Voltage-Dependent Ca2+-Channel Block by Openers of Intermediate and Small Conductance Ca2+-Activated K+ Channels in Urinary Bladder Smooth Muscle Cells

Morimura, Kozo; Yamamura, Hisao; Ohya, Susumu; Imaizumi, Yuji

doi:10.1254/jphs.sc0060011

Cited by 35 publications

(28 citation statements)

References 13 publications

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“…NS309 is a positive modulator of both SK Ca and IK Ca channels with no effect on big-conductance Ca 21 -activated potassium channels (Si et al, 2006). In high concentrations, NS309 has been shown to inhibit the activity of the voltage-dependent calcium channels causing smooth muscle relaxation (Morimura et al, 2006). In the present study, NS309 was applied to confirm the effect of metformin on IK Ca -and SK Ca -mediated vasodilatation (Fig.…”

Section: Discussionsupporting

confidence: 52%

Metformin Restores Intermediate-Conductance Calcium-Activated K+ Channel– and Small-Conductance Calcium-Activated K+ Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

Zhao

Wang

Yang

et al. 2014

Molecular Pharmacology

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The present study was designed to investigate the effect of metformin on the impairment of intermediate-conductance and small-conductance Ca 21-activated potassium channels (IK Ca and SK Ca )-mediated relaxation in diabetes and the underlying mechanism. The endothelial vasodilatation function of mesenteric arteries was assessed with the use of wire myography. Expression levels of IK Ca and SK Ca and phosphorylated Thr 172 of AMPactivated protein kinase (AMPK) were measured using Western blot technology. The channel activity was observed using a whole-cell patch voltage clamp. Reactive oxygen species (ROS) were measured using dihydroethidium and 29,79-dichlorofluorescein diacetate. Metformin restored the impairment of IK Ca -and SK Camediated vasodilatation in mesenteric arteries from streptozotocininduced type 2 diabetic rats and that from normal rats incubated with advanced glycation end products (AGEs) for 3 hours. In cultured human umbilical vein endothelial cells (HUVECs), 1 mM metformin reversed AGE-induced increase of ROS and attenuated AGEand H 2 O 2 -induced downregulation of IK Ca and SK Ca after longterm incubation (.24 hours). Short-term treatment (3 hours) with 1 mM metformin reversed the decrease of IK Ca and SK Ca currents induced by AGE incubation for 3 hours without changing the channel expression or the AMPK activation in HUVECs. These results are the first to demonstrate that metformin restored IK Ca -and SK Ca -mediated vasodilatation impaired by AGEs in rat mesenteric artery, in which the upregulation of channel activity and protein expression is likely involved.

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Section: Discussionsupporting

confidence: 52%

Metformin Restores Intermediate-Conductance Calcium-Activated K+ Channel– and Small-Conductance Calcium-Activated K+ Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

Zhao

Wang

Yang

et al. 2014

Molecular Pharmacology

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“…Inhibiting COX and NOS or inhibiting COX and blocking SK Ca or BK Ca channels did not alter the relaxation to NS309 or salbutamol, whereas inhibiting COX and blocking IK Ca channels or inhibiting COX and NOS and blocking IK Ca channels completely abolished NS309 relaxation at concentrations below 10 M and reduced salbutamol relaxation. As previously reported, NS309 at low concentrations is a specific opener of SK Ca and IK Ca channels (11), but might at high concentrations (Ͼ10 M) operate through a different mechanism, e.g., blocking of L-type calcium channels (34). In bronchioles and pulmonary arteries without epithelium and endothelium, respectively, this could explain why relaxation to NS309 is not completely abolished.…”

