Differences in the effects of Na+–H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts

Hotta, Yoshihiro; Nishimaki, Haruaki; Takeo, Tomohiro; Itoh, Gen; Yajima, Michio; Otsuka-Murakami, Hidetsugu; Ishikawa, Naohisa; Kawai, Norio; Huang, Lei; Yamada, Kazuto; Yamamoto, Seigo; Matsui, Kazuki; Ohashi, Naohito

doi:10.1016/j.ejphar.2004.08.036

Cited by 15 publications

(15 citation statements)

References 25 publications

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“…It has previously been demonstrated that NHE-1 inhibition preserves the mitochondrial proton gradient and delays ATP depletion during ischemia (Ruiz-Meana et al, 2003), protects the ⌬ m during H 2 O 2 -induced oxidative stress , inhibits MPT pore opening, and improves respiratory function during postinfarcted remodeling (Javadov et al, 2005). Antioxidant effects of various NHE-1 inhibitors have been demonstrated in terms of their ability to quench superoxide and hydroxyl radicals production in guinea pig ischemia-reperfused heart (Hotta et al, 2004). The results of the present study show that ⌬ m dissipation in PE-stimulated cells is accompanied by superoxide production and MPT pore opening, which were nearly completely abrogated by EMD.…”

Section: Discussionmentioning

confidence: 99%

Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Javadov¹,

Baetz²,

Rajapurohitam³

et al. 2006

J Pharmacol Exp Ther

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Although inhibition of Naϩ /H ϩ exchanger isoform 1 (NHE-1) reduces cardiomyocyte hypertrophy, the mechanisms underlying this effect are not known. Recent evidence suggests that this may be associated with improved mitochondrial function. To understand the mechanistic bases for mitochondrial involvement in the antihypertrophic effect of NHE-1 inhibition, we examined the effect of the NHE-1-specific inhibitor N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD87580; 5 M) on the hypertrophic phenotype, mitogen-activated protein kinase (MAPK) activity, mitochondrial membrane potential (⌬ m ), permeability transition (MPT) pore opening, and superoxide generation in phenylephrine (PE)-treated neonatal rat cardiomyocytes. EMD significantly suppressed markers of cell hypertrophy, including cell surface area and gene expression of atrial natriuretic peptide and ␣-skeletal actin. EMD inhibited the PE-induced MPT pore opening, prevented the loss in ⌬ m , and attenuated superoxide generation induced by PE. Moreover, the activation of p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) 1/2 MAPKs induced by PE was significantly attenuated in the presence of EMD as well as the antioxidant catalase. To examine the role of MPT and mitochondrial Ca 2ϩ uniport in parallel with EMD, the effects of cyclosporin A (0.2 M) and ruthenium red (10 M) were evaluated. Both agents significantly attenuated PE-induced hypertrophy and inhibited both mitochondrial dysfunction and p38 and ERK1/2 MAPK activation. Our results suggest a novel mechanism for attenuation of the hypertrophic phenotype by NHE-1 inhibition that is mediated by a reduction in PE-induced MAPK activation and superoxide production secondary to improved mitochondrial integrity.

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Section: Discussionmentioning

confidence: 99%

Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Javadov¹,

Baetz²,

Rajapurohitam³

et al. 2006

J Pharmacol Exp Ther

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“…The elevations in [Ca 2+ ] m due to a perfusate change in the mitochondrial preparation were similar to those obtained with the MPTP opener, atractyroside. 19) Meanwhile, a depression in the [Ca 2+ ] m elevation due to the fluvoxamine or (S)-(−)-pyrapyrydolol treatment was similar to that obtained with cyclosporin A, pH 8.5, or Mg 2+ , a well-known inhibitor of the MPTP.…”

Section: )mentioning

confidence: 67%

“…The effluent was removed from a level above the heart with a peristaltic pump, leaving the heart submerged in a fixed volume of the perfusate. In the ischemia-reperfusion experiments, 31 P-NMR spectra were monitored along with simultaneous recordings of ventricular pressure, as described previously [16][17][18][19] and paced at a rate of 3-4 Hz stimulation via a 3 M KCl agar electrode. 31 P-NMR spectra were obtained at 161.8 MHz on a GSX 400 spectrometer (JEOL Datum Co., Ltd., Tokyo, Japan) equipped with a 9.4-Tesla vertical-bore magnet.…”

