Inhibitors of sodium-calcium exchange: identification and development of probes of transport activity

Kaczorowski, Gregory J.; Slaughter, Robert S.; King, V F; García, María L.

doi:10.1016/0304-4157(89)90022-1

Cited by 121 publications

(44 citation statements)

References 93 publications

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“…Halfmaximal block was obtained at a DCB concentration of approximately 25 /SM (Fig. 4A) 128 Garcia, 1989). The complete abolition of the current by 1 mM Mg2" and 1 mm Ni2+ is shown in Fig.…”

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confidence: 81%

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H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

Schlief

Heinemann

1995

The Journal of Physiology

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1. Defolliculated Xenopus oocytes were voltage clamped in bathing solutions containing 115 mM KCl and 1.8 mM CaCl2. External application of H2O2 transiently elicited voltage‐dependent outward rectifying currents within several seconds. Upon depolarization to +50 mV these currents had an activation time constant of 370 ms and reached amplitudes of up to 70 microA. This current was also observed in oocytes without the vitelline membrane. 2. The current was abolished by 500 microM niflumic acid, by the replacement of external Cl‐ by methanesulphonate, or when extracellular Ca2+ was removed indicating the involvement of Ca2+‐activated Cl‐ channels, which are very abundant in Xenopus oocytes. 3. While the current could be recorded in bathing solutions containing Li+, K+, Rb+, Cs+ and NH4+, extracellular Na+ abolished the current completely (IC50 = 6 mM Na+). 4. The H2O2‐induced Cl‐ current was half‐maximally blocked by approximately 25 microM 2'4'‐dichlorobenzamil, 250 microM MgCl2, 100 microM CdCl2 and 100 microM NiCl2. These substances have been shown to block Na+‐Ca2+ exchangers in various tissues. 5. The data are consistent with the existence of an endogenous Na+‐Ca2+ exchanger in the plasma membrane of Xenopus oocytes, which runs in reverse mode in the absence of high external Na+ and the presence of external Ca2+. This endogenous component has to be considered when Xenopus oocytes are used for heterologous expression studies.

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confidence: 81%

“…It is known from other tissues (e.g. in cardiac sarcolemmal vesicles, Philipson & Nishimoto, 1980) (Kleyman & Cragoe, 1988;Kaczorowski et al 1989). …”

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confidence: 99%

H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

Schlief

Heinemann

1995

The Journal of Physiology

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“…Both PMCAs and Na ϩ /Ca 2ϩ exchangers derive from multiple genes and occur in multiple splice variants with potentially different properties (Blaustein and Lederer, 1999;Strehler and Zacharias, 2001). Available inhibitors have mostly been tested only on a subset of isoforms and often have nonspecific effects (Kaczorowski et al, 1989;. We therefore used methods that specifically reduce the activity of Na ϩ /Ca 2ϩ exchangers versus PMCAs, independent of the particular isoform.…”

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confidence: 99%

Nonlinear [Ca²⁺] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca²⁺Extrusion

et al. 2006

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“…However, as the NCX inhibitors used in those studies have other non-specific actions including NHE inhibition and Ca 2+ channel blockade (8), the question remains as to whether the benefits seen were actually due to inhibition of the cardiac NCX. Recently, 2-[2-[4-(4-nitrobenzyloxy) phenyl]isothiourea (KB-R7943) (18) and SEA0400 (9) have been introduced as potent and selective inhibitors of the NCX, and the pathophysiological roles of the NCX were investigated in the heart.…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have demonstrated the beneficial effects of NCX inhibitors on myocardial ischemia-reperfusion injuries (6,7). However, as the NCX inhibitors used in those studies have other non-specific actions including Na + / H + exchanger (NHE) inhibition and Ca 2+ channel blockade (8), the question remains as to whether the benefits seen were actually due to inhibition of the cardiac NCX. Therefore, a more selective NCX inhibitor is required for studies on the pharmacological roles of the NCX.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective Effect of SEA0400, a Selective Inhibitor of the Na+/Ca2+ Exchanger, on Myocardial Ischemia-Reperfusion Injury in Rats

et al. 2004

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Abstract. In this study, we investigated whether the Na + / Ca 2+ exchanger (NCX) inhibitor SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy-5-ethoxyaniline) might have a protective effect against myocardial ischemia-reperfusion injury in rats. In particular, we focused on cardiac function using Doppler echocardiography and cardiac gene expression. We intravenously administered either SEA0400 and delivery vehicle or only the vehicle (as a control) to Wistar rats 5 min before ischemia was induced. Reperfusion was performed after 30 min of ischemia. At 1 week after ischemia-reperfusion injury, we assessed hemodynamics by inserting a polyethylene-tubing catheter, cardiac function by Doppler echocardiography, and myocardial mRNA expression was determined by Northern blot analysis. Left ventricular (LV) end-diastolic dimensions (LVDd) and LV end-diastolic volume (LVEDV) were significantly increased in the ischemia-reperfusion rat model group compared to the control group. The SEA0400-treated group had a significantly attenuated LVDd (P<0.05) and LVEDV (P<0.01) increase, compared to the vehicle-treated group. A decrease in the LV ejection fraction (P<0.05) was significantly prevented in the SEA0400-treated group compared to the vehicle-treated group. Moreover, mRNA expression of plasminogen activator inhibitor-1 in the non-infarcted LV of the SEA0400-treated group was significantly lower than in the vehicle-treated group (P<0.05). This study demonstrates that the NCX is an important mechanism for cell death in myocardial ischemia and reperfusion in rats. SEA0400 may prove to be a promising new drug in the clinical treatment of myocardial ischemia and reperfusion.

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Inhibitors of sodium-calcium exchange: identification and development of probes of transport activity

Cited by 121 publications

References 93 publications

H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

Nonlinear [Ca²⁺] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca²⁺Extrusion

Cardioprotective Effect of SEA0400, a Selective Inhibitor of the Na+/Ca2+ Exchanger, on Myocardial Ischemia-Reperfusion Injury in Rats

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Inhibitors of sodium-calcium exchange: identification and development of probes of transport activity

Cited by 121 publications

References 93 publications

H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

H2O2‐induced chloride currents are indicative of an endogenous Na(+)‐Ca2+ exchange mechanism in Xenopus oocytes.

Nonlinear [Ca2+] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca2+Extrusion

Cardioprotective Effect of SEA0400, a Selective Inhibitor of the Na+/Ca2+ Exchanger, on Myocardial Ischemia-Reperfusion Injury in Rats

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Nonlinear [Ca²⁺] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca²⁺Extrusion