KB-R7943 Block of Ca
 2+
 Influx Via Na
 +
 /Ca
 2+
 Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca
 2+
 Overload in Rat Ventricular Myocytes

Satoh, Hiroshi; Ginsburg, Kenneth S.; Qing, Ke; Terada, Hajime; Hayashi, Hideharu; Bers, Donald M.

doi:10.1161/01.cir.101.12.1441

Cited by 164 publications

(140 citation statements)

References 34 publications

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“…Likewise, although it appears clear that the NCX is essential for the action of cardiac glycosides (32), the quantitative role of NCX in this process is poorly understood in the whole heart. Thus, contrary to expectations, the reverse mode NCX blocker KB-R7943 (KBR) did not influence the inotropic effect of strophanthidin in rat ventricular myocytes (35).…”

Section: Nacontrasting

confidence: 74%

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Weiß¹,

Baek²,

Kang³

2004

American Journal of Physiology-Heart and Circulatory Physiology

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To gain more insight into the mechanistic processes controlling the kinetics of inotropic response of digoxin in the perfused whole heart, an integrated kinetic model was developed incorporating digoxin uptake, receptor binding (Na+-K+-ATPase inhibition), and cellular events linking receptor occupation and response. The model was applied to data obtained in the single-pass Langendorff-perfused rat heart for external [Ca2+] of 0.5 and 1.5 mM under control conditions and in the presence of the reverse-mode Na+/Ca2+ exchange inhibitor KB-R7943 (0.1 μM) in perfusate. Outflow concentration and left ventricular developed pressure data measured for three consecutive doses (15, 30, and 45 μg) in each heart were analyzed simultaneously. While disposition kinetics of digoxin was determined by interaction with a heterogeneous receptor population consisting of a high-affinity/low-capacity and a low-affinity/high- capacity binding site, response generation was >80% mediated by binding to the high-affinity receptor. Digoxin sensitivity increased at lower external [Ca2+] due to higher stimulus amplification. Coadministration of KB-R7943 significantly reduced the positive inotropic effect of digoxin at higher doses (30 and 45 μg) and led to a saturated and delayed receptor occupancy-response relationship in the cellular effectuation model. The results provide further evidence for the functional heterogeneity of the Na+-K+-ATPase and suggest that in the presence of KB-R7943 a reduction of the Ca2+ influx rate via the reverse mode Na+/Ca2+ exchanger might become the limiting factor in digoxin response generation.

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Section: Nacontrasting

confidence: 74%

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Weiß¹,

Baek²,

Kang³

2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…21 KB-R7943 (gift of R&D Laboratories, Osaka, Japan) was dissolved in DMSO and 20 mol/L was added immediately after finishing OH exposure. In control experiments, equivalent amounts of DMSO were used.…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

“…The ability of KB-R7943 to inhibit sodium-calcium exchanger reverse-mode activity in the present setting was confirmed by using the procedure described previously. 21 …”

Section: Pharmacological Interventionsmentioning

confidence: 99%

“…Recently, the isothiourea derivative KB-R7943 has been shown to selectively inhibit the reverse mode of the Na ϩ -Ca 2ϩ exchanger. 38 KB-R7943 has been shown to prevent digitalis-induced calcium overload of cardiomyocytes 21 and was also effective in preventing reoxygenationinduced injury in cardiomyocytes 39 and isolated papillary muscles. 40 The data from the present study show that KB-R7943 could prevent hydroxyl radical-induced acute diastolic dysfunction.…”

Section: Hydroxyl Radicals and Calcium Overloadmentioning

confidence: 99%

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Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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Abstract-Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca 2ϩ levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F dia ) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca 2ϩ (EC 50 : 3.27Ϯ0.24ϫ10Ϫ6 versus 2.69Ϯ0.15ϫ10 Ϫ6 mol/L; PϽ0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca 2ϩ sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540Ϯ93%) and pharmacologically blocked sarcoplasmic reticulum (539Ϯ77%), and was also similar in presence of the L-type Ca 2ϩ -channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca 2ϩ sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca 2ϩ influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.

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“…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).…”

mentioning

confidence: 99%

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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KB-R7943 Block of Ca ²⁺ Influx Via Na ⁺ /Ca ²⁺ Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca ²⁺ Overload in Rat Ventricular Myocytes

Cited by 164 publications

References 34 publications

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

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

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KB-R7943 Block of Ca 2+ Influx Via Na + /Ca 2+ Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca 2+ Overload in Rat Ventricular Myocytes

Cited by 164 publications

References 34 publications

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

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

Contact Info

Product

Resources

About

KB-R7943 Block of Ca ²⁺ Influx Via Na ⁺ /Ca ²⁺ Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca ²⁺ Overload in Rat Ventricular Myocytes

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange