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22 results on '"N. Doisne"'

1. P3483Diet governs metabolic and electrical properties of the atrial myocardium in mice

Author

N Suffee-Mosbah, W. Le Goff, V Galand, N Mougeneot, Marie Lhomme, Jérôme Piquereau, M Meriskay, N Doisne, Stéphane N. Hatem, F Ichou, E Baptista, and C Pichard

Subjects
medicine.medical_specialty, business.industry, Internal medicine, medicine, Cardiology, Atrial myocardium, Cardiology and Cardiovascular Medicine, business
Abstract

Background Obesity is associated with an increased risk of atrial fibrillation. This epidemiologic observation may not only be due to shared co-morbidities but also from direct impacts of metabolic disorders on myocardium Here, we examined the impact of high fat diet (HFD) induced obesity on atrial properties in mice. Methods Eight weeks old C57Bl/6J mice were subjected to 2 or 4 months of HFD (60% fat) or normal diet (ND, 4% fat). Rapid burst atrial pacing were delivered using a trans-esophageal probe to induced AF in anesthetized animals. Action potential (AP) were recorded in left atrial trabeculae using glass microelectrode technique. Potassium currents were recorded in isolated atrial myocytes using the whole cell or perforated patch clamp configurations. Metabolomic and lipidomic analysis were performed on whole left atria. Mitochondrial respiration was studied in situ in saponin-permeabilized atrial muscle fibres using a Clarke electrode and oxygen consumption was measured after successive addition of ADP (2 mM), malate (4 mM), palmitoyl-CoA and carnitine (pCoA-Ca) (100 μM and 2 mM), pyruvate (1 mM), glutamate (10 mM), succinate (15 mM), amytal (1 mM) and tetramethyl-paraphenylenediamine (TMPD)/ascorbate (0.5/0.5 mM). Results HFD mice showed a higher atrial vulnerability to AF as indicated by longer AF episodes compared to ND mice. APs were shorter in HFD versus ND mice (AP duration measured at 90% of repolarization: 47.9±2.4 msec in HFD vs 58.2±1.4 msec in ND, P Conclusions High fat diet induces a shift from carbon hydrate to a beta oxidation of the atrial myocardium metabolism together with an enhanced use of fatty acids by mitochondria. These metabolic changes could result in an enhanced activity of K-ATP channels and AP shortening that might contribute to AF vulnerability in this clinical setting. Acknowledgement/Funding ANR-10-IAHU-05

Published
2019
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3. A new SCN5A mutation responsible for Multifocal Ectopic Purkinje-Related Premature Contractions

Author

Xavier Waintraub, Estelle Gandjbakhch, Nathalie Neyroud, F. Hidden-Lucet, Victor Waldmann, N Doisne, L Fosse, Véronique Fressart, and Alban Redheuil

Subjects
medicine.medical_specialty, business.industry, Sodium channel, Mutant, HEK 293 cells, Dilated cardiomyopathy, Transfection, medicine.disease, Exon, Endocrinology, Internal medicine, medicine, Missense mutation, Patch clamp, Cardiology and Cardiovascular Medicine, business
Abstract

Introduction Recently, SCN5A mutations have been associated with Multifocal Ectopic Purkinje-Related Premature Contractions (MEPPC), a cardiac syndrome associating polymorphic ventricular arrhythmia with dilated cardiomyopathy. Methods and Results A new SCN5A mutation was identified in a young woman presenting with polymorphic PVCs and dilated cardiomyopathy since the age of 12. Radiofrequency catheter ablation showed at least three exit sites of purkinje-PVCs. A treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs. A new heterozygous missense mutation was identified in exon 5 of SCN5A (c.611C > A, pAla204Glu) in the DI-S3 domain. We investigated the functional consequences of NaV1.5-A204E expressed in HEK cells by recording the sodium current using the whole-cell configuration of the patch clamp technique. The NaV1.5-A204E mutant channels exhibited a significant leftward shift of the activation curve of 8 mV (V0.5 of activation = −42.9 ± 1.3 mV in A204E transfected cells (n = 24) compared to −34.8 ± 1.9 mV in cells transfected with the wild-type (WT) channel (n = 20), P Conclusion The functional consequences of this new SCN5A mutation associated with MEPPC revealed a pattern of abnormal voltage dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of the syndrome. These features of the mutant sodium channel are likely to be responsible for hyperexcitability of the fascicular-Purkinje system.

Published
2019
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4. NMDA receptor crosstalk with PDGFR-β and BMPR2 is involved in smooth muscle cell proliferation in pulmonary arterial hypertension

Author

Marceau Quatredeniers, Sylvia Cohen-Kaminsky, Audrey Courboulin, Sébastien J. Dumas, Marc Humbert, and N Doisne

Subjects
biology, Cell growth, business.industry, Stimulation, BMPR2, Muscle hypertrophy, biology.protein, Cancer research, Phosphorylation, Medicine, Signal transduction, business, Platelet-derived growth factor receptor, Proto-oncogene tyrosine-protein kinase Src
Abstract

Pulmonary Arterial Hypertension (PAH) is due to remodeling and obstruction of small pulmonary vessels, leading to right heart hypertrophy and death. Remodeling involves smooth muscle cells (SMCs) overproliferation. We have previously shown that NMDA receptor (NMDAR) is expressed by pulmonary SMCs and contributes to their proliferation in PAH. In neurons, Src has been described as a hub for signaling pathways enhancing NMDAR activity. Besides in PAH, Src is known to dysregulate vascular processes, especially vascular cell proliferation. Src has been identified as a binding partner of the C-terminus of BMPR2 (Wong, W.K. et al. AJRCMB. 2005), a protein encoded by the BMPR2 gene which is the main genetic factor of susceptibility in PAH. In addition, Src activity is enhanced by PDGFR-β signaling which is increased in PAH (Perros, F. et al. AJRCCM. 2008). We hypothesized that both BMPR2 impaired signaling and PDGFR-βoveractivation lead to increased Src activationin PAH, thus enhancing the NMDAR activity and leading to SMCs proliferation. Phosphorylation levels were assessed by western blot in explanted lungs of PAH patients and in pulmonary arterial SMCs. Interaction between different partners was studied by immunoprecipitation and immunostainings. We demonstrate that PAH patients show increased Src and NMDAR subunits (GluN2) phosphorylation. BMP2 stimulation decreases Src and GluN2B activation, whereas PDGF stimulation enhances Src, GluN2A and GluN2B phosphorylations in a time-dependent manner, possibly promoting NMDAR subunits trafficking. Thus vascular remodeling in PAH could involve BMPR2-PDGFR-β-NMDAR crosstalk through Src mobilization.

Published
2016
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5. Poster session 3

