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6. Analysis of the contribution of Ito to repolarization in canine ventricular myocardium

Author

Universitat Politècnica de València. Instituto Interuniversitario de Investigación en Bioingeniería y Tecnología Orientada al Ser Humano - Institut Interuniversitari d'Investigació en Bioenginyeria i Tecnologia Orientada a l'Ésser Humà, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Hungarian Scientific Research Fund, Ministry of Human Capacities, Hungría, National Office for Research and Technology, Hungría, Hungarian Academy of Sciences, Ministerio de Ciencia e Innovación, Generalitat Valenciana, National Development Agency, Hungría, European Commission, Virag, L., Jost, N., Papp, R., Koncz, I., Kristof, A., Kohajda, Z., Harmati, G., Carbonell Pascual, Beatriz, Ferrero De Loma-Osorio, José María, Papp, J. G., Nanasi, P. P., Varro, A., Universitat Politècnica de València. Instituto Interuniversitario de Investigación en Bioingeniería y Tecnología Orientada al Ser Humano - Institut Interuniversitari d'Investigació en Bioenginyeria i Tecnologia Orientada a l'Ésser Humà, Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica, Hungarian Scientific Research Fund, Ministry of Human Capacities, Hungría, National Office for Research and Technology, Hungría, Hungarian Academy of Sciences, Ministerio de Ciencia e Innovación, Generalitat Valenciana, National Development Agency, Hungría, European Commission, Virag, L., Jost, N., Papp, R., Koncz, I., Kristof, A., Kohajda, Z., Harmati, G., Carbonell Pascual, Beatriz, Ferrero De Loma-Osorio, José María, Papp, J. G., Nanasi, P. P., and Varro, A.

Abstract

[EN] BACKGROUND AND PURPOSE The contribution of the transient outward potassium current (Ito) to ventricular repolarization is controversial as it depends on the experimental conditions, the region of myocardium and the species studied. The aim of the present study was therefore to characterize Ito and estimate its contribution to repolarization reserve in canine ventricular myocardium. EXPERIMENTAL APPROACH Ion currents were recorded using conventional whole-cell voltage clamp and action potential voltage clamp techniques in canine isolated ventricular cells. Action potentials were recorded from canine ventricular preparations using microelectrodes. The contribution of Ito to repolarization was studied using 100 µM chromanol 293B in the presence of 0.5 µM HMR 1556, which fully blocks IKs. KEY RESULTS The high concentration of chromanol 293B used effectively suppressed Ito without affecting other repolarizing K+ currents (IK1, IKr, Ip). Action potential clamp experiments revealed a slowly inactivating and a ‘late’ chromanol-sensitive current component occurring during the action potential plateau. Action potentials were significantly lengthened by chromanol 293B in the presence of HMR 1556. This lengthening effect induced by Ito inhibition was found to be reverse rate-dependent. It was significantly augmented after additional attenuation of repolarization reserve by 0.1 µM dofetilide and this caused the occurrence of early afterdepolarizations. The results were confirmed by computer simulation. CONCLUSIONS AND IMPLICATIONS The results indicate that Ito is involved in regulating repolarization in canine ventricular myocardium and that it contributes significantly to the repolarization reserve. Therefore, blockade of Ito may enhance pro-arrhythmic risk.

Published
2011

7. Mechanism of reverse rate-dependent action of cardioactive agents

Author

Bányász, T, Bárándi, L, Harmati, G, Virág, L, Szentandrássy, N, Márton, I, Zaza, A, Varró, A, Nánási, P, Nánási, P., ZAZA, ANTONIO, Bányász, T, Bárándi, L, Harmati, G, Virág, L, Szentandrássy, N, Márton, I, Zaza, A, Varró, A, Nánási, P, Nánási, P., and ZAZA, ANTONIO

Abstract

Class 3 antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD), i.e. changes in APD are greater at longer than at shorter cycle lengths. In spite of the several theories developed to explain this reverse rate-dependency, its mechanism has been clarified only recently. The aim of the present study is to elucidate the mechanisms responsible for reverse rate-dependency in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit, guinea pig, and rat ventricular myocardium in a rate-dependent manner. Rate-dependent drug-effects of various origin were studied using agents known to lengthen or shorten action potentials allowing thus to determine the drug-induced changes in APD as a function of the cycle length. Both drug-induced lengthening and shortening of action potentials displayed reverse rate-dependency in human, canine, and guinea pig preparations, but not in rabbit and rat myocardium. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In contrast to reverse rate-dependence, drug-induced changes in APD well correlated with baseline APD values (i.e. that measured before the superfusion of drug or injection of current) in all of the preparations studied. Since the net membrane current (I(net)), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking I(net) to APD. In summary, reverse rate-dependency is an intrinsic property of drug action in the hearts of species showing positive APD - cycle length relationship, including humans. This implies that development of a pure K(+) channel blocking agent without reverse rate-dependent effects is not likely to be successf

Published
2011

8. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations

Author

Bárándi, L, Virág, L, Jost, N, Horváth, Z, Koncz, I, Papp, R, Harmati, G, Horváth, B, Szentandrássy, N, Bányász, T, Magyar, J, Zaza, A, Varró, A, Nánási, P, ZAZA, ANTONIO, Nánási, PP, Bárándi, L, Virág, L, Jost, N, Horváth, Z, Koncz, I, Papp, R, Harmati, G, Horváth, B, Szentandrássy, N, Bányász, T, Magyar, J, Zaza, A, Varró, A, Nánási, P, ZAZA, ANTONIO, and Nánási, PP

Abstract

Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate-dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for RRD in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit and guinea pig ventricular myocardium in a rate-dependent manner varying the cycle length (CL) between 0.3 and 5 s. Rate-dependent drug effects were studied using agents known to lengthen or shorten action potentials, and these drug-induced changes in APD were correlated with baseline APD values. Both drug-induced lengthening (by dofetilide, Sotalol, E-4031, BaCl2, veratrine, BAY K 8644) and shortening (by mexiletine, tetrodotoxin, lemakalim) of action potentials displayed RRD, i.e., changes in APD were greater at longer than at shorter CLs. In rabbit, where APD is a biphasic function of CL, the drug-induced APD changes were proportional to baseline APD values but not to CL. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In each case the change in APD was proportional to baseline APD (i.e., that measured before the superfusion of drug or injection of current). Also, the net membrane current (Inet), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD and consequently with to CL. The results indicate that RRD is a common characteristic of all the drugs tested regardless of the modified ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between Inet and APD. © Springer-Verlag 2010.

