Na&lt;sup&gt;+&lt;/sup&gt;/H&lt;sup&gt;+&lt;/sup&gt; Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

Nakai, Y.; Horimoto, Hitoshi; Mieno, Shigetoshi; Sasaki, Satoshi

doi:10.1159/000063396

Cited by 8 publications

(5 citation statements)

References 28 publications

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“…In accordance with previous reports, 4,5,23 the addition of DMA appeared to be associated with the preservation of cell viability and plasma membrane integrity. Because it is unlikely that lethally injured myocytes would be able to retain [ 3 H]‐2‐DG, increased retention of [ 3 H]‐2‐DG in the ischaemic–reperfused DMA‐treated hearts was evidence that DMA directly or indirectly provided protection against plasma membrane injuries.…”

Section: Discussionsupporting

confidence: 92%

“…However, the mechanisms responsible for these protective effects have yet to be fully understood. [1][2][3][4][5][6][7][8] It is well-known that anaerobic glycolysis is the primary source of energy for the ischaemic heart. Consequently, in the severely ischaemic myocardium, lactate accumulates in the tissue and the intracellular pH falls.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of the Na + /H + exchanger (NHE) has been demonstrated to protect against ischaemia–reperfusion injury, enhancing contractile recovery, reducing the incidence of arrhythmias and delaying cell death. However, the mechanisms responsible for these protective effects have yet to be fully understood 1–8 …”

Section: Introductionmentioning

confidence: 99%

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Protection of Ischaemic‐reperfused Rat Heart by Dimethylamiloride Is Associated With Inhibition of Mitochondrial Permeability Transition

Prendes

Torresín²,

González³

et al. 2007

Clin Exp Pharma Physio

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1. The aim of the present study was to assess whether protection afforded by the Na(+)/H(+) exchanger blocker dimethylamiloride (DMA) is associated with inhibition of mitochondrial permeability transition (MPT). The effects of DMA were compared with those of cyclosporine (Cs) A, an inhibitor of MPT. 2. Rat hearts were Langendorff perfused with Krebs'-bicarbonate medium containing 10 mmol/L glucose and were subjected to 25 min no-flow global ischaemia and 30 min reperfusion in the presence or absence of 10 micromol/L DMA or 0.2 micromol/L CsA. Cell viability was measured using tetrazolium stain. The MPT was determined by loading hearts with 2-deoxy-[(3)H]-glucose (2DG), which enters mitochondria only during MPT. Total heart 2DG content as an estimation of the extent of tissue damage was also measured. To assess whether DMA has any direct effect on glycolysis, a cell-free heart extract containing all the glycolytic enzymes was used. 3. Dimethylamiloride improved functional recovery (rate-pressure product) from 24 +/- 7 to 68 +/- 11% (P < 0.01) at reperfusion end, attenuated the increase in left ventricular end-diastolic pressure (from 29 +/- 7 to 6 +/- 3% 10 min after reperfusion onset; P < 0.01), improved cell viability (from 21.2 +/- 6.6 to 69.6 +/- 7.1% at reperfusion end; P < 0.05) and lessened lactate accumulation at the end of ischaemia (119 +/- 15 vs 163 +/- 14 micromol/g dry weight; P < 0.05). Dimethylamiloride limited MPT: 2DG mitochondrial entrapment, being 33.1 +/- 14.2 and 96.3 +/- 14.0 at reperfusion end in the treated and control hearts, respectively (P < 0.05), and concomitantly raised total 2DG content (51.3 +/- 4.4 vs 86.8 +/- 1.7 x 10(3) d.p.m./g wet weight in control and treated groups, respectively; P < 0.05). Cyclosporine A improved functional recovery and attenuated the amplitude of ventricular diastolic pressure in ischaemic-reperfused hearts. It also reduced mitochondrial entrapment (67.3 +/- 7.7%; P < 0.05 vs control) and increased total cell 2DG content (162.3 +/- 1.3 x 10(3) d.p.m./g wet weight; P < 0.01 vs control) at the end of reperfusion. Dimethylamiloride did not affect glucose consumption and lactate production in the cell-free heart extract. 4. In conclusion, DMA protects against the noxious effects of ischaemia-reperfusion and inhibits MPT, coinciding with present and previous findings concerning the effects of CsA. Dimethylamiloride also diminished lactate accumulation, although it did not exhibit any direct effect on glycolysis. These data suggest that blockade of Na(+)/H(+) exchange by DMA attenuates the extent of MPT in ischaemic-reperfused rat heart.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Protection of Ischaemic‐reperfused Rat Heart by Dimethylamiloride Is Associated With Inhibition of Mitochondrial Permeability Transition

