Prevention of intracellular calcium overload by blocking NCX

Szepesi Judit
Prevention of intracellular calcium overload by blocking NCX.
Doctoral thesis (PhD), University of Szeged.
(2016) (Unpublished)

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Abstract in foreign language

Sodium-calcium exchange (NCX) is the major calcium (Ca) efflux mechanism of ventricular cardiomyocytes. Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentration homeostasis of myocardial cells. Calcium overload of myocardial cells is associated with electrical instability, increased diastolic and reduced systolic force generation, and an increase in oxygen consumption. Nevertheless, both the sodium-hydrogen exchanger (NHE) and abnormal sodium channel conductance (that is, increased late sodium current (INaL)) are likely to contribute to the rise in [Na+]i. The primary aim of the present project was to investigate in detail the effects of [Ca2+]i overload, induced either by increased late Na+ current or by acute ischaemia/reperfusion in isolated canine multicellular preparations and in Langendorff-perfused hearts. The NHE and NCX were inhibited by cariporide and SEA0400 or the novel, more selective ORM-10103, respectively. SEA0400 and ORM-10103 fail to eliminate the APD lengthening effect of ATX-II independently of the sequence of application in canine preparations. NHE inhibition by cariporide was highly efficient in reducing the recorded reperfusion-induced arrhythmias. Following the application of SEA0400 or ORM-10103, the number and duration of arrhythmic periods were efficiently or moderately decreased. Surprisingly, the simultaneous inhibition of the NCX and NHE failed to significantly improve the antiarrhythmic efficacy reached by NCX blockade alone. Our present data support the hypothesis that selective, partial NCX inhibition may be antiarrhythmic via restricting the Na+-induced [Ca2+]i elevation, and this protective effect is mediated primarily by its inhibitory effect on revINCX. Therefore, NCX inhibition can be considered as a promising therapeutic strategy against Ca2+ overload-induced, revNCX-mediated cardiac arrhythmias.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Szepesi Judit
Hungarian title: Az intracelluláris kalcium túltelítődés kivédése az NCX gátlásával
Position, academic title, institution
MTMT author ID
Tóth András
tudományos főmunkatárs, SZTE ÁOK Farmakológiai és Farmakoterápiai Intézet
Subjects: 03. Medical and health sciences > 03.01. Basic medicine
Divisions: Doctoral School of Multidisciplinary Medical Sciences
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2016. March 02.
Item ID: 2667
MTMT identifier of the thesis: 3105218
Date Deposited: 2015. Jul. 01. 08:37
Last Modified: 2020. Apr. 22. 14:18
Defence/Citable status: Defended.

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