Author

O. Nanka, E. Krejci, Z. Pesevski, D. Sedmera, N. Smart, A. Rossdeutsch, K. N. Dube, J. Riegler, A. N. Price, A. Taylor, V. Muthurangu, M. Turner, M. F. Lythgoe, P. R. Riley, S. Kryvorot, T. Vladimirskaya, I. Shved, M. Schwarzl, S. Seiler, S. Huber, P. Steendijk, H. Maechler, M. Truschnig-Wilders, B. Pieske, H. Post, C. Caprio, A. Baldini, E. Chiavacci, L. Dolfi, L. Verduci, F. Meghini, F. Cremisi, L. Pitto, T.-C. Kuan, M.-C. Chen, T.-H. Yang, W.-T. Wu, C. S. Lin, H. Rai, S. Kumar, A. K. Sharma, S. Mastana, A. Kapoor, C. M. Pandey, S. Agrawal, N. Sinha, E. H. Orlowska-Baranowska, G. Placha, J. Gora, R. Baranowski, E. Abramczuk, T. Hryniewiecki, Z. Gaciong, J. J. W. Verschuren, J. A. M. Wessels, S. Trompet, D. J. Stott, N. Sattar, B. Buckley, H. J. Guchelaar, J. W. Jukema, M. Gharanei, A. Hussain, C. J. Mee, H. L. Maddock, W. J. Wijnen, S. Van Den Oever, I. Van Der Made, M. Hiller, A. J. Tijsen, Y. M. Pinto, E. E. Creemers, S. U. Y. Nikulina, A. Chernova, A. Petry, T. Rzymski, D. Kracun, F. Riess, L. Pike, A. L. Harris, A. Gorlach, R. Katare, A. Oikawa, F. Riu, A. P. Beltrami, D. Cesseli, C. Emanueli, P. Madeddu, T. Zaglia, G. Milan, M. Franzoso, P. Pesce, C. Sarais, M. Sandri, M. Mongillo, T. J. Butler, A.-M. L. Seymour, D. Ashford, F. Jaffre, M. Bussen, I. Flohrschutz, G. R. Martin, S. Engelhardt, G. Kararigas, B. T. Nguyen, H. Jarry, V. Regitz-Zagrosek, M. Van Bilsen, A. Daniels, C. Munts, B. J. A. Janssen, G. J. Van Der Vusse, F. A. Van Nieuwenhoven, C. Montalvo, A. V. Villar, D. Merino, R. Garcia, M. Llano, M. Ares, M. A. Hurle, J. F. Nistal, A. Dembinska-Kiec, B. K. W. Beata Kiec-Wilk, A. P. Anna Polus, U. C. Urszula Czech, T. K. Tatiana Konovaleva, G. S. Gerd Schmitz, L. Bertrand, M. Balteau, A. Timmermans, B. Viollet, K. Sakamoto, O. Feron, S. Horman, J. L. Vanoverschelde, C. Beauloye, C. De Meester, E. Martinez, R. Martin, M. Miana, R. Jurado, N. Gomez-Hurtado, M. V. Bartolome, J. A. San Roman, V. Lahera, M. L. Nieto, V. Cachofeiro, F. Rochais, R. Sturny, K. Mesbah, L. Miquerol, R. G. Kelly, S. Messaoudi, B. Gravez, A. Tarjus, V. Pelloux, J. L. Samuel, C. Delcayre, J. M. Launay, K. Clement, N. Farman, F. Jaisser, L. Hadyanto, C. Castellani, G. Vescovo, B. Ravara, R. Tavano, M. Pozzobon, P. De Coppi, E. Papini, R. Vettor, G. Thiene, A. Angelini, M. Meloni, A. Caporali, D. Cesselli, O. Fortunato, E. Avolio, R. Schindler, S. Simrick, T. Brand, N. S. Smart, A. Herman, S. Roura Ferrer, J. Rodriguez Bago, C. Soler-Botija, J. M. Pujal, C. Galvez-Monton, C. Prat-Vidal, A. Llucia-Valldeperas, J. Blanco, A. Bayes-Genis, G. Foldes, M. Maxime, N. N. Ali, M. D. Schneider, S. E. Harding, C. Reni, G. Mangialardi, A. De Pauw, B. Sekkali, A. Friart, H. Ding, A. Graffeuil, D. Catalucci, J. L. Balligand, F. Azibani, F. Tournoux, S. Schlossarek, E. Polidano, L. Fazal, R. Merval, L. Carrier, C. Chatziantoniou, B. Buyandelger, W. Linke, P. Zou, S. Kostin, C. Ku, L. Felkin, E. Birks, P. Barton, M. Sattler, R. Knoell, K. Schroder, S. Benkhoff, H. Shimokawa, O. Grisk, R. P. Brandes, I. R. Parepa, L. Mazilu, A. I. Suceveanu, A. Suceveanu, L. Rusali, L. Cojocaru, L. Matei, M. Toringhibel, E. Craiu, A. L. Pires, M. Pinho, S. Pinho, C. Sena, R. Seica, A. Leite-Moreira, F. Dabroi, S. Schiaffino, E. Kiseleva, N. Krukov, O. Nikitin, L. Ardatova, I. Mourouzis, C. Pantos, A. D. Kokkinos, D. V. Cokkinos, E. Scoditti, M. Massaro, M. A. Carluccio, M. Pellegrino, N. Calabriso, A. Gastaldelli, C. Storelli, R. De Caterina, D. Lindner, C. Zietsch, H.-P. Schultheiss, C. Tschope, D. Westermann, B. R. Everaert, V. J. Nijenhuis, F. C. M. Reith, V. Y. Hoymans, J. P. Timmermans, C. J. Vrints, I. Simova, H. Mateev, T. Katova, L. Haralanov, N. Dimitrov, N. Mironov, S. P. Golitsyn, S. F. Sokolov, Y. U. A. Yuricheva, E. B. Maikov, N. B. Shlevkov, L. V. Rosenstraukh, E. I. Chazov, J. Radosinska, V. Knezl, T. Benova, J. Slezak, L. Urban, N. Tribulova, L. Virag, A. Kristof, Z. S. Kohajda, T. Szel, Z. Husti, I. Baczko, N. Jost, A. Varro, A. Sarusi, A. S. Farkas, S. Z. Orosz, T. Forster, A. Farkas, O. M. Zakhrabova-Zwiauer, M. Hardziyenka, R. Nieuwland, H. L. Tan, A. J. A. Raaijmakers, V. J. A. Bourgonje, G. J. M. Kok, A. A. B. Van Veen, M. E. Anderson, M. A. Vos, M. F. A. Bierhuizen, J. Benes, B. Sebestova, I. A. Ghouri, O. J. Kemi, A. Kelly, F. L. Burton, G. L. Smith, S. Ozdemir, K. Acsai, N. Doisne, R. Van Der Nagel, H. D. M. Beekman, T. A. B. Van Veen, K. R. Sipido, G. Antoons, S. C. Harmer, J. S. Mohal, D. Kemp, A. Tinker, D. Beech, D. S. Burley, C. D. Cox, K. T. Wann, G. F. Baxter, R. Wilders, A. Verkerk, P. Fragkiadaki, G. Germanakis, K. Tsarouchas, C. Tsitsimpikou, M. Tsardi, D. George, A. Tsatsakis, P. Rodrigues, C. Barros, A. K. Najmi, V. Khan, M. Akhtar, K. K. Pillai, M. Mujeeb, M. Aqil, C. R. Bayliss, A. E. Messer, M.-C. Leung, D. Ward, J. Van Der Velden, C. Poggesi, C. S. Redwood, S. Marston, A. Vite, E. Gandjbakhch, F. Gary, V. Fressart, P. Leprince, G. Fontaine, M. Komajda, P. Charron, E. Villard, I. Falcao-Pires, C. Gavina, N. Hamdani, G. J. M. Stienen, H. W. M. Niessens, A. F. Leite-Moreira, W. J. Paulus, M. Memo, S. B. Marston, E. Vafiadaki, J. Qian, D. A. Arvanitis, D. Sanoudou, E. G. Kranias, N. Elmstedt, B. Lind, K. Ferm-Widlund, M. Westgren, L.-A. Brodin, C. Mansfield, T. West, M. Ferenczi, P. J. M. Wijnker, D. B. Foster, A. Coulter, A. Frazier, A. M. Murphy, M. Shah, M. B. Sikkel, T. Desplantez, T. P. Collins, P. O' Gara, A. R. Lyon, K. T. Macleod, A. H. Ottesen, W. E. Louch, C. Carlson, O. J. B. Landsverk, M. Stridsberg, I. Sjaastad, E. Oie, T. Omland, G. Christensen, H. Rosjo, J. Cartledge, L. A. Clark, M. Ibrahim, U. Siedlecka, M. Navaratnarajah, M. H. Yacoub, P. Camelliti, C. M. Terracciano, A. Chester, A. Gonzalez-Tendero, I. Torre, F. Garcia-Garcia, J. Dopazo, E. Gratacos, D. Taylor, S. Bhandari, A.-M. Seymour, D. Fliegner, J. Jost, H. Bugger, R. Ventura-Clapier, A. Carpi, M. Campesan, M. Canton, R. Menabo, P. G. Pelicci, M. Giorgio, F. Di Lisa, M. Hancock, A. Venturini, N. Al-Shanti, C. Stewart, R. Ascione, G. Angelini, M.-S. Suleiman, E. Kravchuk, E. Grineva, M. Galagudza, A. Kostareva, A. Bairamov, K. A. Krychtiuk, L. Watzke, C. Kaun, S. Demyanets, J. Pisoni, S. P. Kastl, K. Huber, G. Maurer, J. Wojta, W. S. Speidl, Z. V. Varga, N. Farago, A. Zvara, G. F. Kocsis, M. Pipicz, C. Csonka, T. Csont, G. L. Puskas, P. Ferdinandy, M. Klevstigova, J. Silhavy, D. Manakov, F. Papousek, J. Novotny, M. Pravenec, F. Kolar, O. Novakova, F. Novak, J. Neckar, J. Barallobre-Barreiro, A. Didangelos, X. Yin, M. Fernandez-Caggiano, I. Drozdov, P. Willeit, N. Domenech, M. Mayr, S. Lemoine, S. Allouche, L. Coulbault, P. Galera, J. L. Gerard, J. L. Hanouz, E. Suveren, M. Whiteman, I. M. Studneva, O. Pisarenko, V. Shulzhenko, L. Serebryakova, O. Tskitishvili, A. Timoshin, J. Fauconnier, A. C. Meli, J. Thireau, S. Roberge, A. M. Lompre, E. Jacotot, A. M. Marks, A. Lacampagne, B. Dietel, R. Altendorf, W. G. Daniel, R. Kollmar, C. D. Garlichs, V. Parente, S. Balasso, G. Pompilio, G. Colombo, G. Milano, L. Squadroni, F. Cotelli, O. Pozzoli, M. C. Capogrossi, Y. Ajiro, N. Saegusa, K. Iwade, W. R. Giles, D. M. Stafforini, K. W. Spitzer, R. Sirohi, L. Candilio, G. Babu, N. Roberts, D. Lawrence, A. Sheikh, S. Kolvekar, J. Yap, D. J. Hausenloy, D. M. Yellon, M. Aslam, S. Rohrbach, K.-D. Schlueter, H. M. Piper, T. Noll, D. Guenduez, L. Malinova, V. P. Ryabukho, D. V. Lyakin, T. P. Denisova, S. Montoro-Garcia, E. Shantsila, G. Y. H. Lip, B. Kalaska, E. Sokolowska, K. Kaminski, K. Szczubialka, K. Kramkowski, A. Mogielnicki, M. Nowakowska, W. Buczko, N. Stancheva, E. Mekenyan, K. Gospodinov, S. Tisheva, A. Darago, I. Rutkai, J. Kalasz, A. Czikora, P. Orosz, H. D. Bjornson, I. Edes, Z. Papp, A. Toth, K. Riches, P. Warburton, D. J. O'regan, S. G. Ball, N. A. Turner, I. C. Wood, K. E. Porter, S. Kogaki, H. Ishida, N. Nawa, K. Takahashi, H. Baden, H. Ichimori, T. Uchikawa, S. Mihara, K. Miura, K. Ozono, R. Lugano, T. Padro, M. Garcia-Arguinzonis, L. Badimon, F. Ferraro, R. Viner, J. Ho, D. Cutler, V. Matchkov, C. Aalkjaer, P. A. J. Krijnen, N. E. Hahn, I. Kholova, J. A. Sipkens, F. P. Van Alphen, S. Simsek, C. G. Schalkwijk, J. D. Van Buul, V. W. M. Van Hinsbergh, H. W. M. Niessen, C. G. Caro, A. Seneviratne, C. Monaco, D. Hou, J. Singh, P. Gilson, M. G. Burke, K. B. Heraty, R. Krams, G. Coppola, K. Albrecht, W. Schgoer, D. Wiedemann, N. Bonaros, C. Steger, M. Theurl, U. Stanzl, R. Kirchmair, S. Amadesi, G. Spinetti, E. Cangiano, M. Valgimigli, A. M. Miller, A. Cardinali, K. Vierlinger, G. Pagano, D. Liccardo, C. Zincarelli, G. D. Femminella, A. Lymperopoulos, C. De Lucia, W. J. Koch, D. Leosco, G. Rengo, R. Hinkel, W. Husada, T. Trenkwalder, Q. Di, S. Lee, B. Petersen, I. Bock-Marquette, H. Niemann, M. Di Maio, C. Kupatt, M. Nourian, Z. Yassin, R. Kelishadi, S. H. Memarian, A. Heidari, A. Leuner, D. M. Poitz, C. Brunssen, U. Ravens, R. H. Strasser, H. Morawietz, F. Vogt, A. Grahl, C. Flege, N. Marx, M. Borinski, B. De Geest, F. Jacobs, I. Muthuramu, S. C. Gordts, E. Van Craeyveld, P. Herijgers, S. Weinert, S. Medunjanin, J. Herold, A. Schmeisser, R. C. Braun-Dullaeus, A. H. Wagner, K. Moeller, O. Adolph, M. Schwarz, C. Schwale, C. Bruehl, R. Nobiling, T. Wieland, S. W. Schneider, M. Hecker, A. Cross, A. Strom, J. Cole, M. Goddard, A. Hultgardh-Nilsson, J. Nilsson, C. Mauri, N. P. Mitkovskaya, T. A. Kurak, E. G. Oganova, E. I. Shkrebneva, Z. H. N. Kot, T. V. Statkevich, F. Molica, F. Burger, C. M. Matter, A. Thomas, C. Staub, A. Zimmer, B. Cravatt, P. Pacher, S. Steffens, R. Blanco, R. Sarmiento, C. Parisi, S. Fandino, F. Blanco, G. Gigena, J. Szarfer, A. Rodriguez, A. Garcia Escudero, M. A. Riccitelli, S. Wantha, S. Simsekyilmaz, R. T. Megens, M. A. Van Zandvoort, E. Liehn, A. Zernecke, D. Klee, C. Weber, O. Soehnlein, L. M. Lima, M. G. Carvalho, K. B. Gomes, I. R. Santos, M. O. Sousa, C. A. S. Morais, S. H. V. Oliveira, I. F. Gomes, F. C. Brandao, M. R. A. Lamego, L. Fornai, A. Kiss, F. Giskes, G. Eijkel, M. Fedrigo, M. L. Valente, R. M. A. Heeren, A. Grdinic, D. Vojvodic, N. Djukanovic, A. G. Grdinic, S. Obradovic, I. Majstorovic, S. Rusovic, Z. Vucinic, D. Tavciovski, M. Ostojic, S.-C. Lai, M.-Y. Chen, H.-T. Wu, L. Gouweleeuw, S. U. Oberdorf-Maass, R. A. De Boer, W. H. Van Gilst, A. H. Maass, I. C. Van Gelder, L. Benard, C. Li, D. Warren, C. M. Shanahan, Q. P. Zhang, A. Bye, R. Vettukattil, S. T. Aspenes, G. Giskeodegaard, I. S. Gribbestad, U. Wisloff, T. F. Bathen, J. Cubedo, R. Alonso, P. Mata, I. Ivic, Z. Vamos, P. Cseplo, D. Kosa, O. Torok, J. Hamar, A. Koller, K. Norita, S. V. De Noronha, M. N. Sheppard, I. Amat-Roldan, I. Iruretagoiena, S. Psilodimitrakopoulos, F. Crispi, D. Artigas, P. Loza-Alvarez, J. C. Harrison, S. D. Smart, E. H. Besely, J. R. Kelly, Y. Yao, I. A. Sammut, M. Hoepfner, W. Kuzyniak, E. Sekhosana, B. Hoffmann, C. Litwinski, A. Pries, E. Ermilov, D. Fontoura, A. P. Lourenco, F. Vasques-Novoa, J. P. Pinto, R. Roncon-Albuquerque, I. P. Oyeyipo, L. A. Olatunji, T. O. Usman, V. A. Olatunji, B. Bacova, C. Viczenczova, V. Dosenko, E. Goncalvesova, J. Vanrooyen, S. K. Maulik, S. Seth, A. K. Dinda, A. Jaiswal, G. Mearini, D. Khajetoorians, E. Kraemer, C. Gedicke-Hornung, G. Precigout, T. Eschenhagen, T. Voit, L. Garcia, S. Lorain, P. Mendes-Ferreira, C. Maia-Rocha, R. Adao, R. J. Cerqueira, M. J. Mendes, P. Castro-Chaves, G. W. De Keulenaer, C. Bras-Silva, G. Ruiter, Y. Y. Wong, M. Lubberink, P. Knaapen, P. Raijmakers, A. A. Lammertsma, J. T. Marcus, N. Westerhof, W. J. Van Der Laarse, A. Vonk-Noordegraaf, N. Steinbronn, E. Koch, G. Steiner, A. Berezin, O. A. Lisovaya, A. M. Soldatova, V. A. Kuznetcov, T. N. Yenina, A. Y. U. Rychkov, P. V. Shebeko, R. Altara, M. H. M. Hessel, J. J. R. Hermans, W. M. Blankesteijn, T. A. Berezina, V. Seden, C. Bonanad, J. Nunez, D. Navarro, M. F. Chilet, F. Sanchis, V. Bodi, G. Minana, F. Chaustre, M. J. Forteza, A. Llacer, G. Galasso, N. Ferrara, A. Akhmedov, R. Klingenberg, C. Brokopp, D. Hof, S. Zoller, R. Corti, S. Gay, A. Von Eckardstein, S. P. Hoerstrup, T. F. Luescher, J. Heijman, A. Zaza, D. M. Johnson, Y. Rudy, R. L. M. Peeters, P. G. A. Volders, R. L. Westra, S. Fujita, R. Okamoto, M. Taniguchi, K. Konishi, I. Goto, K. Sugimoto, M. Nakamura, K. Shiraki, C. Buechler, and M. Ito

