Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects

Touret, Nicolas; Tanneur, Valérie; Godart, Hélène; Seidler, Randolph; Taki, Naoyuki; Bürger, Erich; Dämmgen, Jürgen W.; Counillon, Laurent

doi:10.1016/s0014-2999(02)02824-8

Cited by 39 publications

(24 citation statements)

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“…14 The molecule is closely related to sabiporide, whose pharmacological properties were recently reported. 15 In 5 of the IsoϩBIIB-treated rats, the serum level of the NHE-1 inhibitor was determined on 3 consecutive days (tenth through the twelfth after the onset of treatment). The plasma concentration of the inhibitor attained an average value of 410Ϯ84 nmol/L.…”

Section: Resultsmentioning

confidence: 99%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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Abstract-Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either ␣-or ␤-adrenergic stimulation. Because an association between the Na ϩ /H ϩ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na ϩ /H ϩ exchanger activity (3 mg · kg) was given to male Wistar rats for 30 days. Sex-and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenolϩBIIB723-treated group. Heart weight-to-body weight ratio at necropsy was 2.44Ϯ0.11 in controls and increased to 3.35Ϯ0.10 (PϽ0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82Ϯ0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na ϩ /H ϩ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45Ϯ0.11 vs 0.91Ϯ0.05 arbitrary units, PϽ0.05). This effect was significantly reduced by BIIB723 (1.17Ϯ0.02, PϽ0.05). In conclusion, our results show that Na ϩ /H ϩ exchanger inhibition prevented the development of isoproterenolinduced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy. Key Words: hypertrophy, cardiac Ⅲ signal transduction Ⅲ antiporters Ⅲ fibrosis Ⅲ adrenergic receptor agonists I ncreased sympathetic activity is often implicated in the development of cardiac hypertrophy (CH). A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, 5-7 the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1). This study provides evidence indicating a key role for NHE-1 activity as a mechanism underlying the development of CH and fibrosis induced by I...

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Section: Resultsmentioning

confidence: 99%

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

et al. 2003

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“…However, the effects of NHE-1 inhibitors on the disruption of TJ proteins in BBB endothelial cells after cerebral ischemia have not been clarified. Sabiporide is a selective NHE-1 inhibitor possessing an affinity comparable to that of cariporide on the ubiquitously expressed NHE-1 isoform (Touret et al, 2003). Sabiporide has been reported to elicit cardioprotective effects in rat myocardial infarction model (Pisarenko et al, 2005) and rabbit heart failure model (Aker et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

2010

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“…In previous reports, Na ϩ /H ϩ exchange activity has been determined indirectly in platelets from the rate of volume changes induced by water uptake accompanying Na ϩ influx after cytoplasm acidification (12,21,29,32,33). More directly, Na ϩ uptake determined by flame spectrophotometry (12,28) or 22 Na ϩ influx rate have been used as an assay of NHE activity (12,22,(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…The pH-sensitive fluorochromes as BCECF and SNARF-1 have been used to evaluate pHi by measuring the fluorescence emitted by single cells in a photomultiplier tube coupled to an inverted microscope or other device (32,(37)(38)(39). In both cases, acidification of cytoplasm was achieved by a pulse of NH 4 Cl that induced a rapid intracellular alkalization.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometric kinetic assay of the activity of Na⁺/H⁺ antiporter in mammalian cells

2004

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Background:The Na ϩ /H ϩ exchanger (NHE) of mammalian cells is an integral membrane protein that extrudes H ϩ ion in exchange for extracellular Na ϩ and plays a crucial role in the regulation of intracellular pH (pHi). Thus, when pHi is lowered, NHE extrudes protons at a rate depending of pHi that can be expressed as pH units/s. Methods: To abolish the activity of other cellular pH-restoring systems, cells were incubated in bicarbonate-free Dulbecco's modified Eagle's medium buffered with HEPES. Flow cytometry was used to determine pHi with 2Ј,7Ј-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester or 5-(and-6)-carboxy SNARF-1 acetoxymethyl ester acetate, and the appropriate fluorescence ratios were measured. The calibration of fluorescence ratios versus pHi was established by using ionophore nigericin. The activity of NHE was calculated by a kinetic flow cytometric assay as the slope at time 0 of the best-fit curve of pHi recovery versus time after intracellular acidification with a pulse of exogenous sodium propionate.

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Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects

Cited by 39 publications

References 14 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Flow cytometric kinetic assay of the activity of Na⁺/H⁺ antiporter in mammalian cells

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Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects

Cited by 39 publications

References 14 publications

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Flow cytometric kinetic assay of the activity of Na+/H+ antiporter in mammalian cells

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Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na ⁺ /H ⁺ Exchanger Inhibition

Flow cytometric kinetic assay of the activity of Na⁺/H⁺ antiporter in mammalian cells