Section: Discussionmentioning

confidence: 68%

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

Kroigaard

Dalsgaard

Simonsen

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Kroigaard C, Dalsgaard T, Simonsen U. Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHFtype relaxation in rat pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 298: L531-L542, 2010. First published January 29, 2010 doi:10.1152/ajplung.00220.2009.-This study investigated the mechanisms underlying epithelium-derived hyperpolarizing factor (EpDHF)-type relaxation in rat bronchioles. Immunohistochemistry was performed, and rat bronchioles and pulmonary arteries were mounted in microvascular myographs for functional studies. An opener of small (SKCa) and intermediate (IKCa)-conductance calcium-activated potassium channels, NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) was used to induce EpDHF-type relaxation. IK Ca and SKCa3 positive immunoreactions were observed mainly in the epithelium and endothelium of bronchioles and arteries, respectively. In 5-hydroxytryptamine (1 M)-contracted bronchioles (828 Ϯ 20 m, n ϭ 84) and U46619 (0.03 M)-contracted arteries (720 Ϯ 24 m, n ϭ 68), NS309 (0.001-10 M) induced concentration-dependent relaxations that were reduced by epithelium/endothelium removal and by blocking IK Ca channels with charybdotoxin and in bronchioles also by blocking SK Ca channels with apamin. Inhibition of cyclooxygenase, nitric oxide synthase, and cytochrome 2C isoenzymes, or blockade of large (BK Ca)-conductance calciumactivated potassium channels with iberiotoxin, failed to reduce NS309 relaxation. In contrast to the pulmonary arteries, relaxations to a ␤ 2-adrenoceptor agonist, salbutamol, were reduced in bronchioles by removing the epithelium or blocking IK Ca and/or SK Ca channels. Extracellular K ϩ (2-20 mM) induced relaxation in both bronchioles and arteries. An inhibitor of Na ϩ -K ϩ -ATPase, ouabain, abolished relaxations to NS309, salbutamol, and K ϩ . These results suggest that IK Ca and SKCa3 channels are located in the epithelium of bronchioles and endothelium of pulmonary arteries. Analog to the endotheliumderived hyperpolarizing factor (EDHF)-type relaxation in pulmonary arteries, these channels may be involved in EpDHF-type relaxation of bronchioles caused by epithelial K ϩ efflux followed by activation of Na ϩ -K ϩ -ATPase in the underlying smooth muscle layer.NS309; salbutamol; potassium; endothelium; GEA 3175 THE RESPIRATORY EPITHELIUM releases factors that regulate bronchial smooth muscle relaxations (20), and removal of the bronchial epithelium in larger airways has been shown to enhance the effect of contractile agonists and reduce the relaxing response in bronchioles (50, 51). Nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) are mediators of human bronchiole smooth muscle epithelium-dependent relaxations (22). In addition, a non-NO nonprostanoid epithelium-dependent hyperpolarizing factor (EpDHF) is also involved in epitheliumdependent relaxations. Epoxyeicosatrienoic acids (EETs) have been suggested to account for EpDHF-mediated relaxation in guinea pig airways (3). In comparison, opening of intermediate (IK Ca ) and endothelial subt...

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“…, which is expressed in the peripheral nervous system (33). Therefore, as a novel AED based on K Ca 2-channel activation, it might be important to identify subtype-specific K Ca 2-channel openers to suppress epileptic activities with marginal effects on other channels.…”

Section: +mentioning

confidence: 99%

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

et al. 2008

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Abstract. K + channels are key modulators of neuronal excitability, and mutations in certain types of these channels are known to cause epileptic seizures. Activation of K + channels is reported to suppress epileptic discharge; however, the types of K + -channel openers that are most effective as anti-epileptic agents are not well understood. We established a quantitative fluorescence assay using the Na + indicator sodium-binding benzofuran isophthalate (SBFI) for evaluation of various compounds on epileptiform activities induced by 4-aminopyridine (4-AP) in cultured rat hippocampal neurons. Among the K + -channel openers, the K V 7.2 / K V 7.3-channel openers retigabine and flupirtine and K Ca 2-channel openers NS309, DCEBIO, and 1-EBIO showed potent anti-epileptic effects similar to conventional antiepileptic drugs (AEDs). In contrast, the K Ca 1.1-channel openers NS1619, isopimaric acid, and chlorzoxazone demonstrated moderate inhibition. The K ir 6-channel openers minoxidil, cromakalim, and pinacidil did not show anti-epileptic effects. We concluded that K V 7.2 / K V 7.3, K Ca 2, and, to some extent, K Ca 1.1-channel openers, but not K ir 6-channel openers, suppress 4-AP-induced epileptiform activities in hippocampal neurons. These results suggest that the K + -channel openers for this category of K + channels might have therapeutic potential as new classes of antiepileptic drugs.

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Voltage-Dependent Ca2+-Channel Block by Openers of Intermediate and Small Conductance Ca2+-Activated K+ Channels in Urinary Bladder Smooth Muscle Cells

Cited by 35 publications

References 13 publications

Metformin Restores Intermediate-Conductance Calcium-Activated K+ Channel– and Small-Conductance Calcium-Activated K+ Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

Metformin Restores Intermediate-Conductance Calcium-Activated K+ Channel– and Small-Conductance Calcium-Activated K+ Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

K+-Channel Openers Suppress Epileptiform Activities Induced by 4-Aminopyridine in Cultured Rat Hippocampal Neurons

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