Subjects
AMP-activated protein kinase, biology, Physiology, Chemistry, Physiology (medical), Mesenchymal stem cell, biology.protein, Cardiology and Cardiovascular Medicine, Cell biology
Published
2012
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6. P128Recovery of Scn5a-deficient mice cardiac conduction using AAVs

Author

L Fosse, Michel Clergue, Alain Coulombe, Nathalie Mougenot, N Doisne, Flavien Charpentier, M Grauso-Culetto, Pascale Guicheney, and Nathalie Neyroud

Subjects
medicine.medical_specialty, Endocrinology, Physiology, business.industry, Physiology (medical), Internal medicine, Cardiac conduction, medicine, Deficient mouse, Cardiology and Cardiovascular Medicine, business
Published
2018
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7. P133Atrial fibrillation vulnerability and action potential shortening in high fat diet-induced obesity in mice

Author

V Galand, Alain Coulombe, Stéphane N. Hatem, Nathalie Mougenot, N Suffee-Mosbah, and N Doisne

Subjects
Fibrillation, medicine.medical_specialty, Physiology, business.industry, Vulnerability, High fat diet induced obesity, Endocrinology, Action (philosophy), Physiology (medical), Internal medicine, Medicine, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Published
2018
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10. Control of Rhythm and Rate278Cx43 hemichannels in ventricular cardiomyocytes can be activated by an elevation of cytoplasmic Ca2+ through a CaM-dependent signaling cascade and are a potent contributor to cardiac arrhythmogenesis279Exploration of the dominant-negative effect of a SCN5A mutation in mice using adeno-associated viruses280Modeling susceptibility to drug-induced long qt syndrome with a panel of subject-specific induced pluripotent stem cells

