TY - JOUR AU - Tóth, Noémi AU - Loewe, Axel AU - Szlovák, Jozefina AU - Kohajda, Zsófia AU - Bitay, Gergő AU - Levijoki, Jouko AU - Papp, Gyula AU - Varró, András AU - Nagy, Norbert TI - The reverse mode of the Na+/Ca2+ exchanger contributes to the pacemaker mechanism in rabbit sinus node cells JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 12 PY - 2022 IS - 1 PG - 16 SN - 2045-2322 DO - 10.1038/s41598-022-25574-8 UR - https://m2.mtmt.hu/api/publication/33364863 ID - 33364863 N1 - Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 12, P.O. Box 427, Szeged, 6720, Hungary Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany ELKH-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary Orion Pharma, Espoo, Finland Export Date: 27 January 2023 Correspondence Address: Nagy, N.; Department of Pharmacology and Pharmacotherapy, Dóm tér 12, P.O. Box 427, Hungary; email: nagy.norbert@med.u-szeged.hu Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; sodium chloride, 7647-14-5, 23724-87-0, 49658-21-1; Calcium; ORM-10962; Sodium Chloride; Sodium-Calcium Exchanger AB - Sinus node (SN) pacemaking is based on a coupling between surface membrane ion-channels and intracellular Ca 2+ -handling. The fundamental role of the inward Na + /Ca 2+ exchanger (NCX) is firmly established. However, little is known about the reverse mode exchange. A simulation study attributed important role to reverse NCX activity, however experimental evidence is still missing. Whole-cell and perforated patch-clamp experiments were performed on rabbit SN cells supplemented with fluorescent Ca 2+ -tracking. We established 2 and 8 mM pipette NaCl groups to suppress and enable reverse NCX. NCX was assessed by specific block with 1 μM ORM-10962. Mechanistic simulations were performed by Maltsev–Lakatta minimal computational SN model. Active reverse NCX resulted in larger Ca 2+ -transient amplitude with larger SR Ca 2+ -content. Spontaneous action potential (AP) frequency increased with 8 mM NaCl. When reverse NCX was facilitated by 1 μM strophantin the Ca 2+ i and spontaneous rate increased. ORM-10962 applied prior to strophantin prevented Ca 2+ i and AP cycle change. Computational simulations indicated gradually increasing reverse NCX current, Ca 2+ i and heart rate with increasing Na + i . Our results provide further evidence for the role of reverse NCX in SN pacemaking. The reverse NCX activity may provide additional Ca 2+ -influx that could increase SR Ca 2+ -content, which consequently leads to enhanced pacemaking activity. LA - English DB - MTMT ER - TY - JOUR AU - Kui, Péter AU - Polyák, Alexandra Júlia AU - Morvay, Nikolett AU - Tiszlavicz, László AU - Nagy, Norbert AU - Ördög, Balázs AU - Takács, Hedvig AU - Leprán, István AU - Farkas, András AU - Papp, Gyula AU - Jost, Norbert László AU - Varró, András AU - Baczkó, István AU - Farkas, Attila TI - Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete’s Heart Model JF - FRONTIERS IN PHYSIOLOGY J2 - FRONT PHYSIOL VL - 12 PY - 2022 PG - 14 SN - 1664-042X DO - 10.3389/fphys.2021.741317 UR - https://m2.mtmt.hu/api/publication/32670331 ID - 32670331 N1 - Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary ELKH-SZTE Working Group of Cardiovascular Pharmacology, Szeged, Hungary Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary Export Date: 17 March 2022 Correspondence Address: Varró, A.; Department of Pharmacology and Pharmacotherapy, Hungary; email: varro.andras@med.u-szeged.hu LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Noémi AU - Kohajda, Zsófia AU - Szlovák, Jozefina AU - Bitay, Gergő AU - Veress, R AU - Horváth, Balázs AU - Papp, Gyula AU - Varró, András AU - Nagy, Norbert TI - Aritmogén kamrai alternánsok celluláris mechanizmusának vizsgálata szívizomban = The role of membrane potential and restitution in the mechanism of cardiac alternans JF - CARDIOLOGIA HUNGARICA J2 - CARDIOL HUNG VL - 51 PY - 2021 IS - Suppl B SP - B253 EP - B254 SN - 0133-5596 UR - https://m2.mtmt.hu/api/publication/32462674 ID - 32462674 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Nagy, Norbert AU - Tóth, Noémi AU - Kohajda, Zsófia AU - Szlovák, Jozefina AU - Bitay, Gergő AU - Veress, Roland AU - Horváth, Balázs AU - Papp, Gyula AU - Varró, András TI - The role of action potential restitution versus Ca2+ cycling in the mechanism of alternans in canine ventricular myocardium JF - SCRIPTA MEDICA J2 - SCRIPTA MEDICA VL - 52 PY - 2021 IS - Suppl.1 SP - S72 SN - 1211-3395 UR - https://m2.mtmt.hu/api/publication/32246276 ID - 32246276 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Noémi AU - Loewe, A AU - Kohajda, Zsófia AU - Bitay, Gergő AU - Levijoki, J AU - Papp, Gyula AU - Varró, András AU - Nagy, Norbert TI - Investigation of the reverse Na+/Ca2+ exchanger function in the spontaneous automaticity of rabbit sinus node cells JF - SCRIPTA MEDICA J2 - SCRIPTA MEDICA VL - 52 PY - 2021 IS - Suppl.1 SP - S16 SN - 1211-3395 UR - https://m2.mtmt.hu/api/publication/32246069 ID - 32246069 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Noémi AU - Szlovák, Jozefina AU - Kohajda, Zsófia AU - Bitay, Gergő AU - Veress, Roland AU - Horváth, Balázs AU - Papp, Gyula AU - Varró, András AU - Nagy, Norbert TI - The development of L-type Ca2+ current mediated alternans does not depend on the restitution slope in canine ventricular myocardium JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 11 PY - 2021 IS - 1 PG - 12 SN - 2045-2322 DO - 10.1038/s41598-021-95299-7 UR - https://m2.mtmt.hu/api/publication/32153454 ID - 32153454 N1 - Funding Agency and Grant Number: National Research Development and Innovation OfficeNational Research, Development & Innovation Office (NRDIO) - Hungary [FK-129117]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences [GINOP-2.3.2-15-2016-00006]; Ministry of Human Capacities Hungary [20391-3/2018/FEKUSTRAT, EFOP-3.6.2-16-2017-0006]; Ministry for Innovation and Technology [UNKP-20-5-SZTE-165, UNKP-20-3-SZTE-126] Funding text: This work was supported by grants from the National Research Development and Innovation Office FK-129117, the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, GINOP-2.3.2-15-2016-00006, the Ministry of Human Capacities Hungary (20391-3/2018/FEKUSTRAT and EFOP-3.6.2-16-2017-0006) and the Ministry for Innovation and Technology (UNKP-20-5-SZTE-165, UNKP-20-3-SZTE-126). SZTE Open Access Found 5358. AB - Cardiac alternans have crucial importance in the onset of ventricular fibrillation. The early explanation for alternans development was the voltage-driven mechanism, where the action potential (AP) restitution steepness was considered as crucial determining factor. Recent results suggest that restitution slope is an inadequate predictor for alternans development, but several studies still claim the role of membrane potential as underlying mechanism of alternans. These controversial data indicate that the relationship of restitution and alternans development is not completely understood. APs were measured by conventional microelectrode technique from canine right ventricular papillary muscles. Ionic currents combined with fluorescent measurements were recorded by patch-clamp technique. APs combined with fluorescent measurements were monitored by sharp microelectrodes. Rapid pacing evoked restitution-independent AP duration (APD) alternans. When non-alternating AP voltage command was used, Ca2+i-transient (CaT) alternans were not observed. When alternating rectangular voltage pulses were applied, CaT alternans were proportional to ICaL amplitude alternans. Selective ICaL inhibition did not influence the fast phase of APD restitution. In this study we found that ICaL has minor contribution in shaping the fast phase of restitution curve suggesting that ICaL—if