Published
2010

9. Reverse rate dependency is an intrinsic property of canine cardiac preparations

Author

Bányász, T, Horváth, B, Virág, L, Bárándi, L, Szentandrássy, N, Harmati, G, Magyar, J, Marangoni, S, Zaza, A, Varró, A, Nánási, P, Nánási, PP, MARANGONI, STEFANO FEDERICO, ZAZA, ANTONIO, Bányász, T, Horváth, B, Virág, L, Bárándi, L, Szentandrássy, N, Harmati, G, Magyar, J, Marangoni, S, Zaza, A, Varró, A, Nánási, P, Nánási, PP, MARANGONI, STEFANO FEDERICO, and ZAZA, ANTONIO

Abstract

AIMS: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects. METHODS AND RESULTS: Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CLs) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (I(m)) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between I(m) and APD was tested by numerical modelling. Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl(2)) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. I(m) measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between I(m) and APD. CONCLUSION: RRD of APD modulation is shared, although with differences in magnitude, by interventions of very different nature. RRD can be interpreted as a consequence of the relationship between I(m) and APD and, as such, is expected in all species having positive APD-CL relationship. This implies that the development of agents prolonging APD with direct rate dependency, or even completely devoid of RRD, may be difficult to achieve.

Published
2009

16. Sunday, 18 July 2010

Author

Schuchardt, M., primary, Toelle, M., additional, Huang, T., additional, Wiedon, A., additional, Van Der Giet, M., additional, Mill, C., additional, George, S., additional, Jeremy, J., additional, Santulli, G., additional, Illario, M., additional, Cipolletta, E., additional, Sorriento, D., additional, Del Giudice, C., additional, Anastasio, A., additional, Trimarco, B., additional, Iaccarino, G., additional, Jobs, A., additional, Wagner, C., additional, Kurtz, A., additional, De Wit, C., additional, Koller, A., additional, Suvorava, T., additional, Weber, M., additional, Dao, V., additional, Kojda, G., additional, Tsaousi, A., additional, Lyon, C., additional, Williams, H., additional, Barth, N., additional, Loot, A., additional, Fleming, I., additional, Keul, P., additional, Lucke, S., additional, Graeler, M., additional, Heusch, G., additional, Levkau, B., additional, Biessen, E., additional, De Jager, S., additional, Bermudez-Pulgarin, B., additional, Bot, I., additional, Abia, R., additional, Van Berkel, T., additional, Renger, A., additional, Noack, C., additional, Zafiriou, M., additional, Dietz, R., additional, Bergmann, M., additional, Zelarayan, L., additional, Hammond, J., additional, Hamelet, J., additional, Van Assche, T., additional, Belge, C., additional, Vanderper, A., additional, Langin, D., additional, Herijgers, P., additional, Balligand, J., additional, Perrot, A., additional, Neubert, M., additional, Posch, M., additional, Oezcelik, C., additional, Waldmuller, S., additional, Berger, F., additional, Scheffold, T., additional, Bouvagnet, P., additional, Ozcelik, C., additional, Lebreiro, A., additional, Martins, E., additional, Lourenco, P., additional, Cruz, C., additional, Martins, M., additional, Bettencourt, P., additional, Maciel, M., additional, Abreu-Lima, C., additional, Pilichou, K., additional, Bauce, B., additional, Rampazzo, A., additional, Carturan, E., additional, Corrado, D., additional, Thiene, G., additional, Basso, C., additional, Piccini, I., additional, Fortmueller, L., additional, Kuhlmann, M., additional, Schaefers, M., additional, Carmeliet, P., additional, Kirchhof, P., additional, Fabritz, L., additional, Sanchez, J., additional, Rodriguez-Sinovas, A., additional, Agullo, E., additional, Garcia-Dorado, D., additional, Lymperopoulos, A., additional, Rengo, G., additional, Gao, E., additional, Zincarelli, C., additional, Koch, W., additional, Morgan, P., additional, Diez, A., additional, Perez, N., additional, Cingolani, H., additional, Zahradnikova, A., additional, Polakova, E., additional, Zahradnik, I., additional, Fluschnik, N., additional, Sossalla, S., additional, Ort, K., additional, Neef, S., additional, Hasenfuss, G., additional, Maier, L., additional, Weinert, S., additional, Poitz, D., additional, Herold, J., additional, Schmeisser, A., additional, Strasser, J., additional, Braun-Dullaeus, R., additional, Nazari-Jahantigh, M., additional, Weber, C., additional, Schober, A., additional, Leuner, A., additional, Eichhorn, B., additional, Ravens, U., additional, Morawietz, H., additional, Babes, E., additional, Babes, V., additional, Popescu, M., additional, Ardelean, A., additional, Rus, M., additional, Bustea, C., additional, Gwozdz, P., additional, Csanyi, G., additional, Luzak, B., additional, Gajda, M., additional, Mateuszuk, L., additional, Chmura-Skirlinska, A., additional, Watala, C., additional, Chlopicki, S., additional, Kierzkowska, I., additional, Sulicka, J., additional, Kwater, A., additional, Strach, M., additional, Surdacki, A., additional, Siedlar, M., additional, Grodzicki, T., additional, Olieslagers, S., additional, Pardali, L., additional, Tchaikovski, V., additional, Ten Dijke, P., additional, Waltenberger, J., additional, Renner, M., additional, Redwan, B., additional, Winter, M., additional, Panzenboeck, A., additional, Jakowitsch, J., additional, Sadushi-Kolici, R., additional, Bonderman, D., additional, Lang, I., additional, Toso, A., additional, Tanini, L., additional, Pizzetti, T., additional, Leoncini, M., additional, Maioli, M., additional, Tedeschi, D., additional, Oliviero, C., additional, Bellandi, F., additional, Casprini, P., additional, Amato, M., additional, Molins, B., additional, Pena, E., additional, Badimon, L., additional, Ferreiro Gutierrez, J., additional, Ueno, M., additional, Alissa, R., additional, Dharmashankar, K., additional, Capodanno, D., additional, Desai, B., additional, Bass, T., additional, Angiolillo, D., additional, Chabielska, E., additional, Gromotowicz, A., additional, Szemraj, J., additional, Stankiewicz, A., additional, Zakrzeska, A., additional, Mohammed, S., additional, Molla, F., additional, Soldo, A., additional, Russo, I., additional, Germano, G., additional, Balconi, G., additional, Staszewsky, L., additional, Latini, R., additional, Lynch, F., additional, Austin, C., additional, Prendergast, B., additional, Keenan, D., additional, Malik, R., additional, Izzard, A., additional, Heagerty, A., additional, Czikora, A., additional, Lizanecz, E., additional, Rutkai, I., additional, Boczan, J., additional, Porszasz, R., additional, Papp, Z., additional, Edes, I., additional, Toth, A., additional, Colantuoni, A., additional, Vagnani, S., additional, Lapi, D., additional, Maroz-Vadalazhskaya, N., additional, Koslov, I., additional, Shumavetz, V., additional, Glibovskaya, T., additional, Ostrovskiy, Y., additional, Koutsiaris, A., additional, Tachmitzi, S., additional, Kotoula, M., additional, Giannoukas, A., additional, Tsironi, E., additional, Darago, A., additional, Orosz, P., additional, Megyesi, Z., additional, Schudeja, S., additional, Matschke, K., additional, Deussen, A., additional, Castro, M., additional, Cena, J., additional, Walsh, M., additional, Schulz, R., additional, Poddar, K., additional, Rha, S., additional, Ramasamy, S., additional, Park, J., additional, Choi, C., additional, Seo, H., additional, Park, C., additional, Oh, D., additional, Almeida, J., additional, Pimenta, S., additional, Bernardes, J., additional, Machado, J., additional, Sabatasso, S., additional, Laissue, J., additional, Hlushchuk, R., additional, Brauer-Krisch, E., additional, Bravin, A., additional, Blattmann, H., additional, Michaud, K., additional, Djonov, V., additional, Hirschberg, K., additional, Tarcea, V., additional, Pali, S., additional, Korkmaz, S., additional, Loganathan, S., additional, Merkely, B., additional, Karck, M., additional, Szabo, G., additional, Pagliani, L., additional, Faggin, E., additional, Rattazzi, M., additional, Puato, M., additional, Presta, M., additional, Grego, F., additional, Deriu, G., additional, Pauletto, P., additional, Kaiser, R., additional, Albrecht, K., additional, Schgoer, W., additional, Theurl, M., additional, Beer, A., additional, Wiedemann, D., additional, Steger, C., additional, Bonaros, N., additional, Kirchmair, R., additional, Kharlamov, A., additional, Cabaravdic, M., additional, Breuss, J., additional, Uhrin, P., additional, Binder, B., additional, Fiordaliso, F., additional, Maggioni, M., additional, Biondi, A., additional, Masson, S., additional, Cervo, L., additional, Francke, A., additional, Soenke, W., additional, Strasser, R., additional, Hecht, N., additional, Vajkoczy, P., additional, Woitzik, J., additional, Hackbusch, D., additional, Gatzke, N., additional, Duelsner, A., additional, Tsuprykov, O., additional, Slavic, S., additional, Buschmann, I., additional, Kappert, K., additional, Massaro, M., additional, Scoditti, E., additional, Carluccio, M., additional, Storelli, C., additional, Distante, A., additional, De