Author

Christian Funck-Brentano, Michel Clergue, Dorota Jeziorowska, Alessio Lissoni, Noël Zahr, Nathalie Mougenot, Pascale Guicheney, Jens Hansen, Nathalie Neyroud, Alain Coulombe, M. De Smet, Chi-Wing Kong, Nan Wang, N Doisne, Marta Grauso, Ravi Iyengar, Luc Leybaert, Roger J. Hajjar, Francesca Stillitano, Jean-Sébastien Hulot, and Ronald A. Li

Subjects
medicine.medical_specialty, biology, Calmodulin, Physiology, Long QT syndrome, hERG, Sotalol, Depolarization, KCNE4, medicine.disease, QT interval, Endocrinology, Physiology (medical), Internal medicine, Ventricular fibrillation, medicine, biology.protein, Cardiology and Cardiovascular Medicine, medicine.drug
Abstract

278 Cx43 hemichannels in ventricular cardiomyocytes can be activated by an elevation of cytoplasmic Ca2+ through a CaM-dependent signaling cascade and are a potent contributor to cardiac arrhythmogenesis {#article-title-2} Introduction and purpose: Cx43, most abundantly expressed in the ventricles, is engaged in forming both gap junctions that electrically couple the cardiac tissue and unapposed hemichannels (HCs) that function as a non-selective transmembrane conduit. The latter are typically closed but open in response to electrical or chemical triggers such as pro-inflammatory cytokines or elevation of cytoplasmic Ca2+ ([Ca2+]i). Evidence for hemichannel opening by [Ca2+]i elevation is based on indirect ATP/dye uptake measurements, but conclusive electrophysiological evidence is lacking. Here, we studied [Ca2+]i-dependent activation of cardiac Cx43 HCs with the use of single-channel recordings and further proposed their arrhythmogenic potential. Methods: Left ventricular cardiomyocytes were acutely isolated from C57/Bl6 and inducible Cx43 knockdown mice (Cx43Cre-ER(T)/Fl). We provoked Ca2+ release from the sarcoplasmic reticulum by local application of caffeine (10 mM) under voltage-clamp conditions (Vm = -70 mV) and studied the effect on HC unitary currents using whole-cell patch-clamp techniques. Involvement of Cx43 HCs was verified by the biophysical properties, intracellular application of Gap19 (100 µM) and CT9 (100 µM) (a selective Cx43 HC blocker and positive modulator respectively) and Cx43 knockdown. Involvement of [Ca2+]i was assessed by applying the Ca2+-chelator EGTA (10 mM) intracellularly. Calmodulin (CaM) antagonist W7 (50 µM) was used to investigate the contribution of CaM signaling. Results and conclusions: Applying caffeine pulses (8 s) at resting membrane potential activated an inward current carried by the Na+/Ca2+ exchanger (NCX). Superimposed on this macroscopic current, there appeared microscopic current spiking activity characterized by a unitary conductance of ~210 pS. Unitary currents were inhibited by EGTA, by conditional Cx43 knockdown (Cx43Cre-ER(T)/Fl) and by the Cx43 HC blocking peptide Gap19. Additionally, CT9 peptide promoted the HC currents activated by caffeine-induced Ca2+-release while delivery of W7 into the cell completely abolished HC currents. The results indicate that Cx43 HCs can be opened by Ca2+-stimulation without any associated electrical stimulus through a CaM-dependent signaling cascade. The kinetics of Ca2+-triggered opening activity were very different from voltage-triggered activity (fast spiking versus prolonged opening respectively) indicating a distinct gating mechanism. Computational modeling of the impact of electrically/chemically-triggered Cx43 HC opening on cardiomyocyte excitability indicates that this may contribute to arrhythmogenesis in the heart by providing depolarizing inward currents with potential for generating delayed afterdepolarizations and subsequent focal excitation. # 279 Exploration of the dominant-negative effect of a SCN5A mutation in mice using adeno-associated viruses {#article-title-3} Introduction: Loss-of-function mutations in the cardiac sodium (Na+) channel α-subunit gene, SCN5A, cause Brugada syndrome (BrS), a hereditary disease with an autosomal dominant transmission and variable penetrance, characterized by ventricular fibrillation and sudden cardiac death. We previously evidenced in HEK293 cells, the dominant-negative effect of the R104W BrS mutation in the N-terminal region of the cardiac Na+ channel, inducing the retention of the wild-type (WT) channel and the proteasomal degradation of the mutant protein, leading to a drastic reduction of the resulting Na+ current. Our goal was to further study the effects of this mutation in vivo in mice, taking advantage of adeno-associated viruses (AAV) and pre-mRNA trans-splicing strategy. Methods: Because of the large size of the SCN5A gene, we used a dual AAV vector strategy combining viral DNA recombination and trans-splicing. Mice were injected with two AAV-9: one, AAV-SCN5A-5', packaging the cardiac troponin-T promoter, the 5' half of hSCN5A, the 5' donor site of a synthetic intron and a highly recombinogenic part of the human alkaline phosphatase (AP); and another, AAV-SCN5A-3', packaging the same AP sequence, the 3' acceptor site of the intron, the 3' half of hSCN5A fused to the gfp gene as a reporter and the SV40 polyA signal. Six weeks after systemic injection, the hSCN5A-GFP full-gene expression was assessed by RT-qPCR, western blot and immunohistochemistry on transduced heart tissues. The Na+ current was recorded by the patch-clamp technique in isolated adult trasduced cardiomyocytes. Results: Almost 40% of cells were transduced in injected mice hearts. Overexpression of the R104W mutant channel induced a dilatation of the left vendtricle (+21% in systole, P

Published
2016
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11. G015 Adrenergic regulation of the resting membrane potential in the left atrium and thoracic veins of the rat

Author

Ian Findlay, N. Doisne, N. Zannad, Véronique Maupoil, and Pierre Cosnay

Subjects
Membrane potential, medicine.medical_specialty, business.industry, Thoracic Vein, Cardiac muscle, Adrenergic, Depolarization, General Medicine, Cirazoline, Pulmonary vein, chemistry.chemical_compound, Endocrinology, medicine.anatomical_structure, chemistry, Internal medicine, Isoprenaline, medicine, Cardiology, business, Cardiology and Cardiovascular Medicine, medicine.drug
Abstract

The physiology of cardiac muscle in thoracic veins is of interest as a source of ectopic activity which can lead to paroxystic atrial fibrillation (Haissaguerre et al. 1998 N Engl J Med 339: 659-666 ; Chen et al. 1999 Circulation 100:1879-1886). We have shown that noradrenalin can induce automatic ectopic activity in the pulmonary vein of the rat (Maupoil et al. 2007 Br J Pharmacol 150:899-905). Here we describe the effects of adrenergic agonists upon the resting membrane potential recorded with intracellular microelectrodes from cardiac muscle in the left atrium (LA), pulmonary veins (PV) and superior vena cava (SVC) of the rat. Isolated tissues were continuously perfused with Krebs-Heinseleit solution aerated with 95 % O2, 5 % CO2 and maintained at 36-37 °C. The quiescent resting membrane potentials were: LA −84±1 mV (n=14), SVC −74±1 mV (n=14), PV −69±1 mV (n=17). In each tissue noradrenalin (10-5M) induced a biphasic response with an initial hyperpolarisation (LA −3±1 mV, SVC −9±1 mV, PV −8±1 mV) followed by a depolarisation (LA +1±2 mV, SVC +15±2 mV, PV +34±1 mV). Only in PV did noradrenalin induce automatic electrical activity when the membrane potential reached ∼−50 mV. The α-adrenergic agonist cirazoline (10-6M) induced a monophasic depolarisation of the resting membrane potential in each tissue: to −80±2 mV in LA, to −49±1 mV in SVC and to −34±1 mV in PV. In no case did cirazoline induce automatic electrical activity. The β-adrenergic agonist isoprenaline (10-7M) induced a monophasic hyperpolarisation of the resting membrane potential in each tissue: to −87±1 mV in LA, to −79±2 mV in SVC and to −80±2 mV in PV. Conclusions 1. There are significant differences between the resting membrane potentials of the left atrium and both thoracic veins. 2. The responses of the resting membrane potential to adrenergic stimulation are qualitatively similar but quantitatively different with LA 3. Depolarisation is not sufficient to induce automatic electrical activity.

