Blocking Na+–H+Exchange by Cariporide Reduces Na+-overload in Ischemia and is Cardioprotective

Hartmann, Matthias; Decking, Ulrich K. M.

doi:10.1006/jmcc.1999.1029

Cited by 108 publications

(77 citation statements)

References 37 publications

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“…When hearts were perfused with a HCO 3 Ϫ buffer, NHE blockade with cariporide substantially reduced ischemic Na i ϩ overload and was cardioprotective, as we and others have shown before (9,25). This reduced ischemic Na ϩ overload in cariporide-treated hearts can be explained by prevention of Na ϩ influx via NHE.…”

Section: Discussionsupporting

confidence: 66%

Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Hove¹,

Nederhoff²,

Echteld³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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Na ϩ /H ϩ exchanger (NHE) and/or the Na ϩ /HCO 3 Ϫ cotransporter (NBC) were blocked during ischemia in isolated rat hearts. Intracellular Na ϩ concentration ([Na ϩ ]i), intracellular pH (pHi), and energyrelated phosphates were measured by using simultaneous 23 Na and 31 P NMR spectroscopy. Hearts were subjected to 30 min of global ischemia and 30 min of reperfusion. Cariporide (3 M) or HCO 3 Ϫ -free HEPES buffer was used, respectively, to block NHE, NBC, or both. End-ischemic [Na ϩ ]i was 320 Ϯ 18% of baseline in HCO 3 Ϫ -perfused, untreated hearts, 184 Ϯ 6% of baseline when NHE was blocked, 253 Ϯ 19% of baseline when NBC was blocked, and 154 Ϯ 6% of baseline when both NHE and NBC were blocked. End-ischemic pHi was 6.09 Ϯ 0.06 in HCO 3 Ϫ -perfused, untreated hearts, 5.85 Ϯ 0.02 when NHE was blocked, 5.81 Ϯ 0.05 when NBC was blocked, and 5.70 Ϯ 0.01 when both NHE and NBC were blocked. NHE blockade was cardioprotective, but NBC blockade and combined blockade were not, the latter likely due to a reduction in coronary flow, because omission of HCO 3 Ϫ under conditions of NHE blockade severely impaired coronary flow. Combined blockade of NHE and NBC conserved intracellular H ϩ load during reperfusion and led to massive Na ϩ influx when blockades were lifted. Without blockade, both NHE and NBC mediate acid-equivalent efflux in exchange for Na ϩ influx during ischemia, NHE much more than NBC. Blockade of either one does not affect the other.

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Section: Discussionsupporting

confidence: 66%

Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Hove¹,

Nederhoff²,

Echteld³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although NHE plays a very important role in regulating the intracellular electrolytes and acid-base balance in the physiological state, it can lead to intracellular Ca 2+ overload in hypoxic myocytes and thus takes an important responsibility for further cell damage [23]. Therefore, NHE inhibitors have been shown to reduce the intracellular Na + concentration and Ca 2+ overload in ischemic myocardial cells [18,34]. In order to further validate our results, effects of TTX on increased I Na.P and I NCX during hypoxia and after the administration of Na + channel activator veratridine were also compared, and the results were found to be similar.…”

Section: Discussionsupporting

confidence: 54%

Persistent sodium current and Na+/H+ exchange contributes to the augmentation of the reverse Na+/Ca2+ exchange during hypoxia or acute ischemia in ventricular myocytes

Tang

Zhang

et al. 2012

Pflugers Arch - Eur J Physiol

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The increases in persistent sodium currents (I Na.P ) and Na + /H + exchange (NHE) causes intracellular Ca 2+ overload. The objective of this study was to determine the contribution of I Na.P and NHE on the hypoxia-or acute ischemia-induced increase in the reverse Na + /Ca 2+ exchange current (HIR-or AIR-I NCX ). I Na.P and I NCX in rabbit ventricular myocytes were recorded during hypoxia or acute ischemia, combination of acidosis (pH values were 6.0 intracellularly and 6.8 extracellularly) and hypoxia, using whole-cell patch-clamp techniques. The results indicate that (1) under hypoxic condition, the augmentation of both HIR-I NCX and I Na.P was inhibited by TTX (2 to 8 μM) in a concentration-dependent manner. The inhibitions of I Na,P and HIR-I NCX reached maximum in the presence of either 4 μM TTX or 10 μM KR-32568 (a NHE inhibitor), respectively. The maximal inhibitions of HIR-I NCX by 4 μM TTX and 10 μM KR-32568 were 72.54% and 16.89%, respectively.(2) Administration of 2 μM TTX and 10 μM KR-32568 in either order in the same cells decreased HIR-I NCX by 64.83% and 16.94%, respectively. (3) I Na.P and the reverse I NCX were augmented during acute ischemia. TTX (4 μM) and KR-32568 (10 μM) reduced AIR-I NCX by 73.39% and 24.13%, respectively. (4) Under normoxic condition, veratridine (20 μM) significantly increased I Na.P and the reverse I NCX , which was reversed by 4 μM TTX. In conclusion, during hypoxia or acute ischemia, both increased I Na.P and NHE contribute to the HIR-or AIR-I NCX with the former playing a major role comparing with the latter.