Caterina, R., additional, Barandi, L., additional, Harmati, G., additional, Simko, J., additional, Horvath, B., additional, Szentandrassy, N., additional, Banyasz, T., additional, Magyar, J., additional, Nanasi, P., additional, Kaya, A., additional, Uzunhasan, I., additional, Yildiz, A., additional, Yigit, Z., additional, Turkoglu, C., additional, Doisne, N., additional, Zannad, N., additional, Hivert, B., additional, Cosnay, P., additional, Maupoil, V., additional, Findlay, I., additional, Virag, L., additional, Kristof, A., additional, Koncz, I., additional, Szel, T., additional, Jost, N., additional, Biliczki, P., additional, Papp, J., additional, Varro, A., additional, Bukowska, A., additional, Skopp, K., additional, Hammwoehner, M., additional, Huth, C., additional, Bode-Boeger, S., additional, Goette, A., additional, Workman, A., additional, Dempster, J., additional, Marshall, G., additional, Rankin, A., additional, Revnic, C., additional, Ginghina, C., additional, Revnic, F., additional, Yakushev, S., additional, Petrushanko, I., additional, Makhro, A., additional, Segato Komniski, M., additional, Mitkevich, V., additional, Makarov, A., additional, Gassmann, M., additional, Bogdanova, A., additional, Rutkovskiy, A., additional, Mariero, L., additional, Stenslokken, K., additional, Valen, G., additional, Vaage, J., additional, Dizayee, S., additional, Kaestner, S., additional, Kuck, F., additional, Piekorz, R., additional, Hein, P., additional, Matthes, J., additional, Nurnberg, B., additional, Herzig, S., additional, Hertel, F., additional, Switalski, A., additional, Bender, K., additional, Kienitz, M.-C., additional, Pott, L., additional, Fornai, L., additional, Angelini, A., additional, Erika Amstalden Van Hove, E., additional, Fedrigo, M., additional, Heeren, R., additional, Kruse, M., additional, Pongs, O., additional, Lehmann, H., additional, Martens-Lobenhoffer, J., additional, Roehl, F., additional, Radicke, S., additional, Cotella, C., additional, Sblattero, D., additional, Schaefer, M., additional, Wettwer, E., additional, Santoro, C., additional, Seyler, C., additional, Kulzer, M., additional, Zitron, E., additional, Scholz, E., additional, Welke, F., additional, Thomas, D., additional, Karle, C., additional, Schmidt, K., additional, Dobrev, D., additional, Houshmand, N., additional, Menesi, D., additional, Cotella, D., additional, Szuts, V., additional, Puskas, L., additional, Kiss, I., additional, Deak, F., additional, Tereshchenko, S., additional, Gladyshev, M., additional, Kalachova, G., additional, Syshchik, N., additional, Gogolashvili, N., additional, Dedok, E., additional, Evert, L., additional, Wenzel, J., additional, Brandenburger, M., additional, Bogdan, R., additional, Richardt, D., additional, Reppel, M., additional, Hescheler, J., additional, Dendorfer, A., additional, Terlau, H., additional, Wiegerinck, R., additional, Galvez-Monton, C., additional, Jorge, E., additional, Martinez, R., additional, Ricart, E., additional, Cinca, J., additional, Bagavananthem Andavan, G., additional, Lemmens Gruber, R., additional, Brack, K., additional, Coote, J., additional, Ng, G., additional, Daimi, H., additional, Haj Khelil, A., additional, Neji, A., additional, Ben Hamda, K., additional, Maaoui, S., additional, Aranega, A., additional, Chibani, J., additional, Franco Jaime, D., additional, Tanko, A.-S., additional, Daniel, J.-M., additional, Bielenberg, W., additional, Stieger, P., additional, Tillmanns, H., additional, Sedding, D., additional, Fortini, C., additional, Toffoletto, B., additional, Fucili, A., additional, Beltrami, A., additional, Fiorelli, V., additional, Francolini, G., additional, Ferrari, R., additional, Beltrami, C., additional, Castellani, C., additional, Ravara, B., additional, Tavano, R., additional, Vettor, R., additional, De Coppi, P., additional, Papini, E., additional, Gunetti, M., additional, Fagioli, F., additional, Suffredini, S., additional, Sartiani, L., additional, Stillitano, F., additional, Mugelli, A., additional, Cerbai, E., additional, Krausgrill, B., additional, Halbach, M., additional, Soemantri, S., additional, Schenk, K., additional, Lange, N., additional, Saric, T., additional, Muller-Ehmsen, J., additional, Kavanagh, D., additional, Zhao, Y., additional, Yemm, A., additional, Kalia, N., additional, Wright, E., additional, Farrell, K., additional, Wallrapp, C., additional, Geigle, P., additional, Lewis, A., additional, Stratford, P., additional, Malik, N., additional, Holt, C., additional, Raths, M., additional, Zagallo, M., additional, Luni, C., additional, Serena, E., additional, Cimetta, E., additional, Zatti, S., additional, Giobbe, G., additional, Elvassore, N., additional, Zaglia, T., additional, Zambon, A., additional, Gordon, K., additional, Mioulane, M., additional, Foldes, G., additional, Ali, N., additional, Harding, S., additional, Gorbe, A., additional, Szunyog, A., additional, Varga, Z., additional, Pirity, M., additional, Rungaruniert, S., additional, Dinnyes, A., additional, Csont, T., additional, Ferdinandy, P., additional, Iqbal, A., additional, Schneider, M. D., additional, Khodjaeva, E., additional, Ibadov, R., additional, Khalikulov, K., additional, Mansurov, A., additional, Astvatsatryan, A., additional, Senan, M., additional, Nemeth, A., additional, Lenkey, Z., additional, Ajtay, Z., additional, Cziraki, A., additional, Sulyok, E., additional, Horvath, I., additional, Lobenhoffer, J., additional, Bode-Boger, S., additional, Li, J., additional, He, Y., additional, Yang, X., additional, Wang, F., additional, Xu, H., additional, Li, X., additional, Zhao, X., additional, Lin, Y., additional, Juszynski, M., additional, Ciszek, B., additional, Jablonska, A., additional, Stachurska, E., additional, Ratajska, A., additional, Atkinson, A., additional, Inada, S., additional, Sleiman, R., additional, Zhang, H., additional, Boyett, M., additional, Dobrzynski, H., additional, Fedorenko, O., additional, Hao, G., additional, Yanni, J., additional, Buckley, D., additional, Anderson, R., additional, Ma, Y., additional, Ma, X., additional, Hu, Y., additional, Yang, Y., additional, Huang, D., additional, Liu, F., additional, Huang, Y., additional, Liu, C., additional, Jedrzejczyk, T., additional, Balwicki, L., additional, Wierucki, L., additional, Zdrojewski, T., additional, Agarkova, I., additional, Vogel, J., additional, Korybalska, K., additional, Pyda, M., additional, Witowski, J., additional, Ibatov, A., additional, Sozmen, N., additional, Seymen, A., additional, Tuncay, E., additional, Turan, B., additional, Chen, B., additional, Houston-Feenstra, L., additional, Chiong, J. R., additional, Jutzy, K., additional, Furundzija, V., additional, Kaufmann, J., additional, Meyborg, H., additional, Fleck, E., additional, Stawowy, P., additional, Ksiezycka-Majczynska, E., additional, Lubiszewska, B., additional, Kruk, M., additional, Kurjata, P., additional, Ruzyllo, W., additional, Driesen, R., additional, Coenen, T., additional, Fagard, R., additional, Sipido, K., additional, Petrov, V., additional, Aksentijevic, D., additional, Lygate, C., additional, Makinen, K., additional, Sebag-Montefiore, L., additional, Medway, D., additional, Schneider, J., additional, Neubauer, S., additional, Gasser, R., additional, Holzwart, E., additional, Rainer, P., additional, Von