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Novel Na+/Ca2+ Exchanger Inhibitor ORM-10962 Supports Coupled Function of Funny-Current and Na+/Ca2+ Exchanger in Pacemaking of Rabbit Sinus Node Tissue

Kohajda, Zsófia; Tóth, Noémi; Szlovák, Jozefina; Loewe, Axel; Bitay, Gergő; Gazdag, Péter; Prorok, János; Jost, Norbert; Levijoki, Jouko; Pollesello, Piero; Papp, Julius Gy.; Varró, András; Nagy, Norbert

Abstract:
Background and Purpose: The exact mechanism of spontaneous pacemaking is not fully understood. Recent results suggest tight cooperation between intracellular Ca$^{2+}$ handling and sarcolemmal ion channels. An important player of this crosstalk is the Na$^{+}$/ Ca$^{2+}$ exchanger (NCX), however, direct pharmacological evidence was unavailable so far because of the lack of a selective inhibitor. We investigated the role of the NCX current in pacemaking and analyzed the functional consequences of the I$_{f-}$NCX coupling by applying the novel selective NCX inhibitor ORM-10962 on the sinus node (SAN).
Experimental Approach: Currents were measured by patch-clamp, Ca$^{2+}$-transients were monitored by fluorescent optical method in rabbit SAN cells. Action potentials (AP) were recorded from rabbit SAN tissue preparations. Mechanistic computational data were obtained using the Yaniv et al. SAN model.
Key Results: ORM-10962 (ORM) marginally reduced the SAN pacemaking cycle length with a marked increase in the diastolic Ca$^{2+}$ level as well as the transient amplitude. The bradycardic effect of NCX inhibition was augmented when the funny-current (I$_{f}$) was previously inhibited and vice versa, the effect of I$_{f}$ was augmented when the Ca$^{2+}$ handling was suppressed.
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Verlagsausgabe §
DOI: 10.5445/IR/1000117580
Veröffentlicht am 06.03.2020
Originalveröffentlichung
DOI: 10.3389/fphar.2019.01632
Scopus
Zitationen: 1
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biomedizinische Technik (IBT)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2020
Sprache Englisch
Identifikator ISSN: 1663-9812
KITopen-ID: 1000117580
Erschienen in Frontiers in pharmacology
Band 10
Seiten Art. Nr.: 1632
Vorab online veröffentlicht am 29.01.2020
Schlagwörter Na+/Ca2+ exchanger, funny-current, ORM-10962, pacemaking, sinus-node
Nachgewiesen in Web of Science
Scopus
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