Activation of Glibenclamide-Sensitive ATP-Sensitive K
            <sup>+</sup>
            Channels During β-Adrenergically Induced Metabolic Stress Produces a Substrate for Atrial Tachyarrhythmia

Kim, Shang Jin; Zhang, Haifei; Khaliulin, Igor; Choisy, Stéphanie C.M.; Bond, Richard; Lin, Hua; Haou, Said El; Milnes, James T.; Hancox, Jules C.; Suleiman, M‐Saadeh; James, Andrew F.

doi:10.1161/circep.112.975425

Cited by 14 publications

(13 citation statements)

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“…The inwardly rectifying current was effectively abolished on removal of external K + , consistent with the contributions of inwardly rectifying K + channels (K ir ) to I K1 (Hibino et al., 2010; Yan et al., 2005). Note that while the strong inward rectification of I K1 recorded from LA and PV cardiomyocytes is consistent with a major contribution of K ir 2.x in either cell type, in principle, constitutively active G‐protein‐gated K ir 3.x channels and ATP‐sensitive K ir 6.x/SURx (K ATP ) channels may also have contributed to the K + e ‐sensitive inwardly rectifying currents in the present study (Ehrlich et al., 2004; Hibino et al., 2010; Kim et al., 2012). In addition, a component of I Kss , evident at positive potentials using the ramp protocol, was also inhibited by removal of external K + .…”

Section: Resultssupporting

confidence: 89%

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

et al. 2020

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The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole-cell patch-clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell-types in zero-current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L-type Ca 2+ current (I CaL ) was ~×1.5 smaller (p = .0029, Student's t test) and the steady-state K + current (I Kss ) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward-rectifier current (I K1 ) was slightly smaller than LA cardiomyocyte I K1 . In LA cardiomyocytes, NA significantly prolonged APD 30 . In PV cells, APD 30 responses to 1 μM NA were heterogeneous: while the mean percentage change in APD 30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one-sample t test), three cells showed shortening (-18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on I K1 in either cell-type but inhibited PV I Kss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased I CaL in most PV cardiomyocytes (median × 2.2-increase, p < .0001, n/N = 32/14, Wilcoxonsigned-rank test), although in 7/32 PV cells I CaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA. K E Y W O R D Saction potential, delayed afterdepolarization, early afterdepolarization, inward-rectifier K + current (I K1 ), L-type Ca 2+ current (I CaL ), noradrenaline, pulmonary vein sleeves, steady-state K + current (I Kss ), triggered activity

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Section: Resultssupporting

confidence: 89%

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

et al. 2020

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“…Most studies of cardiac arrhythmias resulting from myocardial ischaemia have been focused predominantly on the abnormalities of ventricular rhythm and relatively little is known about the role of K ATP channels in abnormal atrial rhythm. A recent study has shown that activation of K ATP channels by β‐adrenoceptor‐induced metabolic stress provides a substrate for atrial tachyarrhythmias in mouse isolated heart (Kim et al ., ). In support, pinacidil shortens atrial AP duration and increases arrhythmia inducibility in human right atrial and right ventricular wall (Fedorov et al ., ).…”

Section: Pathophysiological Function Of Katp Channels In the Cardiovamentioning

confidence: 97%

The role of ATP‐sensitive potassium channels in cellular function and protection in the cardiovascular system