Lewinski, D., additional, Maechler, H., additional, Gasser, S., additional, Roessl, U., additional, Pieske, B., additional, Krueger, J., additional, Kintscher, U., additional, Podramagi, T., additional, Paju, K., additional, Piirsoo, A., additional, Roosimaa, M., additional, Kadaja, L., additional, Orlova, E., additional, Ruusalepp, A., additional, Seppet, E., additional, Auquier, J., additional, Ginion, A., additional, Hue, L., additional, Horman, S., additional, Beauloye, C., additional, Vanoverschelde, J., additional, Bertrand, L., additional, Fekete, V., additional, Zvara, A., additional, Pipis, J., additional, Konya, C., additional, Csonka, C., additional, Kraigher-Krainer, E., additional, Von Lewinksi, D., additional, Gonzalez-Loyola, A., additional, Barba, I., additional, Fernandez-Sanz, C., additional, Ruiz-Meana, M., additional, Forteza, M., additional, Bodi Peris, V., additional, Monleon, D., additional, Mainar, L., additional, Morales, J., additional, Moratal, D., additional, Trapero, I., additional, Chorro, F., additional, Leszek, P., additional, Sochanowicz, B., additional, Szperl, M., additional, Kolsut, P., additional, Piotrowski, W., additional, Rywik, T., additional, Danko, B., additional, Kruszewski, M., additional, Stanley, W., additional, Khairallah, R., additional, Khanna, N., additional, O'shea, K., additional, Kristian, T., additional, Hecker, P., additional, Des Rosiers, R., additional, Fiskum, G., additional, Fernandez-Alfonso, M., additional, Guzman-Ruiz, R., additional, Somoza, B., additional, Gil-Ortega, M., additional, Attane, C., additional, Castan-Laurell, I., additional, Valet, P., additional, Ruiz-Gayo, M., additional, Denissevich, T., additional, Schrepper, A., additional, Schwarzer, M., additional, Amorim, P., additional, Schoepe, M., additional, Mohr, F., additional, Doenst, T., additional, Chiellini, G., additional, Ghelardoni, S., additional, Saba, A., additional, Marchini, M., additional, Frascarelli, S., additional, Raffaelli, A., additional, Scanlan, T., additional, Zucchi, R., additional, Van Den Akker, N., additional, Molin, D., additional, Kolk, F., additional, Jeukens, F., additional, Olde Engberink, R., additional, Post, M., additional, Verbruggen, S., additional, Schulten, H., additional, Rochais, F., 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Dyer, E., additional, Leung, M.-C., additional, Monserrat, L., additional, Marston, S., additional, Fusco, A., additional, Paillard, M., additional, Liang, J., additional, Strub, G., additional, Gomez, L., additional, Hait, N., additional, Allegood, J., additional, Lesnefsky, E., additional, Spiegel, S., additional, Zuchi, C., additional, Coiro, S., additional, Bettini, M., additional, Ciliberti, G., additional, Mancini, I., additional, Tritto, I., additional, Becker, L., additional, Ambrosio, G., additional, Adam, T., additional, Sharp, S., additional, Opie, L., additional, Lecour, S., additional, Khaliulin, I., additional, Parker, J., additional, Halestrap, A., additional, Kandasamy, A., additional, Osterholt, M., additional, Miro-Casas, E., additional, Boengler, K., additional, Menazza, S., additional, Canton, M., additional, Sheeran, F., additional, Di Lisa, F., additional, Pepe, S., additional, Borchi, E., additional, Manni, M., additional, Bargelli, V., additional, Giordano, C., additional, D'amati, G., additional, Nediani, C., additional, Raimondi, L., additional, Micova, P., additional, Balkova, P., additional, Kolar, F., additional, Neckar, J., additional, Novak, F., additional, Novakova, O., additional, Schuchardt, M., additional, Pruefer, N., additional, Pruefer, J., additional, Jankowski, V., additional, Jankowski, J., additional, Su, Y., additional, Zervou, S., additional, Seidel, B., additional, Radovits, T., additional, Barnucz, E., additional, Aggeli, I., additional, Kefaloyianni, E., additional, Beis, I., additional, Gaitanaki, C., additional, Lacerda, L., additional, Somers, S., additional, Paur, H., additional, Nikolaev, V., additional, Lyon, A., additional, Silva, S., additional, Gomes, M., additional, Ferreira, P., additional, Capuano, V., additional, Ferron, L., additional, Ruchon, Y., additional, Ben Mohamed, F., additional, Renaud, J.-F., additional, Goncalves, N., additional, Gavina, C., additional, Pinho, S., additional, Moura, C., additional, Amorim, M., additional, Pinho, P., additional, Christ, T., additional, Molenaar, P., additional, Kaumann, A., additional, Kletsiou, E., additional, Giannakopoulou, M., additional, Bozas, E., additional, Iliodromitis, E., additional, Anastasiou-Nana, M., additional, Papathanassoglou, E., additional, Chottova Dvorakova, M., additional, Mistrova, E., additional, Slavikova, J., additional, Hynie, S., additional, Sida, P., additional, Klenerova, V., additional, Zakrzewicz, A., additional, Hoffmann, C., additional, Hohberg, M., additional, Chlench, S., additional, Maroski, J., additional, Drab, M., additional, Siegel, G., additional, Pries, A., additional, Schrot, G., additional, Wilck, N., additional, Fechner, M., additional, Arias, A., additional, Meiners, S., additional, Baumann, G., additional, Stangl, V., additional, Stangl, K., additional, Ludwig, A., additional, Christ, A., additional, Eijgelaar, W., additional, Daemen, M., additional, Penfold, M., additional, Schall, T., additional, Hintenberger, R., additional, Kaun, C., additional, Pfaffenberger, S., additional, Maurer, G., additional, Huber, K., additional, Wojta, J., additional, Demyanets, S., additional, Titov, V., additional, Chin-Dusting, J., additional, Vaisman, B., additional, Khong, S., additional, Remaley, A., additional, Andrews, K., additional, Hoeper, A., additional, Khalid, A., additional, Fuglested, B., additional, Aasum, E., additional, Larsen, T., additional, Diebold, I., additional, Petry, A., additional, Djordjevic, T., additional, Belaiba, R., additional, Fratz, S., additional, Hess, J., additional, Kietzmann, T., additional, Goerlach, A., additional, Chess, D., additional, Walsh, K., additional, Van Der Velden, J., additional, Moreira-Goncalves, D., additional, Paulus, W., additional, Niessen, H., additional, Perlini, S., additional, Azibani, F., additional, Tournoux, F., additional, Fazal, L., additional, Polidano, E., additional, Merval, R., additional, Chatziantoniou, C., additional, Samuel, J., additional, Delcayre, C., additional, Mgandela, P., additional, Brooksbank, R., additional, Maswanganyi, T., additional, Woodiwiss, A., additional, Norton, G., additional, Makaula, S., additional, Bucciantini, M., additional, Spinelli, V., additional, Coppini, R., additional, Russo, E., additional, Stefani, M., additional, Sukumaran, V., additional, Watanabe, K., additional, Ma, M., additional, Thandavarayan, R., additional, Azrozal, W., additional, Sari, F., additional, Shimazaki, H., additional, Kobayashi, Y., additional, Roleder, T., additional, Golba, K., additional, Deja, M., additional, Malinowski, M., additional, Wos, S., additional, Grebe, M., additional, Preissner, K., additional, Ercan, E., additional, Guven, A., additional, Asgun, F., additional, Ickin, M., additional, Ercan, F., additional, Kaplan, A., additional, Yavuz, O., additional, Bagla, S., additional, Kuka, J., additional, Vilskersts, R., additional, Vavers, E., additional, Liepins, E., additional, Dambrova, M., additional, Duerr, G., additional, Suchan, G., additional, Heuft, T., additional, Klaas, T., additional, Zimmer, A., additional, Welz, A., additional, Fleischmann, B., additional, Dewald, O., additional, Voelkl, J., additional, Haubner, B., additional, Kremser, C., additional, Mayr, A., additional, Klug, G., additional, Reiner, M., additional, Pachinger, O., additional, Metzler, B., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Pelogeykina, Y., additional, Khatri, D., additional, Studneva, I., additional, Bencsik, P., additional, Kocsis, G., additional, Shamloo, M., additional, Woodburn, K., additional, Szucs, G., additional, Kupai, K., additional, Csont, C., additional, Kocsisne Fodor, G., additional, Monostori, P., additional, and Turi, S., additional