Section: P-nmr Measurement and Data Analysismentioning

confidence: 99%

Protective Effects of Fluvoxamine against Ischemia/Reperfusion Injury in Isolated, Perfused Guinea-Pig Hearts

Muto

Usuda

Yamamura

et al. 2014

Biological & Pharmaceutical Bulletin

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Key words fluvoxamine; left ventricular developed pressure; 31 P-NMR; mitochondrial permeability transition pore (MPTP); ischemia-reperfusion injury; apoptosis Serotonin (5-hydroxytryptamine; 5-HT) is a neurohormone that has been shown to regulate cardiovascular functions. 1)Circulating 5-HT can also be taken up by sympathetic neurons and vascular endothelial cells, from which it can then be co-released.2) Previous studies reported that antagonists of 5-HT 2A may be potential therapeutic agents for hypertension as well as peripheral vascular disease, 3) and also prevented cardiac dysfunction in ischemic-reperfusion injury hearts. 4,5) Sarpogrelate, a 5-HT 2A antagonist, was shown to have a beneficial effect on ischemia-reperfusion injury in isolated Langendorff-perfused guinea-pig hearts perfused with no-blood solution.6) The cardiac stimulatory effects of 5-HT in the heart 7) were similarly attributed to the 5-HT 2 receptors present in cardiomyocytes.8) However, the role of 5-HT antagonists in myocardial ischemic cellular damage remains unclear.The identification of factors regulating cardiomyocyte survival and growth is important to more clearly understand the pathogenesis of congenital heart diseases. Interest in the link between the signaling circuitry for external stimuli and mitochondrial apoptotic machinery in cardiac disease is increasing. Mitochondria are also known to play an important role in apoptotic signaling, 9) especially in the heart. 10) In relation to our investigation of Ca 2+ systems, the effects of an increase in mitochondrial Ca 2+ ([Ca 2+ ] m ) uptake on changes in the Ca 2+ content or acidification of the perfusate, similar to the end of ischemia or reperfusion following global ischemia in hearts, was previously examined after the administration of each optical isomer of a 5-HT 1A antagonist pyrapyridolol. 11) Changes in [Ca 2+ ] m were measured to assess their contribution to injury using an opener or inhibitor of the mitochondrial permeability transition pore (MPTP). 12)The results of the present study indicate that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Fig. 1A) may inhibit opening of the MPTP by preventing [Ca 2+ ] m overloadinduced apoptosis in ischemia-reperfusion hearts, similar to the 5-HT 1A antagonist pyrapyridolol.11) Evidence now suggests that apoptosis, or programmed cell death, is an important response of the myocardium to ischemia, which precedes cell necrosis and appears to contribute to the overall sequelae of cardiac injury.13) The molecular mechanisms of cardiac functions triggered by 5-HT have to be elucidated in detail. The role of 5-HT in this response can be delineated with 5-HT inhibitors.14) Therefore, we examined which protective action was associated with the beneficial effects of SSRI, with respect to reductions in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive myocytes and caspase-3 activity, in order to compare these effects to those of 5-HT-rela...

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“…Therefore, mitochondrial fura-2 Ca 2ϩ signals resulting from changes in the Ca 2ϩ concentration or acidification of the perfusate were clearly observed during the time course of MPTP opening or closing. The increases in [Ca 2ϩ ] m were suppressed by infusion of the Na ϩ /H ϩ exchange (NHE) inhibitor SM198110 18) and many other drugs that also promote favarable LVDP recovery in the Langendorff ischemia-reperfusion injury model. 19,27,29,30) These results suggest that MPTP is closely involved in postischemic myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with Ru360, ryanosine, verapamil, diazoxide, and chlonazepam, which do not transport Ca 2ϩ to mitochondria, also led to the release of Ca 2ϩ from the mitochondria. 18,28) Detailed data will be presented in another report. Therefore, mitochondrial fura-2 Ca 2ϩ signals resulting from changes in the Ca 2ϩ concentration or acidification of the perfusate were clearly observed during the time course of MPTP opening or closing.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Cyclo(L-Leu-L-Tyr) against Postischemic Myocardial Dysfunction in Guinea-Pig Hearts

