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https://www.readbyqxmd.com/read/28408648/azithromycin-causes-a-novel-proarrhythmic-syndrome
#1
Zhenjiang Yang, Joseph K Prinsen, Kevin R Bersell, Wangzhen Shen, Liudmila Yermalitskaya, Tatiana Sidorova, Paula B Luis, Lynn Hall, Wei Zhang, Liping Du, Ginger Milne, Patrick Tucker, Alfred L George, Courtney M Campbell, Robert A Pickett, Christian M Shaffer, Nagesh Chopra, Tao Yang, Bjorn C Knollmann, Dan M Roden, Katherine T Murray
BACKGROUND: The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells...
April 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28389584/control-of-kir-channel-gating-by-cytoplasmic-domain-interface-interactions
#2
William F Borschel, Shizhen Wang, Sunjoo Lee, Colin G Nichols
Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and play critical roles in the control of excitability. Pancreatic ATP-sensitive K (KATP) channels are key regulators of insulin secretion and comprise Kir6.2 subunits coupled to sulfonylurea receptors. Because these channels are reversibly inhibited by cytoplasmic ATP, they link cellular metabolism with membrane excitability. Loss-of-function mutations in the pore-forming Kir6.2 subunit cause congenital hyperinsulinism as a result of diminished channel activity...
April 7, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28383527/activation-of-the-hypoglossal-to-tongue-musculature-motor-pathway-by-remote-control
#3
Garret A Horton, Jimmy J Fraigne, Zoltan A Torontali, Matthew B Snow, Jennifer L Lapierre, Hattie Liu, Gaspard Montandon, John H Peever, Richard L Horner
Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a "designer" receptor into the HMN and selectively modulated it with a "designer" drug...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28365825/inhibition-of-inwardly-rectifying-kir2-x-channels-by-the-novel-anti-cancer-agent-gambogic-acid-depends-on-both-pore-block-and-pip2-interference
#4
Daniel Scherer, Benedikt Schworm, Claudia Seyler, Panagiotis Xynogalos, Eberhard P Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential...
April 2, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28345117/inwardly-rectifying-k-currents-in-cultured-oligodendrocytes-from-rat-optic-nerve-are-insensitive-to-ph
#5
Alberto Pérez-Samartín, Edith Garay, Juan Pablo H Moctezuma, Abraham Cisneros-Mejorado, María Victoria Sánchez-Gómez, Guadalupe Martel-Gallegos, Leticia Robles-Martínez, Manuel Canedo-Antelo, Carlos Matute, Rogelio O Arellano
Inwardly rectifying K(+) (Kir) channel expression signals at an advanced stage of maturation during oligodendroglial differentiation. Knocking down their expression halts the generation of myelin and produces severe abnormalities in the central nervous system. Kir4.1 is the main subunit involved in the tetrameric structure of Kir channels in glial cells; however, the precise composition of Kir channels expressed in oligodendrocytes (OLs) remains partially unknown, as participation of other subunits has been proposed...
March 27, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28331977/role-of-plasma-membrane-associated-akaps-for-the-regulation-of-cardiac-ik1-current-by-protein-kinase-a
#6
Claudia Seyler, Daniel Scherer, Christoph Köpple, Martin Kulzer, Sevil Korkmaz, Panagiotis Xynogalos, Dierk Thomas, Ziya Kaya, Eberhard Scholz, Johannes Backs, Christoph Karle, Hugo A Katus, Edgar Zitron
The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream β-adrenoreceptors...
March 22, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28319610/capillary-k-sensing-initiates-retrograde-hyperpolarization-to-increase-local-cerebral-blood-flow
#7
Thomas A Longden, Fabrice Dabertrand, Masayo Koide, Albert L Gonzales, Nathan R Tykocki, Joseph E Brayden, David Hill-Eubanks, Mark T Nelson
Blood flow into the brain is dynamically regulated to satisfy the changing metabolic requirements of neurons, but how this is accomplished has remained unclear. Here we demonstrate a central role for capillary endothelial cells in sensing neural activity and communicating it to upstream arterioles in the form of an electrical vasodilatory signal. We further demonstrate that this signal is initiated by extracellular K(+) -a byproduct of neural activity-which activates capillary endothelial cell inward-rectifier K(+) (KIR2...
March 20, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28301408/k-cl-cotransporter-2-mediated-cl-extrusion-determines-developmental-stage-dependent-impact-of-propofol-anesthesia-on-dendritic-spines
#8
Martin Puskarjov, Hubert Fiumelli, Adrian Briner, Timea Bodogan, Kornel Demeter, Claudia-Marvine Lacoh, Martina Mavrovic, Peter Blaesse, Kai Kaila, Laszlo Vutskits
BACKGROUND: General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2)...
