Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury

Schäfer, Claudia; Ladilov, Yury; Inserte, Javier; Schäfer, Matthias; Haffner, Silvia; Garcı́a-Dorado, David; Piper, H. M.

doi:10.1016/s0008-6363(01)00282-6

Cited by 147 publications

(106 citation statements)

References 28 publications

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“…Both SEA0400 and KB-R7943 inhibited the Na þ -dependent Ca 2 þ uptake in rat cardiomyocytes. Similar, positive effects of NCX inhibition were reported from isolated guinea pig papillary muscles and rat hearts (Anderson, 2002;Schafer et al, 2001;Wang et al, 2007). NCX inhibitors were shown to attenuate myocardial reperfusion injury using in vivo experimental models (Takahashi et al, 2003).…”

Section: Introductionsupporting

confidence: 76%

“…The raise in [Ca 2 þ ] i, induced by the removal of extracellular Na þ , was blocked by 90% in the presence of KB-R7943 (Tokuno et al, 2000). In reoxygenated rat cardiomyocytes hypercontracture and [Ca 2 þ ] i oscillations were significantly reduced in the presence of KB-R7943 (Schafer et al, 2001). Both SEA0400 and KB-R7943 inhibited the Na þ -dependent Ca 2 þ uptake in rat cardiomyocytes.…”

Section: Introductionmentioning

confidence: 97%

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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: Introductionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 97%

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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“…However, we cannot rule out a direct modulation of NCX by H 2 O 2 because HOE-642 did not completely block H 2 O 2 -induced Ca 2ϩ overload at concentrations that completely inhibited H 2 O 2 -induced, Na ϩ -dependent recovery from an acid load. This possibility is supported by a recent report (33) demonstrating that direct activation of the reverse mode of NCX contributes to reoxygenation-induced cardiomyocyte injury and altered Ca 2ϩ flux. In addition, a recent report (13) shows that high concentrations of H 2 O 2 activate the reverse mode of NCX in guinea pig ventricular myocytes.…”

Section: Discussionsupporting

confidence: 54%

H₂O₂-induced Ca²⁺overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway

Rothstein

Byron

Reed

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Generation of reactive oxygen species (ROS) and intracellular Ca2+ overload are key mechanisms involved in ischemia-reperfusion (I/R)-induced myocardial injury. The relationship between I/R injury and Ca2+overload has not been fully characterized. The increase in Na+/H+ exchanger (NHE-1) activity observed during I/R injury is an attractive candidate to link increased ROS production with Ca2+ overload. We have shown that low doses of H2O2 increase NHE-1 activity in an extracellular signal-regulated kinase (ERK)-dependent manner. In this study, we examined the effect of low doses of H2O2 on intracellular Ca2+ in fura 2-loaded, spontaneously contracting neonatal rat ventricular myocytes. H2O2 induced a time- and concentration-dependent increase in diastolic intracellular Ca2+ concentration that was blocked by inhibition of ERK1/2 activation with 5 μM U-0126 (88%) or inhibition of NHE-1 with 5 μM HOE-642 (50%). Increased NHE activity was associated with phosphorylation of the NHE-1 carboxyl tail that was blocked by U-0126. These results suggest that H2O2 induced Ca2+ overload is partially mediated by NHE-1 activation secondary to phosphorylation of NHE-1 by the ERK1/2 MAP kinase pathway.

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“…42 Aynı anda, hücre içi pH değerinin hızla normale dönmesi, lizozomal olmayan Ca 2+ 'a bağımlı bir proteaz olan kalpainin etkisinin düşük pH değerine bağlı inhibisyonunu tersine döndürerek ve mitokondriyal permeabilite değişimini geri çevirerek reperfüzyo-nun erken döneminde miyokardiyal zedelenmeyi hızlandırır. 43 Miyokardiyal sitozol ve mitokondride Ca 2+ birikimi kalpainleri etkinleştirir ve kalpainlerin etkinleşmesi ile kontraktil aparat zedelenir.…”