Published
2009
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12. 0235 : In vivo overexpression of a cardiac sodium channel mutant in mice

Author

Pascale Guicheney, Nathalie Mougenot, Nathalie Neyroud, Alain Coulombe, Marta Grauso, Michel Clergue, and N Doisne

Subjects
Mutation, medicine.diagnostic_test, business.industry, Sodium channel, Mutant, HEK 293 cells, medicine.disease_cause, Virology, Molecular biology, Green fluorescent protein, Western blot, In vivo, Mutant protein, medicine, Cardiology and Cardiovascular Medicine, business
Abstract

Loss-of-function mutations in the cardiac Na+ channel α-subunit gene, SCN5A, cause Brugada syndrome (BrS), a hereditary disease characterized by ventricular fibrillation and sudden cardiac death. We previously evidenced, in HEK cells, the dominant-negative effect of the R104W BrS mutation in Nav1.5, inducing the retention of the wild-type (WT) channel and the proteasomal degradation of the mutant protein. To explore this dominant-negative effect in vivo, we created a murine model using adeno-associated viruses (AAV). We used a dual AAV vector strategy combining viral DNA recombination and trans-splicing. One-week old mice were injected with two AAV serotypes capsid 9: one, packaging the cardiac specific troponin-T promoter, the 5’ half of hSCN5A, the 5’ donor site of a synthetic intron and a highly recombinogenic sequence; and another, packaging the same recombinogenic sequence, the 3’ acceptor site of the synthetic intron, the 3’ half of hSCN5A, the gfp gene as a reporter, and the SV40 polyA signal. Six weeks after injection, the hSCN5A full-gene expression and the percentage of transduced cardiac cells were assessed by qPCR, western blot (WB) analysis and immunohistochemistry on transduced heart tissues. The Na+ current was recorded by the patchclamp technique in isolated cardiomyocytes. Both WT and mutant human Nav1.5 transcripts and proteins were observed by RT-qPCR, WB and immunohistochemistry on injected-mice heart tissues. Patch-clamp recordings in WT-channel injected mice evidenced a two-fold increase of the Na+ current. In contrast, the cardiac Na+ current of R104Winjected mice was impaired (i.e. the current density was decreased by 45% and the activation was shifted by -4mV). Our data suggest that the trans-splicing and viral DNA recombination strategy using AAV9 serotype and a cardiac-specific promoter is successful to overexpress WT or mutant Na+ channels in mouse hearts. This approach allowed us to modulate the cardiac Na+ current in adult mice.

Published
2015
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13. Poster Session 4