May 2017: Anesthesiology
https://www.readbyqxmd.com/read/28289282/the-schizophrenia-and-autism-associated-gene-transcription-factor-4-regulates-the-columnar-distribution-of-layer-2-3-prefrontal-pyramidal-neurons-in-an-activity-dependent-manner
#9
S C Page, G R Hamersky, R A Gallo, M D Rannals, N E Calcaterra, M N Campbell, B Mayfield, A Briley, B N Phan, A E Jaffe, B J Maher
Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2...
March 14, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28284503/renal-denervation-regulates-the-atrial-arrhythmogenic-substrates-through-reverse-structural-remodeling-in-heart-failure-rabbit-model
#10
Shinya Yamada, Li-Wei Lo, Yu-Hui Chou, Wei-Lun Lin, Shih-Lin Chang, Yenn-Jiang Lin, Shih-Ann Chen
BACKGROUND: Heart failure (HF) causes atrial remodeling and increases the incidence of atrial fibrillation (AF). Renal denervation (RDN) has been shown to decrease the development of AF. This study aimed to identify the effects of RDN on the atrial arrhythmogenic substrates in HF. METHODS: Rabbits were classified into four groups: control (n=9), RDN (n=10), HF (n=6) and HF-RDN (n=9). Surgical and chemical RDN was approached through bilateral retroperitoneal flank incisions in RDN and HF-RDN...
May 15, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28255076/beneficial-effect-of-renal-denervation-on-ventricular-premature-complex-induced-cardiomyopathy
#11
Shinya Yamada, Li-Wei Lo, Yu-Hui Chou, Wei-Lun Lin, Shih-Lin Chang, Yenn-Jiang Lin, Shin-Huei Liu, Wen-Han Cheng, Tsung-Ying Tsai, Shih-Ann Chen
BACKGROUND: Frequent ventricular premature complexes (VPCs) can lead to the development of dilated cardiomyopathy and sudden cardiac death. Renal artery sympathetic denervation (RDN) may protect the heart from remodeling. This study aimed to investigate the effect of frequent VPCs on structural and electrical properties and whether RDN can protect the heart from remodeling. METHODS AND RESULTS: Eighteen rabbits were randomized to control (n=6), VPC (n=6), and VPC-RDN (n=6) groups...
March 2, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28235908/potencies-of-effector-genes-in-silencing-odor-guided-behavior-in-drosophila-melanogaster
#12
Tom Retzke, Michael Thoma, Bill S Hansson, Markus Knaden
The genetic toolbox in Drosophila offers a multitude of different effector constructs to silence neurons and neuron populations. In this study we investigated the potencies of several effector genes - when expressed in olfactory sensory neurons (OSNs) - to abolish odor-guided behavior in three different bioassays. We find that two of the tested effectors (tetanus toxin and Kir2.1) are capable of mimicking the Orco mutant phenotype in all of our behavioral paradigms. In both cases the effectiveness depended on effector expression levels as full suppression of odor-guided behavior was observed only in flies homozygous for both Gal4-driver and UAS-effector constructs...
February 24, 2017: Journal of Experimental Biology
https://www.readbyqxmd.com/read/28216048/chloroquine-blocks-the-kir4-1-channels-by-an-open-pore-blocking-mechanism
#13
Leticia G Marmolejo-Murillo, Iván A Aréchiga-Figueroa, Eloy G Moreno-Galindo, Ricardo A Navarro-Polanco, Aldo A Rodríguez-Menchaca, Meng Cui, José A Sánchez-Chapula, Tania Ferrer
Kir4.1 channels have been implicated in various physiological processes, mainly in the K(+) homeostasis of the central nervous system and in the control of glial function and neuronal excitability. Even though, pharmacological research of these channels is very limited. Chloroquine (CQ) is an amino quinolone derivative known to inhibit Kir2.1 and Kir6.2 channels with different action mechanism and binding site. Here, we employed patch-clamp methods, mutagenesis analysis, and molecular modeling to characterize the molecular pharmacology of Kir4...
April 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28188270/dual-mechanism-for-inhibition-of-inwardly-rectifying-kir2-x-channels-by-quinidine-involving-direct-pore-block-and-pip2-interference
#14
Christoph Koepple, Daniel Scherer, Claudia Seyler, Eberhard Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies IK1 current. While a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild type and mutant Kir2...
February 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28148533/inhibition-of-vascular-smooth-muscle-inward-rectifier-k-channels-restores-myogenic-tone-in-mouse-urinary-bladder-arterioles
#15
Nathan R Tykocki, Adrian D Bonev, Thomas Andrew Longden, Thomas J Heppner, Mark T Nelson
Prolonged decreases in urinary bladder blood flow are linked to overactive and underactive bladder pathologies. However, the mechanisms regulating bladder vascular reactivity are largely unknown. To investigate these mechanisms, we examined myogenic and vasoactive properties of mouse bladder feed arterioles (BFAs). Unlike similar-sized arterioles from other vascular beds, BFAs failed to constrict in response to increases in intraluminal pressure (5-80 mmHg). Consistent with this lack of myogenic tone, arteriolar smooth muscle cell membrane potential was hyperpolarized (-72...