Section: Mi̇yokardi̇yal İskemi̇/reperfüzyon Zedelenmesi̇unclassified

Myocardial and Renal Ischemia/Reperfusion Injury and Experimental Models: Review

Şenol¹,

Tunçtan²

2016

Turkiye Klinikleri J Pharm Sci

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Ö ÖZ ZE ET T Doku iskemisi, miyokard infarktüsü ve inme gibi klinik durumlarda ya da damar cerrahisi ve organ transplantasyonunda komplikasyon olarak ortaya çıkabilen bir durumdur. Reperfüzyon, iskemiye maruz kalan dokunun yeniden kanlanarak oksijenlenmesidir. İskemi/reperfüzyon (İ/R) zedelenmesi, kan akışının yeniden düzenlenmesiyle gelişen inflamatuar tepkilerin bir sonucudur. Erken evrede glikoliz yoluyla laktat üretimi sonucu hücre içi pH değeri düşer. Hücreleri nekroza karşı koruyan bu düşüş, reperfüzyon sıra-sında normal pH değerine yükseldiğinde iskemik hücrelerin ölümünü hızlandırır. Orta evre ise oksidatif stres ile belirgindir. Oksidatif stres belli bir eşiği aşarsa hücresel işlev bozukluğu, geri döndürülemez zedelenme ve hücre ölümü gerçekleşir. Geç evrede, inflamatuar hücreler ve adezyon molekülleri baskındır. Birçok inflamatuar molekül tarafından uyarılan nötrofil etkinliği İ/R süreci boyunca görülür. Miyokardiyal İ/R zedelenmesi miyokardiyal sersemleme (stunning), reperfüzyon aritmileri, miyositlerde nekroz ile koroner endotelyal ve mikrovasküler işlev bozukluğu gibi istenmeyen durumların ortaya çıkmasına yol açabilir. Deneysel olarak çalışılan konular miyokardiyal sersemleme, hibernasyon, reperfüzyon aritmileri ve ön koşul-lamadır. Akut renal yetmezlik (ARY) insanlarda yüksek mortalite ile ilişkili majör bir böbrek hastalığıdır. Kalp debisinin azalması, renal vasküler oklüzyon veya obstrüksiyon ile renal transplantasyon gibi durumların neden olduğu iskemi, ARY gelişmesine neden olabilir. Deneysel olarak çift taraflı (bilateral) ve tek taraflı (unilateral) renal İ/R zedelenmesi oluşturulabilmektedir. Çift taraflı iskemik ARY modeli insandaki patolojik duruma çok daha uygun olmasından dolayı yaygın olarak kullanılmaktadır. Bu çalışmada, ilaçla-rın miyokardiyal veya renal İ/R zedelenmesine bağlı olarak gelişen fizyopatolojik değişiklikler üzerindeki etkilerinin araştırılması amacıyla kullanılan deneysel modeller üzerinde durulmuştur.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : İskemi; reperfüzyon hasarı; oksidatif stres; inflamasyon; miyokardiyal reperfüzyon hasarı; akut böbrek hasarı A AB BS S T TR RA AC CT T Tissue ischemia is a condition that can occur with clinical conditions like myocardial infarction and stroke or as a complication of vascular surgery and organ transplantation. Reperfusion is reoxygenation of tissue exposed to ischemia by restoration of blood flow. Ischemia/reperfusion (I/R) injury is a consequence of inflammatory reaction induced by modulating blood flow. Intracellular pH falls as a result of lactate production through glycolysis at early stage. The decrease protecting cells against necrosis accelerates ischemic cell death at normal pH value during reperfusion. Intermediate phase is characterized by oxidative stress. If oxidative stress exceeds a certain threshold, cellular dysfunction, irreversible injury, and cell death occurs. At the late stage, inflammatory cells and adhesion molecules are dominant. Neutrophil activity stimulated by many inflammatory molecules ...

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Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury

Abstract: Our study shows that inhibition of the reverse mode of the NCE, during reperfusion only, protects cardiomyocytes and whole hearts against reperfusion injury.

Cited by 147 publications

References 28 publications

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

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

H₂O₂-induced Ca²⁺overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway

Myocardial and Renal Ischemia/Reperfusion Injury and Experimental Models: Review

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Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury

Abstract: Our study shows that inhibition of the reverse mode of the NCE, during reperfusion only, protects cardiomyocytes and whole hearts against reperfusion injury.

Cited by 147 publications

References 28 publications

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

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

H2O2-induced Ca2+overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway

Myocardial and Renal Ischemia/Reperfusion Injury and Experimental Models: Review

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H₂O₂-induced Ca²⁺overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway