Importance of Ca2+ influx by Na+/Ca2+ exchange under normal and sodium-loaded conditions in mammalian ventricles

Satoh, Hiroshi; Mukai, Makoto; Urushida, Tsuyoshi; Katoh, Hideki; Terada, Hajime; Hayashi, Hideharu

doi:10.1007/978-1-4757-4712-6_2

Cited by 8 publications

(12 citation statements)

References 34 publications

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“…Ischemic tissue injury causes an increase in free intracellular calcium that leads to diminished recovery of dilatation function after ischemia (vasoconstriction), compromised membrane integrity and decrease in reserves of cellular adenosine triphosphate (12). There is no report to support the assertion that amlodipine directly affects mitochondria and Bcl-2.…”

Section: Discussionmentioning

confidence: 99%

Calcium antagonist prevents calcium flux induced necrosis and apoptosis in ischemic reperfusion of rat liver

Chattopadhyay¹,

Verma²,

Verma³

et al. 2008

Indian J Clin Biochem

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Section: Discussionmentioning

confidence: 99%

Calcium antagonist prevents calcium flux induced necrosis and apoptosis in ischemic reperfusion of rat liver

Chattopadhyay¹,

Verma²,

Verma³

et al. 2008

Indian J Clin Biochem

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“…The basis of induced automaticity is the Ca 2＋ oscillation triggered by Na ＋ and Ca 2＋ overload and subsequent oscillatory activation of INaCa. Ca 2＋ oscillation, and arrhythmia was identified in rat ventricular myocytes, which were Na ＋ -loaded by strophanthidin which is known as a selective inhibitor of Na ＋ /K ＋ ATPase (Satoh et al, 2003).…”

Section: Role Of Inaca In the Automaticity Induced By Stretchmentioning

confidence: 99%

Modeling of Arrhythmogenic Automaticity Induced by Stretch in Rat Atrial Myocytes

Youm

Leem

Zhang

et al. 2008

Korean J Physiol Pharmacol

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Since first discovered in chick skeletal muscles, stretch-activated channels (SACs) have been proposed as a probable mechano-transducer of the mechanical stimulus at the cellular level. Channel properties have been studied in both the single-channel and the whole-cell level. There is growing evidence to indicate that major stretch-induced changes in electrical activity are mediated by activation of these channels. W e aimed to investigate the mechanism of stretch-induced automaticity by exploiting a recent mathematical model of rat atrial myocytes which had been established to reproduce cellular activities such as the action potential, Ca 2＋ transients, and contractile force. The incorporation of SACs into the mathematical model, based on experimental results, successfully reproduced the repetitive firing of spontaneous action potentials by stretch. The induced automaticity was composed of two phases. The early phase was driven by increased background conductance of voltage-gated Na ＋ channel, whereas the later phase was driven by the reverse-mode operation of Na ＋ /Ca 2＋ exchange current secondary to the accumulation of Na ＋ and Ca 2＋ through SACs. These results of simulation successfully demonstrate how the SACs can induce automaticity in a single atrial myocyte which may act as a focus to initiate and maintain atrial fibrillation in concert with other arrhythmogenic changes in the heart.

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“…Peptidases generated during early phases of ischemia cleave the prodrug and unmask an NHE inhibitor molecule. The advantages of this approach are selective inhibition of NHE in ischemic tissues with prodrug activation during a critical phase where early NHE inhibition can limit the cell death caused by sodium-mediated Ca 2ϩ overload (Satoh et al, 2003). Additionally, inactive peptide prodrugs can be converted to small, water-soluble molecules whose biological activities are restricted to cell surface exchangers, thereby limiting unintended intracellular toxicity (Numata and Orlowski, 2001).…”