February 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28131627/down-regulation-of-kir2-6-channel-by-c-termini-mutation-d252n-and-its-association-with-the-susceptibility-to-thyrotoxic-periodic-paralysis
#16
Rolf Matias Paninka, Estevão Carlos-Lima, Susan C Lindsey, Ilda S Kunii, Magnus R Dias-da-Silva, Manoel Arcisio-Miranda
Inward rectifying potassium - Kir - channels drive the resting potential to potassium reversal potential and, when disrupted, might be related to muscular diseases. Recently, Thyrotoxic Periodic Paralysis (TPP) has emerged as a channelopathy related to mutations in KCNJ18 gene, which encodes Kir2.6 channel. TPP is a neuromuscular disorder characterized by a triad of muscle weakness, hypokalemia, and thyrotoxicosis, the latter being essential for the crisis. Direct sequencing revealed two heterozygous mutations - D252N and R386C - in two TPP patients...
January 25, 2017: Neuroscience
https://www.readbyqxmd.com/read/28112313/soluble-epoxide-hydrolase-inhibitors-might-prevent-ischemic-arrhythmias-via-microrna-1-repression-in-primary-neonatal-mouse-ventricular-myocytes
#17
Qiong Liu, Xuan Zhao, Ran Peng, Mi Wang, Wang Zhao, Ya-Jun Gui, Cai-Xiu Liao, Dan-Yan Xu
Ischemic arrhythmias are the main causes of sudden cardiac death. It has been reported that soluble epoxide hydrolase inhibitors (sEHis) could prevent arrhythmias; however, the underlying molecular mechanisms remain unclear. In recent years, the proarrhythmic role of microRNA-1 (miR-1) has been investigated. This study aimed to elucidate whether sEHis prevented ischemic arrhythmias by suppressing miR-1. The primary neonatal mouse ventricular myocyte model of miR-1 overexpression was established by incubating with agonist microONTM mmu-miR-1a-3p agomir (DAEDstain(TM) Dye) (agomiR-1)...
January 23, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28007664/effects-of-seasonal-acclimatization-on-action-potentials-and-sarcolemmal-k-currents-in-roach-rutilus-rutilus-cardiac-myocytes
#18
Ahmed Badr, Minna Hassinen, Mohamed F El-Sayed, Matti Vornanen
Temperature sensitivity of electrical excitability is a potential limiting factor for high temperature tolerance of ectotherms. The present study examines whether heat resistance of electrical excitability of cardiac myocytes is modified by seasonal thermal acclimatization in roach (Rutilus rutilus), a eurythermal teleost species. To this end, temperature dependencies of ventricular action potentials (APs), and atrial and ventricular K(+) currents were measured from winter-acclimatized (WiR) and summer-acclimatized (SuR) roach...
March 2017: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
https://www.readbyqxmd.com/read/28004830/fluid-flow-facilitates-inward-rectifier-k-current-by-convectively-restoring-k-at-the-cell-membrane-surface
#19
Jae Gon Kim, Sang Woong Park, Doyoung Byun, Wahn Soo Choi, Dong Jun Sung, Kyung Chul Shin, Hyun-Ji Kim, Young-Eun Leem, Jong-Sun Kang, Hana Cho, Bokyung Kim, Sung I Cho, Young Min Bae
The inward rectifier Kir2.1 current (IKir2.1) was reported to be facilitated by fluid flow. However, the mechanism underlying this facilitation remains uncertain. We hypothesized that during K(+) influx or efflux, [K(+)] adjacent to the outer mouth of the Kir2.1 channel might decrease or increase, respectively, compared with the average [K(+)] of the bulk extracellular solution, and that fluid flow could restore the original [K(+)] and result in the apparent facilitation of IKir2.1. We recorded the IKir2.1 in RBL-2H3 cells and HEK293T cells that were ectopically over-expressed with Kir2...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27882143/expression-of-connexin-43-ion-channels-and-ca-2-handling-proteins-in-rat-pulmonary-vein-cardiomyocytes
#20
Yaqiong Xiao, Xue Cai, Andrew Atkinson, Sunil Jit Logantha, Mark Boyett, Halina Dobrzynski
Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is thought to be triggered by ectopic beats, originating primarily in the myocardial sleeves surrounding the pulmonary veins (PVs). The mechanisms underlying these cardiac arrhythmias remain unclear. To investigate this, frozen sections of heart and lung tissue from adult rats without arrhythmia were obtained in different planes, stained with Masson's trichrome, and immunolabeled for connexin 43 (Cx43), caveolin-3 (Cav3), hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), Nav1...
November 2016: Experimental and Therapeutic Medicine
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