Tinker

Aziz

Thomas

2013

British J Pharmacology

102

100

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ATP-sensitive potassium channels (KATP) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated KATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system. AbbreviationsABC, ATP binding cassette; AP, action potential; KATP, ATP-sensitive potassium channel; KCO, ATP-sensitive potassium channel opening drug; PIP2, phosphatidyl 4,5-bisphosphate; SUR, sulphonylurea receptor; VSM, vascular smooth muscle IntroductionTwo independent laboratories can lay claim to having first described the ATP-sensitive potassium channels (KATP; channel nomenclature follows Alexander et al., 2013). Noma (1983) observed the appearance of an outward K + current in heart muscle cells when treated with metabolic poisons or hypoxia. This was reversed by ATP injected into the cell. Similar observations were made by another group (Trube and Hescheler, 1984). Such channels were subsequently described in pancreatic beta cells (Ashcroft et al., 1984), skeletal muscle (Spruce et al., 1985), smooth muscle (Standen et al., 1989) and neurones (Ashford et al., 1988). During this period, the basic electrophysiological and pharmacological properties of the channel were elucidated (Ashcroft, 1988;Noma and Takano, 1991). In inside-out patches in ∼140 mM symmetrical K + concentrations, the single-channel conductance is ohmic with a conductance of 70-80 pS. The lower values sometimes noted in the literature generally have lower and asymmetric K + concentrations. The channel is highly selective for potassium (PNa/PK∼0.01). Activity is inhibited by the application of ATP with a Ki of 10-500 μM with a Hill coefficient of more than 1 (generally around 2) depending on the tissue and recording configuration. The ATP inhibition is not dependent on ATP hydrolysis: it is not reliant on Mg 2+ and ATP can be substituted by non-hydrolysable derivatives. In the absence of magnesium other adenine nucleotides can inhibit channel activity but they are less potent. However, in the presence of Mg 2+ and ATP, ADP is stimulatory. Even at the beginning of the 1990s the channels were known to have a rich pharmacology (see Edwards and Weston, 1993). Sulphonylureas were discovered accidentally when it was noted that the anti-microbial sulphonamides caused hypoglycaemia in animals. It became apparent that stimulation of insulin release from pancreatic beta cells occurred because of inhibition of KATP channels. There is a family of these drugs: the most widely known are the firstgeneration agents (e.g. tolbutamide, chlorpropamide) and the more potent second-generation agents (e.g. glibenclamide, gliclazide, glipizide). Th...

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“…Studies have also investigated arrhythmia inducibility in atrial preparations. In a rat model β-adrenergic induced metabolic stress caused reduced intracellular ATP concentration and led to inducible atrial tachyarrhythmia that was reversed with glibenclamide (279). In a murine model with salt-induced hypertension, atrial K ATP channel upregulation was seen coinciding with a shortened effective refractory period and increased atrial arrhythmia inducibility (300).…”

Section: Cardiac Arrhythmiamentioning

confidence: 99%

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Tinker

Aziz

et al. 2018

Comprehensive Physiology

111

112

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ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.

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Activation of Glibenclamide-Sensitive ATP-Sensitive K ⁺ Channels During β-Adrenergically Induced Metabolic Stress Produces a Substrate for Atrial Tachyarrhythmia

Abstract: channels activate in response to β-adrenergic metabolic stress in Langendorffperfused rat hearts, resulting in a proarrhythmic substrate. (Circ Arrhythm Electrophysiol. 2012;5:1184-1192.)

Cited by 14 publications

References 50 publications

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

The role of ATP‐sensitive potassium channels in cellular function and protection in the cardiovascular system

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

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Activation of Glibenclamide-Sensitive ATP-Sensitive K + Channels During β-Adrenergically Induced Metabolic Stress Produces a Substrate for Atrial Tachyarrhythmia

Abstract: channels activate in response to β-adrenergic metabolic stress in Langendorffperfused rat hearts, resulting in a proarrhythmic substrate. (Circ Arrhythm Electrophysiol. 2012;5:1184-1192.)

Cited by 14 publications

References 50 publications

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

Ion currents, action potentials, and noradrenergic responses in rat pulmonary vein and left atrial cardiomyocytes

The role of ATP‐sensitive potassium channels in cellular function and protection in the cardiovascular system

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

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Product

Resources

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Activation of Glibenclamide-Sensitive ATP-Sensitive K ⁺ Channels During β-Adrenergically Induced Metabolic Stress Produces a Substrate for Atrial Tachyarrhythmia