it plays important role in the alternans mechanism—could be an additional factor that attenuates the reliability of APD restitution slope to predict alternans. LA - English DB - MTMT ER - TY - JOUR AU - Gazdag, Péter AU - Oravecz, Kinga AU - Acsai, Károly AU - Demeter-Haludka, Vivien AU - Ördög, Balázs AU - Szlovák, Jozefina AU - Kohajda, Zsófia AU - Polyák, Alexandra Júlia AU - Barta, Bálint András AU - Oláh, Attila AU - Radovits, Tamás AU - Merkely, Béla Péter AU - Papp, Gyula AU - Baczkó, István AU - Varró, András AU - Nagy, Norbert AU - Prorok, János TI - Author Correction: Increased Ca2+ content of the sarcoplasmic reticulum provides arrhythmogenic trigger source in swimming-induced rat athlete’s heart model JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 11 PY - 2021 IS - 1 PG - 2 SN - 2045-2322 DO - 10.1038/s41598-021-91695-1 UR - https://m2.mtmt.hu/api/publication/32073842 ID - 32073842 N1 - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Dóm tér 12, P.O. Box 427, Szeged, 6720, Hungary MTA‑SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary 2Nd Department of Internal Medicine and Cardiology Centre, Faculty of Medicine, University of Szeged, Szeged, Hungary Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, Hungary Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary Export Date: 18 June 2021 Correspondence Address: Varró, A.; Department of Pharmacology and Pharmacotherapy, Dóm tér 12, P.O. Box 427, Hungary; email: varro.andras@med.u-szeged.hu AB - An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2021, The Author(s). LA - English DB - MTMT ER - TY - JOUR AU - Szlovák, Jozefina AU - Tomek, Jakub AU - Zhou, Xin AU - Tóth, Noémi AU - Veress, Roland AU - Horváth, Balázs AU - Szentandrássy, Norbert AU - Levijoki, Jouko AU - Papp, Gyula AU - Herring, Neil AU - Varró, András AU - Eisner, David A AU - Rodriguez, Blanca AU - Nagy, Norbert TI - Blockade of sodium‑calcium exchanger via ORM-10962 attenuates cardiac alternans JF - JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY J2 - J MOL CELL CARDIOL VL - 153 PY - 2021 SP - 111 EP - 122 PG - 12 SN - 0022-2828 DO - 10.1016/j.yjmcc.2020.12.015 UR - https://m2.mtmt.hu/api/publication/31795546 ID - 31795546 N1 - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary Department of Physiology, Anatomy, and Genetics, University of Oxford, United Kingdom Department of Computer Science, University of Oxford, United Kingdom Department of Physiology, Faculty of Medicine, University of Debrecen, Hungary Faculty of Pharmacy, University of Debrecen, Hungary Orion Pharma, Espoo, Finland MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Unit of Cardiac Physiology, Manchester Academic Health Science Centre, University of Manchester, Core Technology Facility, Manchester, United Kingdom Cited By :3 Export Date: 8 April 2022 CODEN: JMCDA Correspondence Address: Tomek, J.; Department of Physiology, United Kingdom; email: jakub.tomek.mff@gmail.com Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; Acetamides; Calcium; Chromans; ORM-10962; Piperidines; Sodium-Calcium Exchanger Tradenames: orm 10962 AB - Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium‑calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug's mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodium‑calcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans. LA - English DB - MTMT ER - TY - JOUR AU - Magyar, Tibor AU - Árpádffy-Lovas, Tamás AU - Pászti, Bence József AU - Tóth, Noémi AU - Szlovák, Jozefina AU - Gazdag, Péter AU - Kohajda, Zsófia AU - Gyökeres, András AU - Györe, Balázs AU - Gurabi, Zsolt AU - Jost, Norbert László AU - Virág, László AU - Papp, Gyula AU - Nagy, Norbert AU - Koncz, Istvan TI - Muscarinic agonists inhibit the ATP-dependent potassium current and suppress the ventricle-Purkinje action potential dispersion JF - CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY J2 - CAN J PHYSIOL PHARM VL - 99 PY - 2021 IS - 2 SP - 247 EP - 253 PG - 7 SN - 0008-4212 DO - 10.1139/cjpp-2020-0408 UR - https://m2.mtmt.hu/api/publication/31709067 ID - 31709067 N1 - Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Faculty of Dentistry, University of Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary Export Date: 16 March 2021 CODEN: CJPPA Correspondence Address: Koncz, I.; Department of Pharmacology and Pharmacotherapy, Hungary; email: koncz.istvan@med.u-szeged.hu Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Faculty of Dentistry, University of Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary Export Date: 18 March 2021 CODEN: CJPPA Correspondence Address: Koncz, I.; Department of Pharmacology and Pharmacotherapy, Hungary; email: koncz.istvan@med.u-szeged.hu Funding Agency and Grant Number: National Research, Development and Innovation Office - NKFIH [PD-116011, FK-129117]; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-18-4, UNKP-19-4, UNKP-20-5-SZTE-165]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT]; University of SzegedEuropean Commission; [EFOP-3.6.2-16-2017-00006]; [EFOP 3.6.3-VEKOP-16-2017-00009] Funding text: We are grateful to Dr. Karoly Acsai for his valuable contribution in performing statistical comparisons. This work was supported by grants from the National Research, Development and Innovation Office - NKFIH PD-116011 (for IK), FK-129117 (for NN), and the UNKP-18-4, UNKP-19-4 and UNKP-20-5-SZTE-165 New National Excellence Program of the Ministry for Innovation and Technology (for IK and NN), the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (for NN) and EFOP-3.6.2-16-2017-00006 (LIVE LONGER) and EFOP 3.6.3-VEKOP-16-2017-00009 and Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT, and the University of Szeged. AB - Activation of the parasympathetic nervous system has been reported to have an antiarrhythmic role during ischemia-reperfusion injury by decreasing the arrhythmia triggers. Furthermore, it was reported that the parasympathetic neurotransmitter acetylcholine is able to modulate the ATP-dependent K-current (IK-ATP), a crucial current activated during hypoxia. However, the possible significance of this current modulation in the antiarrhythmic mechanism is not fully clarified.Action potentials were measured using the conventional microelectrode technique from canine left ventricular papillary muscle and free-running Purkinje fibers, under normal and hypoxic conditions. Ionic currents were measured using the whole-cell configuration of the patch clamp method.5 μM acetylcholine did not influence the action potential duration (APD) either in Purkinje fibers or in papillary muscle preparations. In contrast, it significantly lengthened the APD and suppressed the Purkinje-ventricle APD dispersion when it was administered after 5 μM pinacidil application. 3 μM carbachol reduced the pinacidil-activated IK-ATP under voltage-clamp condition. Acetylcholine lengthened the ventricular action potential under simulated ischemia condition.In this study we found that acetylcholine inhibits the IK-ATP and thus suppresses the ventricle-Purkinje APD dispersion. We conclude that parasympathetic tone may reduce the arrhythmogenic substrate exerting a complex antiarrhythmic mechanism during hypoxic conditions. LA - English DB - MTMT ER - TY - JOUR AU - Szlovák, Jozefina AU - Tóth, Noémi AU - Gazdag, Péter AU - Papp, Gyula AU - Varró, András AU - Nagy, Norbert TI - A­ Na+/Ca 2+ ­cseremechanizmus­ szerepének­ vizsgálata­ a­ Ca 2+ ­vezérelt­ alternánsokban = The­ role­ of­ Na+/Ca 2+ ­exchanger­ in­ the­ Ca 2+ -­governed­ alternans JF - CARDIOLOGIA HUNGARICA J2 - CARDIOL HUNG VL - 50 PY - 2020 IS - Suppl. D SP - 178 EP - 178 PG - 1 SN - 0133-5596 UR - https://m2.mtmt.hu/api/publication/31975178 ID - 31975178 LA - English DB - MTMT ER -