Published
2010
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17. Mechanism of reverse rate-dependent action of cardioactive agents

Author

Gábor Harmati, Antonio Zaza, Norbert Szentandrássy, László Bárándi, László Virág, András Varró, Péter P. Nánási, Tamás Bányász, Ildikó Márton, Bányász, T, Bárándi, L, Harmati, G, Virág, L, Szentandrássy, N, Márton, I, Zaza, A, Varró, A, and Nánási, P

Subjects
Potassium Channel Blocker, Heart Ventricles, Guinea Pigs, Action Potentials, Rabbit, Drug action, Pharmacology, Biology, Klinikai orvostudományok, Biochemistry, Guinea Pig, Heart Ventricle, Guinea pig, Dogs, Heart Rate, Drug Discovery, Dog, Potassium Channel Blockers, medicine, Animals, Humans, Ventricular Function, Repolarization, Myocytes, Cardiac, Action Potential, Potassium Channels, Inwardly Rectifying, Animal, Organic Chemistry, Rate dependent, Potassium channel blocker, Orvostudományok, Membrane current, Rats, Anti-Arrhythmia Agent, cardiovascular system, Biophysics, Rat, Molecular Medicine, Action potential duration, Rabbits, Anti-Arrhythmia Agents, Microelectrodes, Human, medicine.drug
Abstract

