KB-R7943 mesylate

KB-R7943 mesylate is a potent and selective inhibitor of Na+/Ca2+ exchanger (NCE) with IC50 value of 0.7 μM.
NCE is an antiporter membrane protein that exchanges 3 Na+ for 1 Ca2+ and can function to cause Ca2+ accumulation (reverse mode) or Ca2+ extrusion (forward mode) depending on the concentrations of each ion on either side of the membrane and on the membrane potential [1].
In transfected Chinese hamster ovary (CHO) cells expressing NCE, KB-R7943 (10 μM) inhibited NCX activity at high (140mM) but not at low (10mM) cytosolic Na+ concentrations [2].
In cultured rat forebrain neurons loaded with glutamate- (3 μM), N-methyl-D-aspartate- (30 μM), kainate- (100 μM) or KCl- (50 mM) induced [Ca2+] transients, KBR7943 inhibited these transients with IC50 values of 6.6, 8.2, 5.2 and 2.9 μM, respectively. While, KB-R7943 didn’t inhibit glutamate-induced neuronal injury [1]. In mice with ischemic acute renal failure (ARF), KB-R7943 significantly decreased endothelin-1 (ET-1) in the kidney and relieved the ARF-induced renal dysfunction [3].
References:
[1]. Hoyt KR, Arden SR, Aizenman E, et al. Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. Mol Pharmacol, 1998, 53(4): 742-749.
[2]. Condrescu M, Reeves JP. Inhibition of sodium-calcium exchange by KB-R7943: Dodecylamine and sphingosine in transfected Chinese hamster ovary cells. Cell Calcium, 2010, 47(5): 404-411.
[3]. Yamashita J, Ogata M, Takaoka M, et al. KB-R7943, a selective Na+/Ca2+ exchange inhibitor, protects against ischemic acute renal failure in mice by inhibiting renal endothelin-1 overproduction. J Cardiovasc Pharmacol, 2001, 37(3): 271-279.

Mechanical strain injury increases intracellular sodium and reverses Na+/Ca2+ exchange in cortical astrocytes.[Pubmed:15779085]

Glia. 2005 Jul;51(1):35-46.

Traditionally, astrocytes have been considered less susceptible to injury than neurons. Yet, we have recently shown that astrocyte death precedes neuronal death in a rat model of traumatic brain injury (TBI) (Zhao et al.: Glia 44:140-152, 2003). A main mechanism hypothesized to contribute to cellular injury and death after TBI is elevated intracellular calcium ([Ca2+]i). Since calcium regulation is also influenced by regulation of intracellular sodium ([Na+]i), we used an in vitro model of strain-induced traumatic injury and live-cell fluorescent digital imaging to investigate alterations in [Na+]i in cortical astrocytes after injury. Changes in [Na+]i, or [Ca2+]i were monitored after mechanical injury or L-glutamate exposure by ratiometric imaging of sodium-binding benzofuran isophthalate (SBFI-AM), or Fura-2-AM, respectively. Mechanical strain injury or exogenous glutamate application produced increases in [Na+]i that were dependent on the severity of injury or concentration. Injury-induced increases in [Na+]i were significantly reduced, but not completely eliminated, by inhibition of glutamate uptake by DL-threo-beta-benzyloxyaspartate (TBOA). Blockade of sodium-dependent calcium influx through the sodium-calcium exchanger with 2-[2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate (KB-R7943) reduced [Ca2+]i after injury. KB-R7943 also reduced astrocyte death after injury. These findings suggest that in astrocytes subjected to mechanical injury or glutamate excitotoxicity, increases in intracellular Na+ may be a critical component in the injury cascade and a therapeutic target for reduction of lasting deficits after traumatic brain injury.

Na-K-Cl cotransporter-mediated intracellular Na+ accumulation affects Ca2+ signaling in astrocytes in an in vitro ischemic model.[Pubmed:15509746]

J Neurosci. 2004 Oct 27;24(43):9585-97.

