TY - JOUR AU - Grandits, Thomas AU - Augustin, Christoph M AU - Haase, Gundolf AU - Jost, Norbert László AU - Mirams, Gary R AU - Niederer, Steven A AU - Plank, Gernot AU - Varró, András AU - Virág, László AU - Jung, Alexander TI - Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies JF - ELIFE J2 - ELIFE VL - 12 PY - 2024 SN - 2050-084X DO - 10.7554/eLife.91911 UR - https://m2.mtmt.hu/api/publication/34786266 ID - 34786266 N1 - Funding Agency and Grant Number: Austrian Science Fund; Austrian Science Fund (FWF); German Research Foundation (DFG); National Institutes of Health; National Research, Development and Innovation Office (NRDI); Hungarian Research Network (HUN-REN); Wellcome Trust Funding text: This research was funded by the Austrian Science Fund (FWF), the German Research Foundation (DFG), the National Institutes of Health, the National Research, Development and Innovation Office (NRDI), the Hungarian Research Network (HUN-REN), and the Wellcome Trust. For the purpose of open access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. AB - Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.22 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies. LA - English DB - MTMT ER - TY - JOUR AU - Mohammed, Aiman AU - Mohácsi, Gábor AU - Naveed, Muhammad AU - Prorok, János AU - Jost, Norbert László AU - Virág, László AU - Baczkó, István AU - Topal, Leila AU - Varró, András TI - Cellular electrophysiological effects of the citrus flavonoid hesperetin in dog and rabbit cardiac ventricular preparations JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 14 PY - 2024 IS - 1 PG - 10 SN - 2045-2322 DO - 10.1038/s41598-024-57828-y UR - https://m2.mtmt.hu/api/publication/34763568 ID - 34763568 N1 - Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi School of Medicine, University of Szeged, Szeged, Hungary HUN-REN-SZTE Research Group for Cardiovascular Pharmacology, Hungarian Research Network, Szeged, Hungary Export Date: 17 April 2024 Correspondence Address: Baczkó, I.; Department of Pharmacology and Pharmacotherapy, Hungary; email: baczko.istvan@med.u-szeged.hu Correspondence Address: Varró, A.; Department of Pharmacology and Pharmacotherapy, Hungary; email: varro.andras@med.u-szeged.hu AB - Recent experimental data shows that hesperetin, a citrus flavonoid, affects potassium channels and can prolong the QT c interval in humans. Therefore, in the present study we investigated the effects of hesperetin on various transmembrane ionic currents and on ventricular action potentials. Transmembrane current measurements and action potential recordings were performed by patch-clamp and the conventional microelectrode techniques in dog and rabbit ventricular preparations. At 10 µM concentration hesperetin did not, however, at 30 µM significantly decreased the amplitude of the I K1 , I to , I Kr potassium currents. Hesperetin at 3–30 µM significantly and in a concentration-dependent manner reduced the amplitude of the I Ks current. The drug significantly decreased the amplitudes of the I NaL and I CaL currents at 30 µM. Hesperetin (10 and 30 µM) did not change the action potential duration in normal preparations, however, in preparations where the repolarization reserve had been previously attenuated by 100 nM dofetilide and 1 µg/ml veratrine, caused a moderate but significant prolongation of repolarization. These results suggest that hesperetin at close to relevant concentrations inhibits the I Ks outward potassium current and thereby reduces repolarization reserve. This effect in certain specific situations may prolong the QT interval and consequently may enhance proarrhythmic risk. LA - English DB - MTMT ER - TY - JOUR AU - Naveed, Muhammad AU - Mohammed, Aiman AU - Topal, Leila AU - Kovács, Zsigmond Máté AU - Dienes, Csaba Bálint AU - Óvári, József AU - Szentandrássy, Norbert AU - Magyar, János AU - Bányász, Tamás AU - Prorok, János AU - Jost, Norbert László AU - Virág, László AU - Baczkó, István AU - Varró, András AU - Nánási, Péter Pál AU - Horváth, Balázs TI - Selective Inhibition of Cardiac Late Na+ Current Is Based on Fast Offset Kinetics of the Inhibitor JF - BIOMEDICINES J2 - BIOMEDICINES VL - 11 PY - 2023 IS - 9 PG - 13 SN - 2227-9059 DO - 10.3390/biomedicines11092383 UR - https://m2.mtmt.hu/api/publication/34113182 ID - 34113182 N1 - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, H-6720, Hungary Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, H-6720, Hungary Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, H-6720, Hungary Division of Sport Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, H-6720, Hungary ELKH-SZTE Research Group for Cardiovascular Pharmacology, Loránd Eötvös Research Network, Szeged, 1097, Hungary Division of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, H-6720, Hungary Cited By :1 Export Date: 23 April 2024 Correspondence Address: Nánási, P.P.; Department of Physiology, Hungary; email: nanasi.peter@med.unideb.hu AB - The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor. LA - English DB - MTMT ER - TY - JOUR AU - Topal, Leila AU - Pintér, Jenő Antal AU - Farkas, Attila AU - Farkas, András AU - Virág, László AU - Jost, Norbert László AU - Baczkó, István AU - Varró, András TI - A szív repolarizációs és celluláris elektrofiziológiai eltéréseinek vizsgálata krónikus tesztoszteron szupplementációt követően nagyállat modellben = Altered cardiac repolarization associated with cellular electrophysiological remodeling following chronic testosterone administration in a large animal model JF - CARDIOLOGIA HUNGARICA J2 - CARDIOL HUNG VL - 53 PY - 2023 IS - Suppl A SP - A330 EP - A330 PG - 1 SN - 0133-5596 UR - https://m2.mtmt.hu/api/publication/33834230 ID - 33834230 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Prorok, János AU - Naveed, Muhammad AU - Mohácsi, G AU - Mohammed, Aiman AU - Topal, Leila AU - Jost, Norbert László AU - Virág, László AU - Baczkó, István AU - Varró, András TI - A hesperetin szívelektrofiziológiai hatásai csökkenthetik a repolarizációs tartalékot = Cardiac electrophysiological effects of hesperetin can decrease the repolarization reserve JF - CARDIOLOGIA HUNGARICA J2 - CARDIOL HUNG VL - 53 PY - 2023 IS - Suppl A SP - A329 EP - A329 SN - 0133-5596 UR - https://m2.mtmt.hu/api/publication/33834219 ID - 33834219 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Polyák, Alexandra Júlia AU - Topal, Leila AU - Pintér, Jenő Antal AU - Husti, Zoltán AU - Hornyik, Tibor AU - Nagy, Norbert AU - Jost, Norbert László AU - Virág, László AU - Farkas, András AU - Baczkó, István AU - Farkas, Attila AU - Varró, András TI - A tartós állóképességi tréning elektorfiziológiai hatásainak vizsgálata kutya sportszív-modellen = Electrophysiological effects of endurance training in a canine sports heart model JF - CARDIOLOGIA HUNGARICA J2 - CARDIOL HUNG VL - 53 PY - 2023 IS - Suppl A SP - A328 EP - A328 PG - 1 SN - 0133-5596 UR - https://m2.mtmt.hu/api/publication/33834195 ID - 33834195 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Polyák, Alexandra Júlia AU - Topal, Leila AU - Zombori-Tóth, Noémi AU - Tóth, Noémi AU - Prorok, János AU - Kohajda, Zsófia AU - Déri, Szilvia AU - Demeter-Haludka, Vivien AU - Hegyi, Péter AU - Venglovecz, Viktória AU - Ágoston, Gergely AU - Husti, Zoltán AU - Gazdag, Péter AU - Szlovák, Jozefina AU - Árpádffy-Lovas, Tamás AU - Naveed, Muhammad AU - Sarusi, Annamária AU - Jost, Norbert László AU - Virág, László AU - Nagy, Norbert AU - Baczkó, István AU - Farkas, Attila AU - Varró, András TI - Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise JF - ELIFE J2 - ELIFE VL - 12 PY - 2023 PG - 27 SN - 2050-084X DO - 10.7554/eLife.80710 UR - https://m2.mtmt.hu/api/publication/33685694 ID - 33685694 N1 - * Megosztott szerzőség AB - The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42) and increased the short term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hour to 29.7±20.3/hour) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training. LA - English DB - MTMT ER - TY - JOUR AU - Déri, Szilvia AU - Hartai, Teodóra AU - Virág, László AU - Jost, Norbert László AU - Labro, Alain J. AU - Varró, András AU - Baczkó, István AU - Nattel, Stanley AU - Ördög, Balázs TI - MiRP2 rescues long QT syndrome type 5 JF - JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY J2 - J MOL CELL CARDIOL VL - 173 PY - 2022 SP - S87 EP - S88 PG - 1 SN - 0022-2828 DO - 10.1016/j.yjmcc.2022.08.175 UR - https://m2.mtmt.hu/api/publication/33744836 ID - 33744836 LA - English DB - MTMT ER - TY - JOUR AU - Topal, Leila AU - Polyák, Alexandra Júlia AU - Tóth, Noémi AU - Zombori-Toth, N AU - Déri, Szilvia AU - Virág, László AU - Jost, Norbert László AU - Farkas, András AU - Baczkó, István AU - Farkas, Attila AU - Varró, András TI - Endurance training induced cellular electrophysiological remodeling in a small and a large animal athlete’s heart model JF - EUROPACE J2 - EUROPACE VL - 24 PY - 2022 IS - Suppl. 1 SP - i811 EP - i811 PG - 1 SN - 1099-5129 DO - 10.1093/europace/euac053.554 UR - https://m2.mtmt.hu/api/publication/33707927 ID - 33707927 N1 - Topal T = Topal L A közleményben hibásan Topal T szerepel Topal L helyett. LA - English DB - MTMT ER - TY - CHAP AU - Jost, Norbert László AU - Kohajda, Zsófia AU - Virág, László AU - Hornyik, Tibor AU - Husti, Zoltán AU - Sztojkov-Ivanov, A AU - Nagy, Norbert AU - Prorok, János AU - Tóth, Noémi AU - Tamás, AL AU - Koncz, Istvan AU - Déri, Szilvia AU - Demeter-Haludka, Vivien AU - Ördög, Balázs AU - Patfalusi, M AU - Tálosi, László AU - Tiszlavicz, László AU - Földesi, Imre AU - Baczkó, István AU - Varró, András ED - M., Barteková ED - T., Ravingerová ED - V., Farkašová TI - New wine in an old bottle or old wine in a new bottle?" in vivo and cellular antiarrhythmic and cardiac electrophysiological effects of desethylamiodarone in dogs T2 - New Frontiers in Basic Cardiovascular Research Meeting : France – New EU members PB - Slovak Academy of Sciences CY - Bratislava SN - 9788082400246 PY - 2022 SP - 38 EP - 38 PG - 1 UR - https://m2.mtmt.hu/api/publication/33702328 ID - 33702328 LA - English DB - MTMT ER -