Class 3 antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD), i.e. changes in APD are greater at longer than at shorter cycle lengths. In spite of the several theories developed to explain this reverse rate-dependency, its mechanism has been clarified only recently. The aim of the present study is to elucidate the mechanisms responsible for reverse rate-dependency in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit, guinea pig, and rat ventricular myocardium in a rate-dependent manner. Rate-dependent drug-effects of various origin were studied using agents known to lengthen or shorten action potentials allowing thus to determine the drug-induced changes in APD as a function of the cycle length. Both drug-induced lengthening and shortening of action potentials displayed reverse rate-dependency in human, canine, and guinea pig preparations, but not in rabbit and rat myocardium. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In contrast to reverse rate-dependence, drug-induced changes in APD well correlated with baseline APD values (i.e. that measured before the superfusion of drug or injection of current) in all of the preparations studied. Since the net membrane current (I(net)), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking I(net) to APD. In summary, reverse rate-dependency is an intrinsic property of drug action in the hearts of species showing positive APD - cycle length relationship, including humans. This implies that development of a pure K(+) channel blocking agent without reverse rate-dependent effects is not likely to be successful.

Published
2011

18. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations

Author

Balázs Horváth, Zoltán Horváth, László Virág, Norbert Szentandrássy, Antonio Zaza, László Bárándi, János Magyar, Norbert Jost, Gábor Harmati, András Varró, Rita Papp, István Koncz, Tamás Bányász, Péter P. Nánási, Bárándi, L, Virág, L, Jost, N, Horváth, Z, Koncz, I, Papp, R, Harmati, G, Horváth, B, Szentandrássy, N, Bányász, T, Magyar, J, Zaza, A, Varró, A, and Nánási, P

Subjects
Patch-Clamp Techniques, Time Factors, Physiology, Guinea Pigs, Action Potentials, Dofetilide, Action potential duration, Tetrodotoxin, Pharmacology, Membrane Potentials, chemistry.chemical_compound, Dogs, Membrane current, BIO/09 - FISIOLOGIA, Heart Rate, Physiology (medical), Mexiletine, medicine, Repolarization, Myocyte, Animals, Humans, Ventricular Function, Myocytes, Cardiac, Patch clamp, 03.02. Klinikai orvostan, Human myocardium, Chemistry, musculoskeletal, neural, and ocular physiology, Sotalol, Mammalian cardiac cell, Ion current, 03.01. Általános orvostudomány, General Medicine, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Ventricular repolarization, Calcium Channel Agonists, Models, Animal, Reverse rate dependence, cardiovascular system, Rabbits, Cardiology and Cardiovascular Medicine, Anti-Arrhythmia Agents, medicine.drug, Sodium Channel Blockers
Abstract

Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate-dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for RRD in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit and guinea pig ventricular myocardium in a rate-dependent manner varying the cycle length (CL) between 0.3 and 5 s. Rate-dependent drug effects were studied using agents known to lengthen or shorten action potentials, and these drug-induced changes in APD were correlated with baseline APD values. Both drug-induced lengthening (by dofetilide, Sotalol, E-4031, BaCl2, veratrine, BAY K 8644) and shortening (by mexiletine, tetrodotoxin, lemakalim) of action potentials displayed RRD, i.e., changes in APD were greater at longer than at shorter CLs. In rabbit, where APD is a biphasic function of CL, the drug-induced APD changes were proportional to baseline APD values but not to CL. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In each case the change in APD was proportional to baseline APD (i.e., that measured before the superfusion of drug or injection of current). Also, the net membrane current (Inet), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD and consequently with to CL. The results indicate that RRD is a common characteristic of all the drugs tested regardless of the modified ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between Inet and APD. © Springer-Verlag 2010.

Published
2010

19. Reverse rate dependency is an intrinsic property of canine cardiac preparations

Author

Stefano Marangoni, Norbert Szentandrássy, László Bárándi, Péter P. Nánási, Antonio Zaza, László Virág, Balázs Horváth, János Magyar, Gábor Harmati, András Varró, Tamás Bányász, Bányász, T, Horváth, B, Virág, L, Bárándi, L, Szentandrássy, N, Harmati, G, Magyar, J, Marangoni, S, Zaza, A, Varró, A, Nánási, P, Élettani Intézet -- 10, ÁOK -- OEC, and Debreceni Egyetem

Subjects
Male, Time Factors, Physiology, Barium Compounds, Action Potentials, 030204 cardiovascular system & hematology, Veratrine, 0302 clinical medicine, BIO/09 - FISIOLOGIA, Myocyte, Myocytes, Cardiac, Rate dependency, Nicorandil, Sulfonamides, 0303 health sciences, Pulse (signal processing), musculoskeletal, neural, and ocular physiology, Cardiac Pacing, Artificial, Models, Cardiovascular, Orvostudományok, cardiovascular system, Action potential duration, Female, Cardiology and Cardiovascular Medicine, Anti-Arrhythmia Agents, medicine.drug, circulatory and respiratory physiology, medicine.medical_specialty, Heart Ventricles, Biophysics, Dofetilide, In Vitro Techniques, Klinikai orvostudományok, Purkinje Fibers, 03 medical and health sciences, Dogs, Chlorides, Physiology (medical), Internal medicine, Phenethylamines, medicine, Repolarization, Animals, Computer Simulation, 030304 developmental biology, business.industry, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Membrane current, rate-dependency, action potential, action potential duration, reverse rate dependence, ventricular repolarization, membrane current, dog myocytes, Endocrinology, Nonlinear Dynamics, business, 030217 neurology & neurosurgery
Abstract

AIMS: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects. METHODS AND RESULTS: Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CLs) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (I(m)) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between I(m) and APD was tested by numerical modelling. Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl(2)) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. I(m) measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between I(m) and APD. CONCLUSION: RRD of APD modulation is shared, although with differences in magnitude, by interventions of very different nature. RRD can be interpreted as a consequence of the relationship between I(m) and APD and, as such, is expected in all species having positive APD-CL relationship. This implies that the development of agents prolonging APD with direct rate dependency, or even completely devoid of RRD, may be difficult to achieve.