Author

H. Tada, H. Yamasaki, Y. Sekiguchi, M. Igarashi, K. Kuroki, T. Machino, K. Yoshida, K. Aonuma, F. R. Heinzel, H. Forstner, P. Lercher, E. Bisping, B. Rotman, F. M. Fruhwald, B. M. Pieske, R. Dabrowski, I. Kowalik, A. Borowiec, E. Smolis-Bak, A. Trybuch, C. Sosnowski, H. Szwed, M. A. Baturova, A. Lindgren, Y. V. Shubik, B. Olsson, P. G. Platonov, K. C. Van Den Broek, J. Denollet, J. Widdershoven, N. Kupper, R. Allam, R. A. G. A. B. Allam, W. A. G. D. Y. Galal, H. A. Y. A. M. El-Damnhoury, A. Y. M. A. N. Mortada, J. Jimenez-Candil, A. Martin, J. Hernandez, F. Martin, M. Gallego, C. Martin-Luengo, J. G. Quintanilla, J. Moreno Planas, R. Molina-Morua, T. Archondo, M. J. Garcia-Torrent, N. Perez-Castellano, C. Macaya, J. Perez-Villacastin, J. Saiz, C. Tobon, J. F. Rodriguez, F. Hornero, J. M. Ferrero, K. Ito, T. Date, M. Kawai, M. Hioki, R. Narui, S. Matsuo, M. Yoshimura, T. Yamane, N. Tabatabaei, G. Lin, B. D. Powell, R. Smairat, J. F. Glockner, P. A. Brady, S. Fichtner, U. Czudnochowsky, H. Estner, T. Reents, C. Jilek, S. Ammar, G. Hessling, I. Deisenhofer, D. C. Shah, J. Kautzner, N. Saoudi, C. Herrera, P. Jais, G. Hindricks, P. Neuzil, K. H. Kuck, K. C. K. Wong, M. Jones, N. Qureshi, A. Muthumala, T. R. Betts, Y. Bashir, K. Rajappan, T. Vogtmann, M. Wagner, J. Schurig, P. Hein, B. Hamm, G. Baumann, A. Lembcke, B. Saad, C. Slater, L. A. Oliveira, R. Elias, A. Camiletti, D. Moura, P. Maldonado, L. E. Camanho, A. Bulava, J. Hanis, D. Sitek, A. Novotny, W. B. Chik, T. W. Lim, H. K. Choon, V. A. See, R. Mccall, L. Thomas, D. L. Ross, S. P. Thomas, J. Chen, A. De Bortoli, O. Rossvoll, P. I. Hoff, E. Solheim, L. Z. Sun, P. Schuster, O. J. Ohm, A. V. Ardashev, E. Zhelyakov, M. S. Rybachenko, A. V. Konev, Y. U. N. Belenkov, M. Gunawardene, K. R. J. Chun, B. Schulte-Hahn, V. Windhorst, M. Kulikoglu, B. Nowak, B. Schmidt, G. A. Albina, R. S. Rivera, F. Scazzuso, R. L. Laino, G. A. Giniger, E. Arbelo, N. Calvo, D. Tamborero, D. Andreu, R. Borras, A. Berruezo, J. Brugada, L. Mont, L. Stefan, M. Eisenberger, E. Celentano, P. Peytchev, O. Bodea, P. Geelen, T. De Potter, M. M. Oliveira, N. Silva, P. S. Cunha, J. Feliciano, A. Lousinha, A. Toste, S. Santos, R. C. Ferreira, H. Matsuda, T. Harada, K. Soejima, Y. Ishikawa, K. Mizukoshi, T. Sasaki, K. Mizuno, F. Miyake, P. P. Adragao, D. Cavaco, R. Miranda, M. Santos, F. Morgado, K. Reis Santos, R. Candeias, S. Marcelino, F. Zoppo, G. Grandolino, F. Zerbo, E. Bertaglia, S. M. Schlueter, O. Grebe, E. G. Vester, A. L. Miracle Blanco, A. Arenal Maiz, F. Atienza Fernandez, T. Datino Romaniega, E. Gonzalez Torrecilla, G. Eidelman, J. Hernandez Hernandez, F. Fernandez Aviles, K. Fukumoto, S. Takatsuki, T. Kimura, N. Nishiyama, Y. Aizawa, T. Sato, S. Miyoshi, K. Fukuda, B. Richter, M. Gwechenberger, A. Socas, G. Zorn, S. Albinni, M. Marx, J. Wojta, H. Goessinger, T. Deneke, O. Balta, M. Paesler, K. Buenz, H. Anders, M. Horlitz, A. Muegge, D.- I. Shin, K. Natsuyama, K. M. Yamaguchi, Y. N. Nishida, J. Kosiuk, K. Bode, A. Arya, C. Piorkowski, T. Gaspar, P. Sommer, A. Bollmann, D. Wichterle, P. Peichl, J. Simek, S. Havranek, V. Bulkova, R. Cihak, A. Jurado Roman, R. Salguero Bodes, M. Lopez Gil, A. Fontenla Cerezuela, M. De Riva Silva, F. Arribas Ynsaurriaga, A. I. Fernandez Herranz, S. De Dios Perez, A. S. Revishvili, M. Dishekov, Z. Tembotova, S. Barsamyan, D. Vaccari, C. Alvarenga, I. Jesus, J. Layher, A. Takahashi, N. Singh, P. Siot, J. P. Elkaim, I. Savelieva, L. Mcclelland, A. Lovegrove, S. Jones, J. Camm, A. F. Folino, R. Breda, P. Calzavara, J. Comisso, F. Borghetti, S. Iliceto, G. Buja, R. Mlynarski, A. Mlynarska, M. Sosnowski, J. Wilczek, P. Mabo, G. Carrault, P. Bordachar, A. Makdissi, L. Duchemin, C. Alonso, G. Neri, G. Masaro, S. Vittadello, A. Gardin, A. Barbetta, F. Di Gregorio, E. Sciaraffia, M. R. Ginks, J. S. Gustafsson, M. C. Hollmark, C. A. Rinaldi, C. Blomstrom Lundqvist, S. Brusich, D. Tomasic, B. Ferek-Petric, Z. Mavric, A. Kutarski, B. Malecka, A. Kolodzinska, M. Grabowski, E. V. Dovellini, L. Giurlani, G. Cerisano, N. Carrabba, R. Valenti, D. Antoniucci, G. Opolski, G. Tomassoni, J. Baker, R. Corbisiero, D. Martin, I. Niazi, R. Sheppard, J. Sperzel, K. Gutleben, J. Petru, L. Sediva, J. Skoda, P. Mazzone, G. Ciconte, P. Vergara, A. Marzi, G. Paglino, N. Sora, S. Gulletta, P. Della Bella, R. Pietura, M. Czajkowski, N. Cabanelas, V. P. Martins, M. Alves, F. X. Valente, L. Marta, A. Francisco, R. Silva, G. Ferreira Da Silva, Y. Huo, F. Holmqvist, J. Carlson, U. Wetzel, P. Platonov, E. Nof, R. Abu Shama, R. Kuperstein, M. S. Feinberg, M. Eldar, M. Glikson, D. Luria, P. Kubus, O. Materna, R. A. Gebauer, T. Matejka, R. Gebauer, T. Tlaskal, J. Janousek, A. Muessigbrodt, S. Richter, M. Stockburger, S. Boveda, P. Defaye, P. Stancak Branislav, G. Kaliska, M. Rolando, J. Moreno, M.- A. G. Ohlow, B. Lauer, B. Buchter, M. Schreiber, J. C. Geller, J. E. Val-Mejias, S. Ouali, S. Azzez, S. Kacem, H. Ben Salem, S. Hammas, E. Neffeti, F. Remedi, E. Boughzela, H. Miyazaki, S. Miyanaga, K. Shibayama, M. Tokuda, T. Kudo, B. Coppola, R. E. N. Shehada, P. Costandi, J. Healey, S. H. Hohnloser, M. R. Gold, A. Capucci, I. C. Van Gelder, M. Carlson, C. P. Lau, S. J. Connolly, M. D. Bogaard, G. E. Leenders, B. Maskara, A. E. Tuinenburg, P. Loh, R. N. Hauer, P. A. Doevendans, M. Meine, B. Thibault, M. Dubuc, E. Karst, K. Ryu, P. Paiement, T. Farazi, V. Puetz, C. Berndt, J. Buchholz, A. Dorszewski, C. Mornos, D. Cozma, A. Ionac, L. Petrescu, A. Mornos, S. Pescariu, M. Benser, G. Roscoe, S. De Jong, G. Roberts, P. Boileau, A. Rec, C. Folman, A. Morttada, M. Abd El Kader, R. Samir, R. Roushdy, S. Khaled, M. Abo El Maaty, B. Van Gelder, P. Houthuizen, F. A. Bracke, J. Osca Asensi, D. Tejada, J. M. Sanchez, B. Munoz, O. Cano, M. Rodriguez, M. J. Sancho-Tello, J. Olague, W. Hou, S. Rosenberg, S. Koh, J. Poore, J. Snell, M. Yang, D. Nirav, G. Bornzin, T. Deering, D. Dan, A. C. Wickliffe, S. Cazeau, K. Karimzadeh, S. Mukerji, C. Loghin, B. Kantharia, M. A. Jones, J. Lamba, C. S. Simpson, D. P. Redfearn, K. A. Michael, M. Fitzpatrick, A. Baranchuk, M. Heinke, B. Ismer, H. Kuehnert, R. Surber, A. M. Haltenberger, D. Prochnau, H. R. Figulla, N. Delarche, O. Bizeau, P. Couderc, A. Chapelet, W. Amara, A. Lazarus, S. Krupickova, C. J. M. Van Deursen, M. Strik, K. Vernooy, A. Van Hunnik, M. Kuiper, H. J. G. M. Crijns, F. W. Prinzen, N. Islam, D. Gras, W. Abraham, L. Calo, U. Birgersdotter-Green, C. Clyne, J. Herre, N. Klein, O. Kowalski, R. Lenarczyk, P. Pruszkowska, A. Sokal, T. Kukulski, T. Zielinska, S. Pluta, Z. Kalarus, J. O. Schwab, M. Gasparini, F. Anselme, J. Clementy, M. Santini, J. Martinez Ferrer, V. Burrone, E. Santi, R. Nevzorov, A. Porter, J. Kusniec, G. Golovchiner, T. Ben-Gal, B. Strasberg, M. Haim, R. Rordorf, S. Savastano, A. Sanzo, A. Vicentini, B. Petracci, M. De Amici, L. Striuli, M. Landolina, J. M. Tolosana, A. M. Martin, A. Hernandez-Madrid, A. Macias, I. Fernandez-Lozano, J. Osca, A. Quesada, Y. Noguchi, S. Shahrzad, N. Karim Soleiman, A. Tavoosi, S. Taban, Z. Emkanjoo, M. Fukunaga, M. Goya, K. Hiroshima, M. Ohe, K. Hayashi, M. Iwabuchi, H. Nosaka, M. Nobuyoshi, D. Doiny, A. Perez-Silva, S. Castrejon Castrejon, A. Estrada, M. Ortega, J. L. Lopez-Sendon, J. L. Merino, F. J. Garcia Fernandez, R. Gallardo, M. Pachon, J. Almendral, J. Martin, D. Yahya, B. Al-Mogheer, S. Gouda, E. Eweis, M. El Ramly, A. Abdelwahab, W. Kassenberg, F. H. M. Wittkampf, I. E. Hof, J. H. Heijden, K. G. E. J. Neven, R. N. W. Hauer, F. Baratto, E. Bignami, F. Pappalardo, G. Maccabelli, D. Nicolotti, A. Zangrillo, M. Nagashima, Y. An, A. Okreglicki, C. Russouw, R. Tilz, Y. Yoshiga, S. Mathew, A. Fuernkranz, A. Rillig, E. Wissner, F. Ouyang, A. De Sisti, J. Tonet, F. Gueffaf, F. Touil, P. Aouate, F. Hidden-Lucet, H. Makimoto, K. Satomi, Y. Yamada, H. Okamura, T. Noda, W. Shimizu, N. Aihara, S. Kamakura, A. Perez Silva, S. Castrejon, M. Gonzalez Vasserot, J. Senges, J. Brachmann, D. Andresen, E. Hoffmann, B. Schumacher, S. Willems, B. Springer, C. Kolb, F. Akca, T. Bauernfeind, N. M. S. De Groot, B. Schwagten, M. Witsenburg, L. Jordaens, T. Szili-Torok, Y. Hata, R. Nakagami, T. Watanabe, A. Sato, H. Watanabe, T. Kabutoya, T. Mituhashi, D. A. M. J. Theuns, T. Smith, S. S. Pedersen, L. Dabiri-Abkenari, M. W. Prull, S. Unverricht, A. Bittlinsky, H. Wirdemann, B. Sasko, S. Wirdeier, H. J. Trappe, E. Zorio Grima, J. Rueda, P. Medina, T. Jaijo, T. Sevilla, M. A. Arnau, A. Salvador, A. H. Starrenburg, K. Kraaier, M. F. Scholten, J. Van Der Palen, S. De Haan, J. Commandeur, K. De Boer, A. M. Beek, A. C. Van Rossum, C. P. Allaart, P. Berne, J. M. Porres, J. A. Arnaiz, R. Brugada, S. Man, A. C. Maan, J. Thijssen, E. E. Van Der Wall, M. J. Schalij, L. Burattini, R. Burattini, C. A. Swenne, A. Bonny, I. Ditah, F. Larrazet, R. Frank, G. Fontaine, P. H. Van Der Voort, M. Alings, A. Shimane, K. Okajima, G. Kanda, K. Yokoi, S. Yamada, Y. Taniguchi, T. Hayashi, T. Kajiya, M. C. Santos, J. Wright, J. Betts, R. Denman, L. Dominguez-Perez, M. A. Arias Palomares, J. Toquero, E. Diaz-Infante, L. Tercedor, I. Valverde, A. Napp, S. Joosten, D. Stunder, M. Zink, N. Marx, P. Schauerte, J. Silny, M. E. Trucco, M. Arce, J. Palazzolo, F. Femenia, J. M. Glad, S. J. Szymkiewicz, J. Fernandez-Armenta, O. Camara, L. L. Mont, E. Diaz, E. Silva, A. Frangi, B. Brembilla-Perrot, F. Laporte, J. Morinigo, C. Ledesma, C. Hadid, M. Ortiz, C. Wolpert, E. Cobo, X. Navarro, F. Arribas, Y. Miki, S. Naitoh, K. Kumagai, K. Goto, K. Kaseno, S. Oshima, K. Taniguchi, S. Rivera, G. Albina, A. Klein, R. Laino, V. Sammartino, A. Giniger, M. Muggenthaler, H. Raju, M. Papadakis, N. Chandra, R. Bastiaenen, E. R. Behr, S. Sharma, N. Samniah, Y. Radezishvsky, H. Omari, U. Rosenschein, A. R. Perez Riera, M. Ferreira, W. M. Hopman, W. F. Mcintyre, A. R. Baranchuk, W. Wongcharoen, K. Keanprasit, A. Phrommintikul, R. Chaiwarith, A. Yagishita, H. Hachiya, T. Nakamura, Y. Tanaka, K. Higuchi, M. Kawabata, K. Hirao, M. Isobe, V. Stoickov, S. Ilic, M. Deljanin Ilic, P. Aagaard, A. Sahlen, L. Bergfeldt, F. Braunschweig, A. Sousa, A. Lebreiro, C. Sousa, S. Oliveira, A. S. Correia, I. Rangel, J. Freitas, M. J. Maciel, E. Asensio Lafuente, A. A. C. Aguilera, M. A. C. C. Corral, K. L. M. C. Mendoza, P. E. N. D. Nava, A. L. R. C. Rendon, L. V. C. Villegas, L. C. M. Castillo, R. Schaerf, R. Develle, C. Oliver, P. Y. Zinzius, R. A. Providencia, A. Botelho, J. Trigo, J. Nascimento, N. Quintal, P. Mota, A. M. Leitao-Marques, J. Borbola, P. Abraham, C. S. Foldesi, A. Kardos, S. Almeida, M. B. Santos, R. Quaresma, F. B. Morgado, P. Adragao, M. Fatemi, R. Didier, G. Le Gal, Y. Etienne, Y. Jobic, M. Gilard, J. Boschat, J. Mansourati, M. Zubaid, W. Rashed, A. Alsheikh-Ali, W. Almahmeed, A. Shehab, K. Sulaiman, N. Asaad, H. Amin, L. V. A. Boersma, M. Swaans, M. Post, B. Rensing, K. Jarverud, M. Broome, K. Noren, T. Svensson, S. Hjelm, M. Hollmark, A. Bjorling, K. Maeda, M. Takagi, K. Suzuki, H. Tatsumi, M. Yoshiyama, E. Simeonidou, C. Michalakeas, S. Kastellanos, C. Varounis, A. Nikolopoulou, C. Koniari, M. Anastasiou-Nana, T. Furukawa, R. Maggi, C. Bertolone, D. Fontana, M. Brignole, A. Z. Pietrucha, M. Wnuk, I. Bzukala, D. Mroczek-Czernecka, E. Konduracka, O. Kruszelnicka, W. Piwowarska, J. Nessler, N. Edvardsson, G. Rieger, C. Garutti, N. Linker, C. Jorge, J. Silva Marques, A. Veiga, J. Cruz, M. J. Correia, J. Sousa, G. Miltenberger-Miltenyi, A. Nunes Diogo, D. Matic, I. Mrdovic, G. Stankovic, M. Asanin, N. Antonijevic, M. Matic, N. Kocev, Z. Vasiljevic, M. A. Ramirez-Marrero, B. Perez-Villardon, J. L. Delgado-Prieto, M. Jimenez-Navarro, E. De Teresa-Galvan, M. De Mora-Martin, K. Sztefko, A. Malek, N. De Groot, T. Shalganov, M. Schalij, N. Rivas, J. Casaldaliga, I. Roca, A. Pijuan, J. Perez-Rodon, L. Dos, D. Garcia-Dorado, A. Moya, A.- E. Baruteau, A. Behaghel, S. Chatel, J. J. Schott, J. C. Daubert, H. Le Marec, V. Probst, J. Navarro-Manchon, P. Molina, B. Igual, M. Bermejo, J. Giner, V. J. A. Bourgonje, M. A. Vos, S. Ozdemir, N. Doisne, M. A. G. Van Der Heyden, A. A. B. Van Veen, K. Sipido, G. Antoons, P. I. Altieri, N. Escobales, M. Crespo, H. L. Banchs, L. Sciarra, R. Bloise, G. Allocca, E. Marras, E. Lioy, P. Delise, S. Priori, and L. Calo'

