Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca
            <sup>2+</sup>
            Load Attributable to the Predominance of Forward Mode Block

Özdemir, Semir; Bito, Virginie; Holemans, Patricia; Vinet, Laurent; Mercadier, Jean Jacques; Varró, András; Sipido, Karin R.

doi:10.1161/circresaha.108.173922

Cited by 83 publications

(80 citation statements)

References 34 publications

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“…However, this compensation comes with various consequences, including limiting SR loading and an increased risk of arrhythmias (9). Because of these negative consequences, NCX1 inhibition could be a beneficial therapeutic strategy that has been proposed in ischemiareperfusion, as well as in cardiac hypertrophy and failure (21,23,24,41). However, the regulation of both NCX1 activity and expression is incompletely understood, and the effects of NCX1 targeted therapy especially in light of this study are currently quite unpredictable.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have demonstrated that NCX1 inhibitors can act as positive inotropic drugs for the treatment of ischemia-reperfusion injury and congestive heart failure (21,23,41,42). The potential for modulation of NCX1 activity to correct the impaired contractile properties seen in diseased cardiomyocytes makes it an extremely attractive target for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

“…NCX1 Is in Complex with p38-All three benzyloxyphenyl NCX1 inhibitors, KB-R7943, SN-6, and SEA-0400, inhibit NCX1 activity in a [Na ϩ ] i -dependent manner (21,41). The potency of each of these drugs is coupled to the rate of [Na ϩ ] idependent inactivation (I 1 ), and these compounds may stabilize NCX1 molecules in the I 1 confirmation or favor the rate of I 1 formation (24,37).…”

Section: Kb-r7943 Treatment Does Not Activate P38 Via Changes Inmentioning

confidence: 99%

“…All three benzyloxyphenyl NCX inhibitors, KB-R7943, SN-6, and SEA-0400, have been reported to confer some cardioprotective effects against ischemia-reperfusion injury and heart failure. Both KB-R7943 and the more potent and selective but less available SEA-0400 have been utilized in many in vitro and in vivo studies to analyze NCX1 function and its role in ischemia-reperfusion and heart failure (21)(22)(23)(24)(25)(26).…”

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confidence: 99%

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Chronic Administration of KB-R7943 Induces Up-regulation of Cardiac NCX1

Kappler

Mani

et al. 2009

Journal of Biological Chemistry

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The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1 ؊/؊ mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1 ؉/؉ mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca 2؉ ] i . Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of "activity-dependent signal transduction" leading to changes in gene expression.The cardiac NCX1 (Na ϩ -Ca 2ϩ exchanger) plays a critical role in maintaining the balance of Ca 2ϩ flux across the sarcolemmal membrane in excitation-contraction coupling (1). Cardiac muscle contracts in response to the rise in [Ca 2ϩ ] i , which is released from the sarcoplasmic reticulum (SR) 5 and from influx across the sarcolemma through voltage-sensitive channels. SR Ca 2ϩ -ATPase recycles Ca 2ϩ from the cytosol into the lumen of the SR, and NCX1 mediates the movement of [Ca 2ϩ ] i across the sarcolemma to the extracellular space. NCX1 transports ϳ28% of the cytosolic Ca 2ϩ during a contractionrelaxation cycle in large animals and humans, with 70% being reaccumulated in the SR (via SR Ca 2ϩ -ATPase) (2-4). Alterations in any of the activities associated with this complex process causes a corresponding change in the amount of Ca 2ϩ released from the SR, and the resulting force of cardiac contraction.The exchanger is regulated at the transcriptional level in animal models of cardiac hypertrophy (5, 6) and ischemia and failure (7-12). Importantly, both NCX1 mRNA and protein levels are significantly up-regulated in human end-stage heart failure (13-16). The diastolic performance of failing human myocardium correlates inversely with protein levels of NCX1 (17), and up-regulation of Ncx1 alone contributes directly to impaired SR loading and contractile dysfunction (18,19). Ventricular tachycardia, a precursor to ventricular fibrillation and a major cause of sudden death in heart failure, has also been linked to up-regulation of NCX1. NCX1 up-regulation results in a greater potential for delayed after depolarizations, which are major initiators of ventricular tachycardia (9, 20). In addition, Ca 2ϩ loading, which is one of the major causes of myocardial damage following ischemia-reperfusion, is mediated via reverse mode NCX1. All three benzyloxyphenyl NCX inhibitors, KB-R7943, SN-6, and SEA-0400, have been reported to confe...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Kb-r7943 Treatment Does Not Activate P38 Via Changes Inmentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic Administration of KB-R7943 Induces Up-regulation of Cardiac NCX1

Kappler

Mani

et al. 2009

Journal of Biological Chemistry

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“…Such drugs indeed increase SR Ca content, reduce potentially arrhythmogenic currents, but have also unfavorable effects on relaxation [27]. A role for activation of NCX in the setting of heart failure is currently not truly considered and the current paper thus opens an interesting debate.…”

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 94%