Diastolic Ca2+ overload caused by Na+/Ca2+ exchanger during the first minutes of reperfusion results in continued myocardial stunning

Wei, Geng-Ze; Zhou, Jing‐Jun; Wang, Bo; Wu, Feng; Bi, Hui; Wang, Yuemin; Yu, Shuang; Pei, Jianming

doi:10.1016/j.ejphar.2007.05.065

Cited by 34 publications

(22 citation statements)

References 34 publications

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“…More importantly, the significant ischemia induced raise in [Ca 2 þ ] iD and RT 50 were fully blocked by ORM-10103. During reperfusion these parameters significantly further decreased, directly supporting the hypothesis that the predominant effect of NCX blockade during ischemia/reperfusion is an effective suppression of the Na þ i -accumulation induced activation of the reverse mode NCX activity (Wei et al, 2007).…”

Section: [Ca 2 þ ] I Transientsupporting

confidence: 68%

“…[Ca 2 þ ] i overload induces increased leakage of the [Ca 2 þ ] SR , enhancing the probabilities of diastolic Ca 2 þ releases (Wei et al, 2007). The subsequent inward current (mainly via forward I NCX ) facilitates the onset of Ca 2 þ -dependent, potentially lethal ventricular arrhythmias (Nagy et al, 2004).…”

Section: Ap Morphologymentioning

confidence: 99%

“…8). This may be a consequence of the increased stability of Ca 2 þ -handling and is most probably a consequence of the decreased [Ca 2 þ ] i overload and reduced [Ca 2 þ ] iD (Wei et al, 2007).…”

Section: Ap Morphologymentioning

confidence: 99%

“…These alterations often lead to abnormal membrane potential changes (Volders et al, 2000) enhanced probability of diastolic Ca 2 þ releases (Diaz et al, 1997), enhanced arrhythmia propensity (early and delayed afterdepolarizations) and cellular injury (Talukder et al, 2009). During incomplete (low-flow) ischemia/ reperfusion the changes in [Na þ ] i and [Ca 2 þ ] i homeostasis are less dramatic (Wei et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Previous data (Inserte et al, 2002;MacDonald and Howlett, 2008;Wei et al, 2007) suggest that inhibition of the reverse mode NCX activity during ischemia/reperfusion exert effective cardioprotection by reducing [Ca 2 þ ] i overload and improving myocardial recovery during reperfusion. However, the inhibitors used in these studies were not fully selective (Birinyi et al, 2005), consequently the overall effect of NCX inhibition could not be quantitatively analyzed.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion

Kormos¹,

Nagy²,

Acsai³

et al. 2014

European Journal of Pharmacology

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a b s t r a c tIn this study we evaluated the effects of selective Na þ /Ca 2 þ exchanger (NCX) inhibition by ORM-10103 on the [Ca 2 þ ] 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 Ca 2 þ -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. Following the application of ORM-10103 the detrimental effect of ischemia/reperfusion on cell viability and the reperfusioninduced 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 [Ca 2 þ ] i homeostasis, however, it fails to normalize untoward arrhythmogenic changes in AP morphology.

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Section: [Ca 2 þ ] I Transientsupporting

confidence: 68%

Section: Ap Morphologymentioning

confidence: 99%

Section: Ap Morphologymentioning

confidence: 99%