Published
2009

20. Age-dependent changes in ion channel mRNA expression in canine cardiac tissues.

Author

Gönczi M, Birinyi P, Balázs B, Szentandrássy N, Harmati G, Könczei Z, Csernoch L, and Nánási PP

Subjects
Animals, Animals, Newborn, Dogs, Heart embryology, Ion Channels genetics, Models, Animal, Gene Expression Regulation, Developmental physiology, Heart growth & development, Ion Channels metabolism, Myocardium metabolism, RNA metabolism
Abstract

The expression pattern of cardiac ion channels displays marked changes during ontogeny. This study was designed to follow the developmental changes in the expression of major ventricular and atrial ion channel proteins (including both pore forming and regulatory subunits) in canine cardiac tissues at the mRNA level using competitive reverse transcription polymerase chain reaction. Therefore, the corresponding mRNA levels were compared in myocardial tissues excised from embryonic (25-60 days of gestation) and adult (2-3 years old) canine hearts. Expression level of Kv4.3, Kv1.4, KChIP2, KvLQT1, and Cav3.2 mRNAs were higher in the adult than in the embryonic hearts, while expression of Nav1.5 and minK mRNAs were higher in the embryonic than in the adult myocardium. No change in Kir2.1, HERG, Kv1.5, and Cav1.2 mRNA was observed during ontogeny. Direction of the developmental change in the mRNA level, determined for any specific channel protein, was identical in the atrial and ventricular samples. The age-dependent increase observed in the expression of Kv4.3, Kv1.4, KChIP2, and KvLQT1 is congruent with the greater repolarization reserve of the adult myocardium, associated with higher densities of Ito and IKs. The results indicate that age-dependent changes in the expression pattern of many ion channels are similar in canine and healthy human myocardium, therefore, canine cardiac muscle can be considered as a good model of studying developmental changes in the human heart.

Published
2012
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21. Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents.

Author

Harmati G, Papp F, Szentandrássy N, Bárándi L, Ruzsnavszky F, Horváth B, Bányász T, Magyar J, Panyi G, Krasznai Z, and Nánási PP

Subjects
Animals, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, HEK293 Cells, Humans, Myocytes, Cardiac enzymology, Myocytes, Cardiac metabolism, Time Factors, Transfection, Benzophenanthridines pharmacology, Delayed Rectifier Potassium Channels antagonists & inhibitors, Indoles pharmacology, Maleimides pharmacology, Myocytes, Cardiac drug effects, Protein Kinase C antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
Abstract

Protein kinase C (PKC) inhibitors are useful tools for studying PKC-dependent regulation of ion channels. For this purpose, high PKC specificity is a basic requirement excluding any direct interaction between the PKC inhibitor and the ion channel. In the present study, the effects of two frequently applied PKC inhibitors, chelerythine and bisindolylmaleimide I, were studied on the rapid and slow components of the delayed rectifier K(+) current (I(Kr) and I(Ks)) in canine ventricular cardiomyocytes and on the human ether-à-go-go-related gene (hERG) channels expressed in human embryonic kidney (HEK) cells. The whole cell version of the patch clamp technique was used in all experiments. Chelerythrine and bisindolylmaleimide I (both 1 μM) suppressed I(Kr) in canine ventricular cells. This inhibition developed rapidly, suggesting a direct drug-channel interaction. In HEK cells heterologously expressing hERG channels, chelerythrine and bisindolylmaleimide I blocked hERG current in a concentration-dependent manner, having EC(50) values of 0.11 ± 0.01 and 0.76 ± 0.04 μM, respectively. Both chelerythrine and bisindolylmaleimide I strongly modified gating kinetics of hERG--voltage dependence of activation was shifted towards more negative voltages and activation was accelerated. Deactivation was slowed by bisindolylmaleimide I but not by chelerythrine. I(Ks) was not significantly altered by bisindolylmaleimide I and chelerythrine. No significant effect of 0.1 μM bisindolylmaleimide I or 0.1 μM PMA (PKC activator) was observed on I(Kr) arguing against significant contribution of PKC to regulation of I(Kr). It is concluded that neither chelerythrine nor bisindolylmaleimide I is suitable for selective PKC blockade due to their direct blocking actions on the hERG channel.

Published
2011
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22. Xanthine derivatives in the heart: blessed or cursed?

Author

Szentmiklósi AJ, Cseppentō A, Gesztelyi R, Zsuga J, Körtvély A, Harmati G, and Nánási PP

Subjects
Action Potentials drug effects, Animals, Caffeine pharmacology, Cardiovascular Agents adverse effects, Cardiovascular Agents therapeutic use, Clinical Trials as Topic, Heart Diseases drug therapy, Humans, Purinergic P1 Receptor Antagonists chemistry, Purinergic P1 Receptor Antagonists pharmacology, Purinergic P1 Receptor Antagonists therapeutic use, Receptors, Purinergic P1 chemistry, Receptors, Purinergic P1 metabolism, Xanthines adverse effects, Xanthines therapeutic use, Cardiovascular Agents chemistry, Xanthines chemistry
Abstract

Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. The main basic and human studies on the action of xanthines on impulse initiation and conduction, as well as the electrophysiological and mechanical activity of the working myocardium will be overviewed. The potential beneficial and harmful actions of the methylxanthines will be discussed in light of the recent experimental and clinical findings. The pharmacological features and clinical observations with adenosine receptor subtype-specific xanthine antagonists are also the subject of this paper. Based on the adenosine receptor-antagonistic activity of these compounds, it can be raised that xanthine derivatives might inhibit the cardioprotective action of endogenous adenosine on various subtypes (A(1), A(2A), A(2B) and A(3)) of adenosine receptors. Adenosine is an important endogenous substance with crucial role in the regulation of cardiac function under physiological and pathological conditions (preconditioning, postconditioning, ischemia/reperfusion injury). Recent clinical studies show that acute administration of caffeine or theophylline can inhibit various types of preconditioning in human subjects. There are no human studies, however, for the cardiovascular actions of long-term administration of these drugs. Upregulation of adenosine receptors and increased effectiveness of adenosine receptor-related cardiovascular functions have been observed after long-lasting treatment with methylxanthines. In addition, there are data indicating that blood adenosine level increases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine derivatives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthines as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted reactions are minimized.

Published
2011
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23. Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs.

Author

Szentmiklósi AJ, Cseppento A, Harmati G, and Nánási PP

Subjects
Adenosine analogs & derivatives, Adenosine chemistry, Animals, Cardiovascular Diseases enzymology, Cardiovascular Diseases metabolism, Cell Membrane drug effects, Cell Membrane metabolism, Humans, Receptors, Purinergic P1 metabolism, Structure-Activity Relationship, Adenosine therapeutic use, Cardiovascular Diseases drug therapy
Abstract

This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'-nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future.

Published
2011
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24. Effects of ropinirole on action potential characteristics and the underlying ion currents in canine ventricular myocytes.

Author

Simkó J, Szentandrássy N, Harmati G, Bárándi L, Horváth B, Magyar J, Bányász T, Lorincz I, and Nánási PP

Subjects
Animals, Dogs, Dopamine Agonists administration & dosage, Dopamine Agonists toxicity, Dose-Response Relationship, Drug, Female, Heart Ventricles cytology, Heart Ventricles drug effects, Heart Ventricles metabolism, Indoles administration & dosage, Indoles toxicity, Inhibitory Concentration 50, Ion Channels drug effects, Ion Channels metabolism, Male, Myocytes, Cardiac metabolism, Patch-Clamp Techniques, Action Potentials drug effects, Dopamine Agonists pharmacology, Indoles pharmacology, Myocytes, Cardiac drug effects
Abstract

In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the dopamine receptor agonist ropinirole. In the present study, therefore, the concentration-dependent effects of ropinirole on action potential morphology and the underlying ion currents were studied in enzymatically dispersed canine ventricular cardiomyocytes using standard microelectrode, conventional whole-cell patch clamp, and action potential voltage clamp techniques. At concentrations > or = 1 microM, ropinirole increased action potential duration (APD(90)) and suppressed the rapid delayed rectifier K(+) current (I (Kr)) with an IC(50) value of 2.7 +/- 0.25 microM and Hill coefficient of 0.92 +/- 0.09. The block increased with increasing depolarizations to more positive voltages, but paradoxically, the activation of I (Kr) was accelerated by 3 muM ropinirole (time constant decreased from 34 +/- 4 to 14 +/- 1 ms). No significant changes in the fast and slow deactivation time constants were observed with ropinirole. At higher concentrations, ropinirole decreased the amplitude of early repolarization (at concentrations > or = 10 microM), reduced the maximum rate of depolarization and caused depression of the plateau (at concentrations > or = 30 microM), and shortened APD measured at 50% repolarization (at 300 microM) indicating a concentration-dependent inhibition of I (to), I (Na), and I (Ca). Suppression of I (Kr), I (to), and I (Ca) has been confirmed under conventional patch clamp and action potential voltage clamp conditions. I (Ks) and I (K1) were not influenced significantly by ropinirole at concentrations less than 300 microM. All these effects of ropinirole were fully reversible upon washout. The results indicate that ropinirole treatment may carry proarrhythmic risk for patients with inherited or acquired long QT syndrome due to inhibition of I (Kr)-especially in cases of accidental overdose or intoxication.

Published
2010
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25. Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations.

Author

Bárándi L, Virág L, Jost N, Horváth Z, Koncz I, Papp R, Harmati G, Horváth B, Szentandrássy N, Bányász T, Magyar J, Zaza A, Varró A, and Nánási PP

Subjects
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester pharmacology, Action Potentials drug effects, Animals, Anti-Arrhythmia Agents pharmacology, Calcium Channel Agonists pharmacology, Dogs, Guinea Pigs, Heart Rate drug effects, Humans, Membrane Potentials drug effects, Membrane Potentials physiology, Models, Animal, Myocytes, Cardiac drug effects, Myocytes, Cardiac physiology, Patch-Clamp Techniques, Rabbits, Sodium Channel Blockers pharmacology, Tetrodotoxin pharmacology, Time Factors, Ventricular Function drug effects, Action Potentials physiology, Heart Rate physiology, Ventricular Function physiology
Abstract

Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate-dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for RRD in mammalian ventricular myocardium. Action potentials were recorded using conventional sharp microelectrodes from human, canine, rabbit and guinea pig ventricular myocardium in a rate-dependent manner varying the cycle length (CL) between 0.3 and 5 s. Rate-dependent drug effects were studied using agents known to lengthen or shorten action potentials, and these drug-induced changes in APD were correlated with baseline APD values. Both drug-induced lengthening (by dofetilide, sotalol, E-4031, BaCl(2), veratrine, BAY K 8644) and shortening (by mexiletine, tetrodotoxin, lemakalim) of action potentials displayed RRD, i.e., changes in APD were greater at longer than at shorter CLs. In rabbit, where APD is a biphasic function of CL, the drug-induced APD changes were proportional to baseline APD values but not to CL. Similar results were obtained when repolarization was modified by injection of inward or outward current pulses in isolated canine cardiomyocytes. In each case the change in APD was proportional to baseline APD (i.e., that measured before the superfusion of drug or injection of current). Also, the net membrane current (I (net)), determined from the action potential waveform at the middle of the plateau, was inversely proportional to APD and consequently with to CL. The results indicate that RRD is a common characteristic of all the drugs tested regardless of the modified ion current species. Thus, drug-induced RRD can be considered as an intrinsic property of cardiac membranes based on the inverse relationship between I (net) and APD.

Published
2010
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26. Reverse rate dependency is an intrinsic property of canine cardiac preparations.

Author

Bányász T, Horváth B, Virág L, Bárándi L, Szentandrássy N, Harmati G, Magyar J, Marangoni S, Zaza A, Varró A, and Nánási PP

Subjects
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester pharmacology, Action Potentials, Animals, Barium Compounds pharmacology, Cardiac Pacing, Artificial, Chlorides pharmacology, Computer Simulation, Dogs, Female, Heart Ventricles cytology, Heart Ventricles drug effects, In Vitro Techniques, Male, Models, Cardiovascular, Myocytes, Cardiac physiology, Nonlinear Dynamics, Phenethylamines pharmacology, Purkinje Fibers physiology, Sulfonamides pharmacology, Time Factors, Veratrine pharmacology, Anti-Arrhythmia Agents pharmacology, Myocytes, Cardiac drug effects, Purkinje Fibers drug effects
Abstract

Aims: Class III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects., Methods and Results: Action potentials were recorded from multicellular canine ventricular preparations and isolated cardiomyocytes, at cycle lengths (CLs) varying from 0.3 to 5 s, using conventional sharp microelectrodes. APD was either modified by applying inward and outward current pulses, or by superfusion of agents known to lengthen and shorten APD. Net membrane current (I(m)) was calculated from action potential waveforms. The hypothesis that RRD may be implicit in the relationship between I(m) and APD was tested by numerical modelling. Both drug-induced lengthening (by veratrine, BAY-K 8644, dofetilide, and BaCl(2)) and shortening (by lidocaine and nicorandil) of action potentials displayed RRD, i.e. changes in APD were greater at longer than at shorter CL. A similar dependency of effect on CL was found when repolarization was modified by injection of inward or outward current pulses. I(m) measured at various points during repolarization was inversely proportional to APD and to CL. Model simulations showed that RRD is expected as a consequence of the non-linearity of the relationship between I(m) and APD., Conclusion: RRD of APD modulation is shared, although with differences in magnitude, by interventions of very different nature. RRD can be interpreted as a consequence of the relationship between I(m) and APD and, as such, is expected in all species having positive APD-CL relationship. This implies that the development of agents prolonging APD with direct rate dependency, or even completely devoid of RRD, may be difficult to achieve.

Published
2009
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