Subjects
medicine.medical_specialty, business.industry, Physiology (medical), Internal medicine, Diastole, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

spectively), (p

Published
2011
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14. Impacts of a high-fat diet on the metabolic profile and the phenotype of atrial myocardium in mice.

Author

Suffee N, Baptista E, Piquereau J, Ponnaiah M, Doisne N, Ichou F, Lhomme M, Pichard C, Galand V, Mougenot N, Dilanian G, Lucats L, Balse E, Mericskay M, Le Goff W, and Hatem SN

Subjects
Mice, Animals, Metabolomics, Metabolome, Adenosine Triphosphate, Diet, High-Fat, Atrial Fibrillation etiology
Abstract

Aims: Obesity, diabetes, and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favouring the formation of the substrate of AF., Methods and Results: Untargeted metabolomic and lipidomic analysis was used to investigate the consequences of a prolonged high-fat diet (HFD) on mouse atria. Atrial properties were characterized by measuring mitochondria respiration in saponin-permeabilized trabeculae, by recording action potential (AP) with glass microelectrodes in trabeculae and ionic currents in myocytes using the perforated configuration of patch clamp technique and by several immuno-histological and biochemical approaches. After 16 weeks of HFD, obesogenic mice showed a vulnerability to AF. The atrial myocardium acquired an adipogenic and inflammatory phenotypes. Metabolomic and lipidomic analysis revealed a profound transformation of atrial energy metabolism with a predominance of long-chain lipid accumulation and beta-oxidation activation in the obese mice. Mitochondria respiration showed an increased use of palmitoyl-CoA as energy substrate. APs were short duration and sensitive to the K-ATP-dependent channel inhibitor, whereas K-ATP current was enhanced in isolated atrial myocytes of obese mouse., Conclusion: HFD transforms energy metabolism, causes fat accumulation, and induces electrical remodelling of the atrial myocardium of mice that become vulnerable to AF., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Published
2022
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15. In vivo Dominant-Negative Effect of an SCN5A Brugada Syndrome Variant.

Author

Doisne N, Grauso M, Mougenot N, Clergue M, Souil C, Coulombe A, Guicheney P, and Neyroud N

Abstract

Loss-of-function mutations in the cardiac Na + channel α-subunit Na v 1.5, encoded by SCN5A , cause Brugada syndrome (BrS), a hereditary disease characterized by sudden cardiac death due to ventricular fibrillation. We previously evidenced in vitro the dominant-negative effect of the BrS Na v 1.5-R104W variant, inducing retention of wild-type (WT) channels and leading to a drastic reduction of the resulting Na + current ( I Na ). To explore this dominant-negative effect in vivo , we created a murine model using adeno-associated viruses (AAVs)., Methods: Due to the large size of SCN5A , a dual AAV vector strategy was used combining viral DNA recombination and trans -splicing. Mice were injected with two AAV serotypes capsid 9: one packaging the cardiac specific troponin-T promoter, the 5' half of hSCN5A cDNA, a splicing donor site and a recombinogenic sequence; and another packaging the complementary recombinogenic sequence, a splicing acceptor site, the 3' half of hSCN5A cDNA fused to the gfp gene sequence, and the SV40 polyA signal. Eight weeks after AAV systemic injection in wild-type (WT) mice, echocardiography and ECG were recorded and mice were sacrificed. The full-length hSCN5A-gfp expression was assessed by western blot and immunohistochemistry in transduced heart tissues and the Na + current was recorded by the patch-clamp technique in isolated adult GFP-expressing heart cells., Results: Almost 75% of the cardiomyocytes were transduced in hearts of mice injected with hNa v 1.5 and ∼30% in hNa v 1.5-R104W overexpressing tissues. In ventricular mice cardiomyocytes expressing R104W mutant channels, the endogenous I Na was significantly decreased. Moreover, overexpression of R104W channels in normal hearts led to a decrease of total Na v 1.5 expression. The R104W mutant also induced a slight dilatation of mice left ventricles and a prolongation of RR interval and P-wave duration in transduced mice. Altogether, our results demonstrated an in vivo dominant-negative effect of defective R104W channels on endogenous ones., Conclusion: Using a trans -splicing and viral DNA recombination strategy to overexpress the Na + channel in mouse hearts allowed us to demonstrate in vivo the dominant-negative effect of a BrS variant identified in the N-terminus of Na v 1.5., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Doisne, Grauso, Mougenot, Clergue, Souil, Coulombe, Guicheney and Neyroud.)

Published
2021
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16. Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS.

Author

Bączyk M, Alami NO, Delestrée N, Martinot C, Tang L, Commisso B, Bayer D, Doisne N, Frankel W, Manuel M, Roselli F, and Zytnicki D

Subjects
Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Animals, Cyclic AMP-Dependent Protein Kinases genetics, Humans, Mice, Mice, Transgenic, Motor Neurons pathology, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Synapses genetics, Synapses pathology, Amyotrophic Lateral Sclerosis enzymology, Cyclic AMP-Dependent Protein Kinases metabolism, Motor Neurons enzymology, Neuroprotection, Signal Transduction, Synapses enzymology
Abstract

Excessive excitation is hypothesized to cause motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS), but actual proof of hyperexcitation in vivo is missing, and trials based on this concept have failed. We demonstrate, by in vivo single-MN electrophysiology, that, contrary to expectations, excitatory responses evoked by sensory and brainstem inputs are reduced in MNs of presymptomatic mutSOD1 mice. This impairment correlates with disrupted postsynaptic clustering of Homer1b, Shank, and AMPAR subunits. Synaptic restoration can be achieved by activation of the cAMP/PKA pathway, by either intracellular injection of cAMP or DREADD-Gs stimulation. Furthermore, we reveal, through independent control of signaling and excitability allowed by multiplexed DREADD/PSAM chemogenetics, that PKA-induced restoration of synapses triggers an excitation-dependent decrease in misfolded SOD1 burden and autophagy overload. In turn, increased MN excitability contributes to restoring synaptic structures. Thus, the decrease of excitation to MN is an early but reversible event in ALS. Failure of the postsynaptic site, rather than hyperexcitation, drives disease pathobiochemistry., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Bączyk et al.)

Published
2020
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17. Microtubule polymerization state and clathrin-dependent internalization regulate dynamics of cardiac potassium channel: Microtubule and clathrin control of K V 1.5 channel.