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“…4,14 The protection afforded by NHE inhibition has generally been attributed to inhibition of the rise in Ca 2ϩ , but there are studies suggesting that inhibition of the rise in Na ϩ may also contribute to cardioprotection, independent of the effect of Na ϩ on Ca 2ϩ . 15,16 Because NHE inhibitors block both the rise in Ca 2ϩ…”

Section: A Rise In Intracellular Namentioning

confidence: 99%

Cardiac-Specific Ablation of the Na ⁺ -Ca ²⁺ Exchanger Confers Protection Against Ischemia/Reperfusion Injury

Imahashi

Pott

Goldhaber

et al. 2005

Circulation Research

145

100

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Abstract-During ischemia and reperfusion, with an increase in intracellular Na ϩ and a depolarized membrane potential, Ca 2ϩ may enter the myocyte in exchange for intracellular Na ϩ via reverse-mode Na ϩ -Ca 2ϩ exchange (NCX). To test the role of Ca 2ϩ entry via NCX during ischemia and reperfusion, we studied mice with cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode Ca 2ϩ influx is absent in the NCX-KO myocytes. Langendorff perfused hearts were subjected to 20 minutes of global ischemia followed by 2 hours of reperfusion, during which time we monitored high-energy phosphates using 31 P-NMR and left-ventricular developed pressure. In another group of hearts, we monitored intracellular Na ϩ using 23 Na-NMR. Consistent with Ca 2ϩ entry via NCX during ischemia, we found that hearts lacking NCX exhibited less of a decline in ATP during ischemia, delayed ischemic contracture, and reduced maximum contracture. Furthermore, on reperfusion following ischemia, NCX-KO hearts had much less necrosis, better recovery of left-ventricular developed pressure, improved phosphocreatine recovery, and reduced Na ϩ overload. The improved recovery of function following ischemia in NCX-KO hearts was not attributable to the reduced preischemic contractility in NCX-KO hearts, because when the preischemic workload was matched by treatment with isoproterenol, NCX-KO hearts still exhibited improved postischemic function compared with wild-type hearts. Thus, NCX-KO hearts were significantly protected against ischemia-reperfusion injury, suggesting that Ca 2ϩ entry via reverse-mode NCX is a major cause of ischemia/reperfusion injury.

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Blocking Na+–H+Exchange by Cariporide Reduces Na+-overload in Ischemia and is Cardioprotective

Cited by 108 publications

References 37 publications

Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Persistent sodium current and Na+/H+ exchange contributes to the augmentation of the reverse Na+/Ca2+ exchange during hypoxia or acute ischemia in ventricular myocytes

Cardiac-Specific Ablation of the Na ⁺ -Ca ²⁺ Exchanger Confers Protection Against Ischemia/Reperfusion Injury

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Blocking Na+–H+Exchange by Cariporide Reduces Na+-overload in Ischemia and is Cardioprotective

Cited by 108 publications

References 37 publications

Relative contributions of Na+/H+exchange and Na+/HCO3−cotransport to ischemic Nai+overload in isolated rat hearts

Relative contributions of Na+/H+exchange and Na+/HCO3−cotransport to ischemic Nai+overload in isolated rat hearts

Persistent sodium current and Na+/H+ exchange contributes to the augmentation of the reverse Na+/Ca2+ exchange during hypoxia or acute ischemia in ventricular myocytes

Cardiac-Specific Ablation of the Na + -Ca 2+ Exchanger Confers Protection Against Ischemia/Reperfusion Injury

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Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Relative contributions of Na⁺/H⁺exchange and Na⁺/HCO₃⁻cotransport to ischemic Na_i⁺overload in isolated rat hearts

Cardiac-Specific Ablation of the Na ⁺ -Ca ²⁺ Exchanger Confers Protection Against Ischemia/Reperfusion Injury