endothelin (ET) -ROS pathway. We aimed to verify if ISO induced spatially heterogeneous distribution of pPKCε, NAPDH oxidase, MMP-9 and ERG could be mitigated by either an ET receptor antagonist CPU0213 or iNOS inhibitor aminoguanidine. Methods: Rats were treated with ISO (1 mg/kg sc) for 10 days, and drug interventions (mg/kg) either CPU0213 (30 sc) or aminoguanidine (100 ip) were administered on days 8−10. Expression of NADPH oxidase, MMP-9, ERG, and PKCε in the left and right ventricle (LV, RV) and septum (S) were measured separately. Results: Ventricular hypertrophy was found in the LV, S, and RV, in association with dispersed QTc and oxidative stress in ISO-treated rats. mRNA and protein expression of MMP-9, PKCε, NADPH oxidase and ERG in the LV, S, and RV were obviously dispersed, with augmented expression mainly in the LV and S. Dispersed parameters were re-harmonized by either CPU0213, or aminoguanidine. Conclusion: We found at the first time that ISO-induced dispersed distribution of pPKCε, NADPH oxidase, MMP-9, and ERG in the LV, S, and RV of the heart, which were suppressed by either CPU0213 or aminoguanidine. It indicates that the ET-ROS pathway plays a role in the dispersed distribution of bioactive substances following sustained β-receptor stimulation.

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“…This has been demonstrated in macroscopic current measurements (3,4) and single channel measurements (5). HERG channels are one primary target for the pharmacological management of arrhythmias with class III antiarrhythmic drugs: I Kr is blocked and the cardiac action potential is prolonged (5)(6)(7). Mutations in HERG produce chromosome 7-linked congenital long QT syndrome (LQT2) (3).…”

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confidence: 99%

Deletion of Protein Kinase A Phosphorylation Sites in the HERG Potassium Channel Inhibits Activation Shift by Protein Kinase A

Thomas¹,

Zhang²,

Karle³

et al. 1999

Journal of Biological Chemistry

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115

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We investigated the role of protein kinase A (PKA) in regulation of the human ether-a-go-go-related gene (HERG) potassium channel activation. HERG clones with single mutations destroying one of four consensus PKA phosphorylation sites (S283A, S890A, T895A, S1137A), as well as one clone carrying all mutations with no PKA phosphorylation sites (HERG 4M) were constructed. These clones were expressed heterologously in Xenopus oocytes, and HERG potassium currents were measured with the two microelectrode voltage clamp technique. Application of the cAMP-specific phosphodiesterase (PDE IV) inhibitor Ro-20 -1724 (100 M), which results in an increased cAMP level and PKA stimulation, induced a reduction of HERG wild type outward currents by 19.1% due to a shift in the activation curve of 12.4 mV. When 100 M Ro-20 -1724 was applied to the HERG 4M channel, missing all PKA sites, there was no significant shift in the activation curve, and the current amplitude was not reduced. Furthermore, the adenylate cyclase activator forskolin that leads to PKA activation (400 M, 60 min), shifted HERG wild type channel activation by 14.1 mV and reduced currents by 39.9%, whereas HERG 4M channels showed only a small shift of 4.3 mV and a weaker current reduction of 22.3%. We conclude that PKA regulates HERG channel activation, and direct phosphorylation of the HERG channel protein has a functional role that may be important in regulation of cardiac repolarization.In cardiac myocytes, repolarization of the action potential is produced by different potassium currents (1). Activation of the rapid component of the delayed rectifier potassium current, I Kr , 1 initiates repolarization and terminates the plateau phase of the cardiac action potential. The human ether-a-go-go-related gene (HERG) (2) encodes the voltage-gated potassium channel underlying I Kr . This has been demonstrated in macroscopic current measurements (3, 4) and single channel measurements (5). HERG channels are one primary target for the pharmacological management of arrhythmias with class III antiarrhythmic drugs: I Kr is blocked and the cardiac action potential is prolonged (5-7). Mutations in HERG produce chromosome 7-linked congenital long QT syndrome (LQT2) (3). These mutations are associated with delayed cardiac repolarization, prolonged electrocardiographic QT intervals (8), and a high risk for the development of ventricular "torsade de pointes" arrhythmias and sudden cardiac death (9).Cyclic AMP-dependent protein kinase (PKA) is a key enzyme for numerous regulatory processes in almost all types of cells. It has been demonstrated that PKA regulates ion channels in native tissue (10). PKA is a serine/threonine kinase that can be stimulated by extracellular signals that elevate intracellular cAMP concentrations. cAMP binds to the regulatory subunit of the enzyme, which leads to dissociation of regulatory and catalytic subunits. The catalytic subunit phosphorylates the substrate at its specific phosphorylation sites. The substrate may either be the effector protein or an...

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Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels

Cited by 100 publications

References 29 publications

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

Isoproterenol disperses distribution of NADPH oxidase, MMP-9, and pPKCε in the heart, which are mitigated by endothelin receptor antagonist CPU0213

Deletion of Protein Kinase A Phosphorylation Sites in the HERG Potassium Channel Inhibits Activation Shift by Protein Kinase A

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