Mitsui-Saitoh

Furukawa

Akutagawa

et al. 2011

Biological & Pharmaceutical Bulletin

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Cyclic dipeptides have been detected in a variety of natural products as well as in processed foods, beverages, and food and beverage ingredients. A number of bitter prolinebased cyclic dipeptides, namely cyclo(Ala-Pro), cyclo(IlePro), cyclo(Leu-Pro), cyclo(Met-Pro), cyclo(Phe-Pro), and cyclo(Pro-Pro), have now been identified in beer 1) or aged sake.2) Cyclic dipeptides, which are composed of other amino acids than proline, have been identified in the distilled residue of millet brandy (awamori), and many other cyclic dipeptide have been newly synthesized in studies on structure-activity interactions.3) The ability of natural and synthesized cyclic dipeptides to scavenge active oxygen radicals has been measured by electron paramagnetic resonance (EPR), and the cardioprotective effects of these compounds have been investigated in perfused guinea-pig hearts subjected to ischemia and reperfusion. Pretreatment with cyclo(L-Leu-L-Tyr) (cLY) promoted optimal recovery after injury.In order to determine the importance of the cyclic dipeptide in cardioprotection, the effects of cLY in guinea-pig hearts were compared with those of the newly synthesized non-cyclic dipeptides L-Leu-L-Tyr (LY) and L-Tyr-L-Leu (YL) (Fig. 1). We studied the effects of cLY, LY, and YL on sequential changes in left ventricular contractility as well as the cellular metabolism of high-energy phosphorous in isolated guinea-pig Langendorff hearts subjected to normothermic global ischemia and subsequent reperfusion. Additionally, mitochondrial Ca 2ϩ ([Ca 2ϩ ] m ) uptake following changes in the perfusate acidity or Ca 2ϩ content similar to those occurring at the end of ischemia or reperfusion after global ischemia in Langendorff hearts were investigated prior to the administration of cyclic dipeptide. The role of [Ca 2ϩ ] m mediated injury was determined by investigating the mitochondrial permeability transition pore (MPTP) using openers and inhibitors of the MPTP. 4,5) Our results suggest that cyclic dipeptides inhibit the opening of the MPTP by preventing [Ca 2ϩ ] m overload-induced apoptosis in ischemic-reperfusion hearts.6) There is now evi- Tanabe-dori, Mizuho, Nagoya 467-8603, Japan. Received June 23, 2010; accepted December 27, 2010; published online January 6, 2011The protective effects of cyclic dipeptides in alcoholic beverages were investigated in the perfused guinea-pig hearts subjected to ischemia and reperfusion. Subsequently, in order to determine the importance of cyclic dipeptide structure, the effects of cyclo (

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Differences in the effects of Na+–H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts

Cited by 15 publications

References 25 publications

Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Protective Effects of Fluvoxamine against Ischemia/Reperfusion Injury in Isolated, Perfused Guinea-Pig Hearts

Protective Effects of Cyclo(L-Leu-L-Tyr) against Postischemic Myocardial Dysfunction in Guinea-Pig Hearts

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Differences in the effects of Na+–H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts

Cited by 15 publications

References 25 publications

Antihypertrophic Effect of Na+/H+Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Antihypertrophic Effect of Na+/H+Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Protective Effects of Fluvoxamine against Ischemia/Reperfusion Injury in Isolated, Perfused Guinea-Pig Hearts

Protective Effects of Cyclo(L-Leu-L-Tyr) against Postischemic Myocardial Dysfunction in Guinea-Pig Hearts

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Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species

Antihypertrophic Effect of Na⁺/H⁺Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species