title: Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion.
abstract: In this study we evaluated the effects of selective Na+/Ca2+ exchanger (NCX) inhibition by ORM-10103 on the [Ca2+]i transient (CaT), action potential (AP), and cell viability in isolated canine ventricular cardiomyocytes exposed to a simulated ischemia/reperfusion protocol performed either alone (modeling moderate low-flow ischemia) or with simultaneous strophantidine challenge (modeling more severe low-flow ischemia). CaTs were monitored using a Ca2+-sensitive fluorescent dye, APs were recorded by intracellular microelectrodes, and anaerobic shifts in cellular metabolism were verified via monitoring native NADH fluorescence. Simulated ischemia increased the NADH fluorescence, reduced the amplitudes of the AP and CaT and induced membrane depolarization. APs moderately shortened, CaTs prolonged. Diastolic [Ca2+]i ([Ca2+]iD) level increased significantly during ischemia and further elevated following strophantidine application. Reperfusion normalized the NADH level, the amplitude of the AP and duration of the [Ca2+]i transient, but only partially restored action potential triangulation and the amplitude of the CaT. [Ca2+]iD decreased in untreated, but further increased in strophantidine-treated cells. 10 µM ORM-10103 significantly reduced the ischemic [Ca2+]i raise in both untreated and strophantidine-treated cells. During reperfusion ORM-10103 decreased [Ca2+]i and eliminated its diastolic elevation in untreated and strophantidine-treated cardiomyocytes. Following the application of ORM-10103 the detrimental effect of ischemia/reperfusion on cell viability and the reperfusion-induced increase in AP and CaT variabilities were substantially reduced, but ischemia-induced shifts in AP morphology were barely influenced. In conclusion, selective NCX inhibition by ORM-10103 is highly effective against ischemia/reperfusion induced pathologic alterations in [Ca2+]i homeostasis, however, it fails to normalize untoward arrhythmogenic changes in AP morphology.
authors: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6722 Szeged, Hungary.
authors: Anita
authors: A
authors: Kormos
authors: MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: Norbert
authors: N
authors: Nagy
authors: MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: Károly
authors: K
authors: Acsai
authors: Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors: Krisztina
authors: K
authors: Váczi
authors: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6722 Szeged, Hungary.
authors: Szabina
authors: S
authors: Ágoston
authors: Orion Pharma, Espoo, Finland.
authors: Piero
authors: P
authors: Pollesello
authors: Orion Pharma, Espoo, Finland.
authors: Jouko
authors: J
authors: Levijoki
authors: Department of Physiology, University of Debrecen, Debrecen, Hungary.
authors: Norbert
authors: N
authors: Szentandrássy
authors: MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: Julius Gy
authors: JG
authors: Papp
authors: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6722 Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: András
authors: A
authors: Varró
authors: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6722 Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary. Electronic address: toth.andras@med.u-szeged.hu.
authors: András
authors: A
authors: Tóth
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009243:NAD / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C000590774:5-nitro-2-(2-phenylchroman-6-yloxy)pyridine; D001578:Benzopyrans; D011725:Pyridines; D019831:Sodium-Calcium Exchanger; D009243:NAD; D002118:Calcium
keywords: Action potential; Ischemia/reperfusion; NCX inhibitors; ORM-10103; ORM-10103 (PubChem CID: 17978512); [Ca(2+)](i) homeostasis; [Ca(2+)](i) transient