Author

Melgari D, Barbier C, Dilanian G, Rücker-Martin C, Doisne N, Coulombe A, Hatem SN, and Balse E

Subjects
Animals, Atrial Fibrillation etiology, Atrial Fibrillation metabolism, Atrial Fibrillation physiopathology, Atrial Remodeling genetics, Clathrin chemistry, Clathrin-Coated Vesicles, Cytoskeleton chemistry, Cytoskeleton metabolism, Electrophysiological Phenomena, Heart Atria metabolism, Humans, Kv1.5 Potassium Channel genetics, Kv1.5 Potassium Channel metabolism, Microtubules chemistry, Microtubules genetics, Myocytes, Cardiac metabolism, Myocytes, Cardiac ultrastructure, Potassium Channels, Voltage-Gated chemistry, Rats, Sarcolemma metabolism, Signal Transduction, Clathrin metabolism, Microtubules metabolism, Potassium Channels, Voltage-Gated metabolism, Protein Multimerization
Abstract

Ion channel trafficking powerfully influences cardiac electrical activity as it regulates the number of available channels at the plasma membrane. Studies have largely focused on identifying the molecular determinants of the trafficking of the atria-specific K V 1.5 channel, the molecular basis of the ultra-rapid delayed rectifier current I Kur . Besides, regulated K V 1.5 channel recycling upon changes in homeostatic state and mechanical constraints in native cardiomyocytes has been well documented. Here, using cutting-edge imaging in live myocytes, we investigated the dynamics of this channel in the plasma membrane. We demonstrate that the clathrin pathway is a major regulator of the functional expression of K V 1.5 channels in atrial myocytes, with the microtubule network as the prominent organizer of K V 1.5 transport within the membrane. Both clathrin blockade and microtubule disruption result in channel clusterization with reduced membrane mobility and internalization, whereas disassembly of the actin cytoskeleton does not. Mobile K V 1.5 channels are associated with the microtubule plus-end tracking protein EB1 whereas static K V 1.5 clusters are associated with stable acetylated microtubules. In human biopsies from patients in atrial fibrillation associated with atrial remodeling, drastic modifications in the trafficking balance occurs together with alteration in microtubule polymerization state resulting in modest reduced endocytosis and increased recycling. Consequently, hallmark of atrial K V 1.5 dynamics within the membrane is clathrin- and microtubule- dependent. During atrial remodeling, predominance of anterograde trafficking activity over retrograde trafficking could result in accumulation ok K V 1.5 channels in the plasma membrane., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2020
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18. Distinct calcium/calmodulin-dependent serine protein kinase domains control cardiac sodium channel membrane expression and focal adhesion anchoring.

Author

Beuriot A, Eichel CA, Dilanian G, Louault F, Melgari D, Doisne N, Coulombe A, Hatem SN, and Balse E

Subjects
Cell Adhesion, Dystrophin metabolism, Focal Adhesions metabolism, Glycoproteins metabolism, Guanylate Kinases chemistry, Guanylate Kinases metabolism, Protein Kinases metabolism, Serine, Sodium Channels metabolism, Calcium metabolism, Calmodulin metabolism
Abstract

Background: Membrane-associated guanylate kinase proteins function as adaptor proteins to mediate the recruitment and scaffolding of ion channels in the plasma membrane in various cell types. In the heart, the protein calcium/calmodulin-dependent serine protein kinase (CASK) negatively regulates the main cardiac sodium channel Na V 1.5, which carries the sodium current (I Na ) by preventing its anterograde trafficking. CASK is also a new member of the dystrophin-glycoprotein complex and, like syntrophin, binds to the C-terminal domain of the channel., Objective: The purpose of this study was to unravel the mechanisms of CASK-mediated negative I Na regulation and interaction with the dystrophin-glycoprotein complex in cardiac myocytes., Methods: CASK adenoviral truncated constructs with sequential single functional domain deletions were designed for overexpression in cardiac myocytes: CASK ΔCAMKII , CASK ΔL27A , CASK ΔL27B , CASK ΔPDZ , CASK ΔSH3 , CASK ΔHOOK , and CASK ΔGUK . A combination of whole-cell patch-clamp recording, total internal reflection fluorescence microscopy, and biochemistry experiments was conducted in cardiac myocytes to study the functional consequences of domain deletions., Results: We show that both L27B and GUK domains are required for the negative regulatory effect of CASK on I Na and Na V 1.5 surface expression and that the HOOK domain is essential for interaction with the cell adhesion dystrophin-glycoprotein complex., Conclusion: This study demonstrates that the multimodular structure of CASK confers an ability to simultaneously interact with several targets within cardiomyocytes. Through its L27B, GUK, and HOOK domains, CASK potentially provides the ability to control channel delivery at adhesion points in cardiomyocytes., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Published
2020
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19. A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions.

Author

Doisne N, Waldmann V, Redheuil A, Waintraub X, Fressart V, Ader F, Fossé L, Hidden-Lucet F, Gandjbakhch E, and Neyroud N

Subjects
Adolescent, Alleles, Base Sequence, DNA Mutational Analysis, Electrocardiography, Female, Gain of Function Mutation, Genetic Testing, Genotype, Humans, Magnetic Resonance Imaging, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Ventricular Premature Complexes drug therapy, Genetic Association Studies methods, Genetic Predisposition to Disease, Purkinje Fibers metabolism, Purkinje Fibers physiopathology, Ventricular Premature Complexes diagnosis, Ventricular Premature Complexes etiology
Abstract

Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Na v 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Na v 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC., (© 2020 Wiley Periodicals, Inc.)

Published
2020
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20. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

Author

Hébert B, Pietropaolo S, Même S, Laudier B, Laugeray A, Doisne N, Quartier A, Lefeuvre S, Got L, Cahard D, Laumonnier F, Crusio WE, Pichon J, Menuet A, Perche O, and Briault S

Subjects
Animals, Fragile X Syndrome genetics, Humans, Mice, Mice, Knockout, Phenotype, Fragile X Mental Retardation Protein genetics, Fragile X Syndrome prevention & control, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits physiology
Abstract

Background: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes., Methods and Results: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 μM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice., Conclusion: These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.

Published
2014
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21. Combined Na(+)/Ca(2+) exchanger and L-type calcium channel block as a potential strategy to suppress arrhythmias and maintain ventricular function.

Author

Bourgonje VJ, Vos MA, Ozdemir S, Doisne N, Acsai K, Varro A, Sztojkov-Ivanov A, Zupko I, Rauch E, Kattner L, Bito V, Houtman M, van der Nagel R, Beekman JD, van Veen TA, Sipido KR, and Antoons G

Subjects
Action Potentials drug effects, Animals, Anti-Arrhythmia Agents, Arrhythmias, Cardiac physiopathology, Calcium Channels, L-Type metabolism, Disease Models, Animal, Dogs, Electrocardiography, Heart Ventricles physiopathology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Sodium-Calcium Exchanger metabolism, Aniline Compounds pharmacology, Arrhythmias, Cardiac drug therapy, Calcium Channels, L-Type drug effects, Heart Ventricles drug effects, Phenyl Ethers pharmacology, Sodium-Calcium Exchanger antagonists & inhibitors, Ventricular Function drug effects, Ventricular Pressure drug effects
Abstract

Background: L-type calcium channel (LTCC) and Na(+)/Ca(2+) exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics., Methods and Results: Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic., Conclusions: In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.

Published
2013
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22. Catecholaminergic automatic activity in the rat pulmonary vein: electrophysiological differences between cardiac muscle in the left atrium and pulmonary vein.

Author

Doisne N, Maupoil V, Cosnay P, and Findlay I

Subjects
Adrenergic Agonists pharmacology, Adrenergic Antagonists pharmacology, Animals, Electrophysiology, Heart Atria, In Vitro Techniques, Male, Membrane Potentials drug effects, Microelectrodes, Myocardium, Rats, Rats, Wistar, Catecholamines physiology, Heart physiology, Pulmonary Veins physiology
Abstract

Ectopic activity in cardiac muscle within pulmonary veins (PVs) is associated with the onset and the maintenance of atrial fibrillation in humans. The mechanism underlying this ectopic activity is unknown. Here we investigate automatic activity generated by catecholaminergic stimulation in the rat PV. Intracellular microelectrodes were used to record electrical activity in isolated strips of rat PV and left atrium (LA). The resting cardiac muscle membrane potential was lower in PV [-70 +/- 1 (SE) mV, n = 8] than in LA (-85 +/- 1 mV, n = 8). No spontaneous activity was recorded in PV or LA under basal conditions. Norepinephrine (10(-5) M) induced first a hyperpolarization (-8 +/- 1 mV in PV, -3 +/- 1 mV in LA, n = 8 for both) then a slowly developing depolarization (+21 +/- 2 mV after 15 min in PV, +1 +/- 2 mV in LA) of the resting membrane potential. Automatic activity occurred only in PV; it was triggered at approximately -50 mV, and it occurred as repetitive bursts of slow action potentials. The diastolic membrane potential increased during a burst and slowly depolarized between bursts. Automatic activity in the PV was blocked by either atenolol or prazosine, and it could be generated with a mixture of cirazoline and isoprenaline. In both tissues, cirazoline (10(-6) M) induced a depolarization (+37 +/- 2 mV in PV, n = 5; +5 +/- 1 mV in LA, n = 5), and isoprenaline (10(-7) M) evoked a hyperpolarization (-11 +/- 3 mV in PV, n = 7; -3 +/- 1 mV in LA, n = 6). The differences in membrane potential and reaction to adrenergic stimulation lead to automatic electrical activity occurring specifically in cardiac muscle in the PV.

Published
2009
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