Na-K-Cl cotransporter isoform 1 (NKCC1) plays an important role in maintenance of intracellular Na+, K+, and Cl- levels in astrocytes. We propose that NKCC1 may contribute to perturbations of ionic homeostasis in astrocytes under ischemic conditions. After 3-8 hr of oxygen and glucose deprivation (OGD), NKCC1-mediated 86Rb influx was significantly increased in astrocytes from NKCC1 wild-type (NKCC1+/+) and heterozygous mutant (NKCC1+/-) mice. Phosphorylated NKCC1 protein was increased in NKCC1+/+ astrocytes at 2 hr of OGD. Two hours of OGD and 1 hr of reoxygenation (OGD/REOX) triggered an 3.6-fold increase in intracellular Na+ concentration ([Na+]i) in NKCC1+/+ astrocytes. Inhibition of NKCC1 activity by bumetanide or ablation of the NKCC1 gene significantly attenuated the rise in [Na+]i. Moreover, NKCC1+/+ astrocytes swelled by 10-30% during 20-60 min of OGD. Either genetic ablation of NKCC1 or inhibition of NKCC1 by bumetanide-attenuated OGD-mediated swelling. An NKCC1-mediated increase in [Na+]i may subsequently affect Ca2+ signaling through the Na+/Ca2+ exchanger (NCX). A rise in [Ca2+]i was detected after OGD/REOX in the presence of a sarcoplasmic-endoplasmic reticulum (ER) Ca2+-ATPase inhibitor thapsigargin. Moreover, OGD/REOX led to a significant increase in Ca2+ release from ER Ca2+ stores. Furthermore, KB-R7943 (2-[2-[4(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate), an inhibitor of reverse-mode operation of NCX, abolished the OGD/REOX-induced enhancement in filling of ER Ca2+ stores. OGD/REOX-mediated Ca2+ accumulation in ER Ca2+ stores was absent when NKCC1 activity was ablated or pharmacologically inhibited. These findings imply that stimulation of NKCC1 activity leads to Na+ accumulation after OGD/REOX and that subsequent reverse-mode operation of NCX contributes to increased Ca2+ accumulation by intracellular Ca2+ stores.

Sodium hydrogen exchange 1 (NHE-1) regulates connexin 43 expression in cardiomyocytes via reverse mode sodium calcium exchange and c-Jun NH2-terminal kinase-dependent pathways.[Pubmed:18650245]

J Pharmacol Exp Ther. 2008 Oct;327(1):105-13.

Connexin 43, the major connexin isoform in gap junctions of cardiac ventricular myocytes, undergoes changes in distribution and expression in cardiac diseases. The Na(+)-H(+) exchanger (NHE-1), a key mediator of hypertrophy and heart failure, has been shown to be localized in the cardiomyocyte gap junctional regions; however, whether NHE-1 regulates gap junction proteins in the hypertrophied cardiomyocyte is not known. To address this question, neonatal rat ventricular myocytes were treated with phenylephrine (PE) for 24 h to induce hypertrophy. Increased Cx43 expression observed with PE treatment (132.4 +/- 6.3% compared to control; P < 0.05) was further significantly augmented by the specific NHE-1 inhibitor EMD87580 [N-[2-methyl-4,5-bis(methylsulfonyl)-benzoyl]-guanidine hydrochloride] (173.2 +/- 8.7% increase compared to control; P < 0.05 versus PE), an effect that was mimicked by another NHE-1 inhibitor cariporide [4-isopropyl-3-(methylsulfonyl)benzoyl-guanidine methanesulfonate]. PE-induced hypertrophy was associated with mitogen-activated protein kinase c-Jun NH(2)-terminal kinase (JNK) 1/2 activation, whereas inhibition of JNK1/2 with either SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone] or small interfering RNA significantly increased PE-induced up-regulation of Cx43 protein levels. Inhibition of reverse mode Na(+)-Ca(2+) exchange (NCX) with KB-R7943 [2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate] partially reversed JNK1/2 activation (195.2 +/- 21.4 versus 143.7 +/- 14.4% with KB-R7943; P < 0.05) and augmented up-regulation of Cx43 protein (121.1 +/- 8.3 versus 215.9 +/- 25.6% with KB-R7943; P < 0.05) in the presence of PE. Our results demonstrate that NHE-1 negatively regulates Cx43 protein expression in PE-induced cardiomyocyte hypertrophy via a JNK1/2-dependent pathway, which is probably activated by reverse mode NCX activity.

Fowl (Gallus domesticus) sperm motility depends upon mitochondrial calcium cycling driven by extracellular sodium.[Pubmed:15355879]

Biol Reprod. 2005 Jan;72(1):97-101.

A relationship between extracellular Ca(+2), fowl sperm phospholipase A2 activity, long-chain acylcarnitine content, and motility was demonstrated in previous work. Sperm motility appeared to depend upon Na+-dependent Ca(+2) cycling when sperm were incubated at body temperature without glucose. In the present work, motility decreased as a function of time when sperm were incubated in 2 mM Ca(+2) prepared with either buffered isotonic sucrose or LiCl. However, this effect was less pronounced in the case of LiCl. The sparing effect of Li+ was attributed to the mitochondrial Na+/Ca(+2) exchanger. Motile concentration decreased exponentially in response to micromolar concentrations of CGP 37157, a specific inhibitor of the mitochondrial Na+/Ca(+2) exchanger. KB-R7943 mesylate, an inhibitor of the reverse mode of the Na+/Ca(+2) exchanger, prevented re-initiation of motility when exogenous Ca(+2) was added to sperm rendered immotile by incubation with 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, a high-affinity Ca(+2) chelator. The presence of voltage-gated Ca(+2) channels was confirmed by the effect of nifedipine on motile concentration. Neither motile concentration nor straight line velocity was affected by either ouabain or orthovanadate, which inhibit Na+-K+ ATPase and Ca(+2)-ATPase, respectively. In summary, we infer that 1) fowl sperm motility is dependent upon extracellular Ca(+2) cycling through mitochondria; 2) such cycling is dependent upon extracellular Na+; and 3) fowl sperm conserve ATP by moving neither Na+ nor Ca(+2) by active transport. Understanding the relationship between mitochondrial Ca(+2) cycling and ATP production may be applicable to long-term semen storage.

Chronic nicotine exposure selectively activates a carrier-mediated release of endogenous glutamate and aspartate from rat hippocampal synaptosomes.[Pubmed:22417725]

Neurochem Int. 2012 May;60(6):622-30.

The effect of chronic nicotine treatment on the release of endogenous glutamate (GLU), aspartate (ASP) and GABA evoked in vitro by KCl, 4-aminopyridine (4AP) and nicotinic agonists in synaptosomes of rat hippocampus was investigated. Rats were chronically administered with nicotine bitartrate or saline vehicle each for 14 days using osmotic mini-pumps. Hippocampal synaptosomes were stimulated with KCl, 4AP, nicotine or with choline (Ch) and 5-iodo-A-85380 dihydrochloride (5IA85380). The GLU and ASP overflow evoked by Ch, nicotine, KCl and 4AP were increased in treated animals while the nicotine-evoked GABA overflow was reduced and that evoked by Ch, KCl and 4AP was unaffected. The 5IA85380-evoked overflow of the three aminoacids (AAs) was always reduced. The increase of ASP and GLU overflow evoked by KCl, 4AP or Ch was blocked by dl-threo-beta-benzyloxyaspartic acid (dl-TBOA), a carrier transporter inhibitor, and by inhibitors of the Na(+)/Ca(2+) exchangers 2-[[4-[(4-nitrophenyl)methoxy]phenyl]methyl]-4-thiazolidinecarboxylic acid ethyl ester (SN-6) and 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate (KB-R7943). In conclusion long-term nicotine treatment may selectively increase GLU and ASP overflow elicited by KCl, 4AP and Ch through the activation of a carrier-mediated release mechanism and completely abolished the stimulatory effects of alpha4beta2 nAChRs which modulate the release of all the three AA.

KB-R7943 mesylate is a widely used inhibitor of the reverse Na+/Ca2+ exchanger (NCXrev) with IC50 of 5.7±2.1 µM. KB-R7943 mesylate induces cancer cell death via activating the JNK pathway and blocking autophagic flux.

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