Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium

Yokoyama, Hiroyuki; Gunasegaram, Suba; Harding, Siân E.; Avkiran, Metin

doi:10.1016/s0735-1097(00)00730-0

Cited by 117 publications

(76 citation statements)

References 41 publications

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“…However, the cardiovascular and cGMP responses to these hormones are markedly attenuated, indicating impaired receptor or postreceptor responsiveness of GC-A. 1,5 Our present findings in GC-A-deficient mice indicate that an inhibition of cardiac ANP/GC-A signaling might contribute to the increased activity of myocardial NHE-1 that has been observed in these patients 21 and thereby to the progression of cardiac remodeling and dysfunction.…”

Section: Discussionmentioning

confidence: 60%

“…14,18,22 In some studies, increased cardiac protein expression levels of NHE-1 appear to be involved in the subsequent pathological changes. 8 In other studies, and in particular, in human heart failure, enhanced NHE-1 activity is not correlated with an increase in expression, 21,22 suggesting a role for posttranslational mechanisms. In accordance with the latter, in GC-A Ϫ/Ϫ mice the cardiac NHE-1 expression levels were not altered.…”

Section: Enhanced Nhe-1 Activity Leads To Increased Intracellular Camentioning

confidence: 84%

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Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

et al. 2005

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Background— Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na + /H + exchanger NHE-1 to cardiac remodeling in GC-A–deficient (GC-A −/− ) mice. Methods and Results— Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A −/− mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca 2+ levels. Chronic treatment of GC-A −/− mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca 2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A −/− mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca 2+ /calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A −/− mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy. Conclusions— On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca 2+ , and CaMKII as well as Akt activity.

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Section: Discussionmentioning

confidence: 60%

Section: Enhanced Nhe-1 Activity Leads To Increased Intracellular Camentioning

confidence: 84%

Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

et al. 2005

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“…In this regard, Iso-induced CH seems to differ from other models of CH in which enhanced NHE-1 activity 17,18 is not correlated with an increase in expression of the antiporter, 17,19 suggesting a role for posttranslational mechanisms. Iso-induced effects are attenuated by chronic inhibition of the exchanger.…”

Section: Discussionmentioning

confidence: 65%

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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“…2 In addition, comparable myocardial protective actions have been reported in settings of regional and global myocardial ischemia in nonfibrillating hearts from different species. 17,18 Sarcolemmal NHE-1 is expressed in human myocardium, 25 and clinical trials have demonstrated myocardial benefits derived from NHE-1 inhibition in subsets of patients undergoing emergent coronary revascularization. 26 Thus, effects similar to those reported here in pigs may also apply to humans and facilitate closed-chest resuscitation from VF.…”

Section: Discussionmentioning

confidence: 99%

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

Ayoub

Kolarova

et al. 2003

Circulation

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Background-Inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) is emerging as a promising novel strategy for ameliorating myocardial injury associated with ischemia and reperfusion. We investigated whether NHE-1 inhibition (with cariporide) could minimize mechanical and electrical myocardial abnormalities that develop during ventricular fibrillation (VF) and improve outcome using a porcine model of closed-chest resuscitation. Methods and Results-Two groups of 8 pigs each were subjected to 8 minutes of untreated VF and randomized to receive either a 3-mg/kg bolus of cariporide or 0.9% NaCl immediately before an 8-minute interval of conventional closed-chest resuscitation. Cariporide prevented progressive increases in left ventricular free-wall thickness (from 1.0Ϯ0.2 to 1.5Ϯ0.3 cm with NaCl, PϽ0.001 versus 0.9Ϯ0.1 to 1.1Ϯ0.3 cm with cariporide, PϭNS), maintained the coronary perfusion pressure above resuscitability thresholds (10Ϯ8 versus 19Ϯ3 mm Hg before attempting defibrillation, PϽ0.05), and increased resuscitability (2 of 8 versus 8 of 8, PϽ0.005). In 2 additional groups of 4 pigs each subjected to a briefer interval of untreated VF, cariporide ameliorated postresuscitation shortening of the action potential duration (APD) at 30%, 60%, and 90% repolarization (ie, APD 60 at 2 minutes after resuscitation; 75Ϯ29 versus 226Ϯ16 ms, PϽ0.05), minimized postresuscitation ventricular ectopic activity preventing recurrent VF, and lessened postresuscitation myocardial dysfunction. Conclusions-NHE-1 inhibition may represent a highly potent novel strategy for resuscitation from VF that can ameliorate myocardial manifestations of ischemic injury and improve the effectiveness and outcome of closed-chest resuscitation.

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Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium

Cited by 117 publications

References 41 publications

Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

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

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

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Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium

Cited by 117 publications

References 41 publications

Enhanced Activity of the Myocardial Na + /H + Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

Enhanced Activity of the Myocardial Na + /H + Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

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

Sodium-Hydrogen Exchange Inhibition During Ventricular Fibrillation

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Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

Enhanced Activity of the Myocardial Na ⁺ /H ⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

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