Section: Nhe Inhibitor Prodrugs 965mentioning

confidence: 99%

“…1) (Orlowski and Grinstein, 1997). The specifics of normalizing increased [Na ϩ ] i remain unclear but include regulation by Na ϩ /K ϩ ATPase and sodium-dependent calcium influx (reverse mode) by the sodium-calcium exchanger (NCX) (Satoh et al, 2003). Persistent activation of the reverse mode of NCX during vascular perfusion further increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (step 4, Fig.…”

Section: Introductionmentioning

confidence: 99%

Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition

Palandoken¹,

By²,

Hegde³

et al. 2004

J Pharmacol Exp Ther

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Inhibition of the sodium-proton exchanger (NHE) plays an important role in reducing tissue damage during ischemic reperfusion injury; however, pharmacological inhibitors of NHE have restricted access to acutely ischemic tissues because of severely compromised tissue perfusion. We describe the syntheses, characterization, and NHE inhibitory activities of a novel class of amiloride derivatives where peptides are conjugated to the amiloride C(5) amino group. These new peptide-C(5)-amiloride conjugates are inactive; however, peptide residues were chosen such that selective cleavage by neutral endopeptidase 24.11 (enkephalinase) liberates an amino acid-C(5)-amiloride conjugate that inhibits NHE in a glial cell line. These results confirm the feasibility of using peptide-amiloride conjugates as NHE inhibitor prodrugs. We envision the design of analogous peptide-amiloride prodrugs that can be administered prior to ischemic events and subsequently activated by endopeptidases selectively expressed by ischemic tissues.The sodium-proton exchanger (NHE) represents a family of sodium-dependent transport proteins that participate in various cellular functions (Orlowski and Grinstein, 1997). Seven isoforms (NHE1-7) have been identified (Numata and Orlowski, 2001;Brett et al., 2002;Slepkov and Fliegel, 2002). NHE1 and NHE5 to 7 are particularly important in maintaining the intracellular pH (pH i ) in human heart and brain. Additionally, increased NHE1 activity has been shown to maintain an alkalotic pH i in several human cancer cell types, including transformed astrocytes, i.e., malignant glioma cells (McLean et al., 2000;Hegde et al., 2004). Inhibition of NHE1 in glioma cells causes a reduction of intracellular sodium and associated cytotoxic edema (F. A. Gorin, R. Sriram, W. Harley, C. Floyd, A. Marshall, B. Lyeth, and T. Jue, unpublished data).There is a shift from oxidative to nonoxidative glycolysis during ischemia with increased intracellular acidosis. This reduction in pH i activates NHE, which increases intracellular Na ϩ ([Na ϩ ] i ) levels (step 2, Fig. 1) (Orlowski and Grinstein, 1997). The specifics of normalizing increased [Na ϩ ] i remain unclear but include regulation by Na ϩ /K ϩ ATPase and sodium-dependent calcium influx (reverse mode) by the sodium-calcium exchanger (NCX) (Satoh et al., 2003). Persistent activation of the reverse mode of NCX during vascular perfusion further increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (step 4, Fig. 1), which is believed to initiate the irreversible cellular damage observed during ischemia-reperfusion (I/R) (Piper et al., 1996). This sequence of physiological events leading to I/R injury is initiated by NHE activation; consequently, the controlled inhibition of NHE is an area of intense research (Masereel et al., 2003) (Fig. 1).The significance of NHE participation in I/R injury in animals has been shown by demonstrating that NHE inhibitors, such as cariporide (Fig. 2), are effective in preventing cellular damage resulting from cerebral and myocardial ischemia when ad...

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Importance of Ca2+ influx by Na+/Ca2+ exchange under normal and sodium-loaded conditions in mammalian ventricles

Cited by 8 publications

References 34 publications

Calcium antagonist prevents calcium flux induced necrosis and apoptosis in ischemic reperfusion of rat liver

Calcium antagonist prevents calcium flux induced necrosis and apoptosis in ischemic reperfusion of rat liver

Modeling of Arrhythmogenic Automaticity Induced by Stretch in Rat Atrial Myocytes

Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition

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