Prendes

Torresín²,

González³

et al. 2007

Clin Exp Pharma Physio

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“…Middle-aged and senescent hearts have been characterized by increased cellular sodium accumulation at the end of ischemia (Tani et al 1997 and compared with young hearts. They are protected against reperfusion-induced cellular damage by either the NHE-1 inhibitor cariporide (Nakai et al 2002;Besse et al 2004;Simm et al 2008) or the Na + /Ca 2+ exchanger (NCX) inhibitor KB-R7943 (Yamamura et al 2001). This stresses the importance of ischemiainduced proton production and NHE-1/NCX axis in genesis of the ischemia/reperfusion-induced functional disturbances of the aged heart.…”

Section: Discussionmentioning

confidence: 94%

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Mourmoura

Leguen

Dubouchaud

et al. 2010

AGE

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Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10-or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H 2 O 2 release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H 2 O 2 when they oxidize FADH 2 -linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration AGE (2011) of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.

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“…Some work regarding changes in SL Na þ -K þ ATPase and the mechanisms of these alterations in preconditioning has also been carried out [105]; however, the status of changes in other proteins in the SL membrane in preconditioned heart remains to be investigated. In view of the stimulation of Na þ -H þ exchange and Na þ -Ca 2þ exchange activities in the I/R hearts [288][289][290][291], several investigators have shown beneficial effects of the inhibitors of Na þ -H þ exchanger [292][293][294] and Na þ -Ca 2þ exchanger [295][296][297] on cardiac function, dysrhythmias and apoptosis. Nonetheless, little information regarding the actions of these interventions and ischemic preconditioning on subcellular alterations, as well as changes in cardiac gene expression, has appeared in the literature [298][299][300].…”

Section: Subcellular Modification Due To Ischemic Preconditioningmentioning

confidence: 99%

Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease

Dhalla

Saini

Tappia

et al. 2007

Journal of Cardiovascular Medicine

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Several studies have revealed varying degrees of changes in sarcoplasmic reticular and myofibrillar activities, protein content, gene expression and intracellular Ca-handling during cardiac dysfunction due to ischemia-reperfusion (I/R); however, relatively little is known about the sarcolemmal and mitochondrial alterations, as well as their mechanisms in the I/R hearts. Because I/R is associated with oxidative stress and intracellular Ca-overload, it has been indicated that changes in subcellular activities, protein content and gene expression due to I/R are related to both oxidative stress and Ca-overload. Intracellular Ca-overload appears to induce changes in subcellular activities, protein contents and gene expression (subcellular remodeling) by activation of proteases and phospholipases, as well as by affecting the genetic apparatus, whereas oxidative stress is considered to cause oxidation of functional groups of different subcellular proteins in addition to modifying the genetic machinery. Ischemic preconditioning, which is known to depress the development of both intracellular Ca-overload and oxidative stress due to I/R, was observed to attenuate the I/R-induced subcellular remodeling and improve cardiac performance. It is suggested that a combination therapy with antioxidants and interventions, which reduce the development of intracellular Ca-overload, may improve cardiac function by preventing or attenuating the occurrence of subcellular remodeling due to ischemic heart disease. It is proposed that defects in the activities of subcellular organelles may serve as underlying mechanisms for I/R-induced cardiac dysfunction under acute conditions, whereas subcellular remodeling due to alterations in gene expression may explain the impaired cardiac performance under chronic conditions of I/R.

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Na<sup>+</sup>/H<sup>+</sup> Exchanger Inhibitor HOE642 Offers Myoprotection in Senescent Myocardium Independent of Ischemic Preconditioning Mechanisms

Cited by 8 publications

References 28 publications

Protection of Ischaemic‐reperfused Rat Heart by Dimethylamiloride Is Associated With Inhibition of Mitochondrial Permeability Transition

Protection of Ischaemic‐reperfused Rat Heart by Dimethylamiloride Is Associated With Inhibition of Mitochondrial Permeability Transition

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease

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