Cardioprotective effect of TY-12533, a novel Na+/H+ exchange inhibitor, on ischemia/reperfusion injury

Aihara, Kazuyuki; Hisa, Hiroaki; Sato, Takashi; Yoneyama, Fumiya; Sasamori, Jun; Yamaguchi, Fuminari; Yoneyama, Sachiko; Mizuno, Yusuke; Takahashi, Atsuo; Nagai, Atsushi; Kimura, Tooru; Kogi, Kentaro; Satoh, Susumu

doi:10.1016/s0014-2999(00)00613-0

Cited by 41 publications

(23 citation statements)

References 27 publications

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“…To induce myocardial infarction, the myocardial ischemia/reperfusion model was established according to a method reported by Aihara et al (2000) with minor modifications. Briefly, rats were anesthetized with 40 mg/kg sodium pentobarbital i.p.…”

Section: Methodsmentioning

confidence: 99%

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Takada

Hashimoto²,

Kasahara³

et al. 2004

J Pharmacol Exp Ther

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In a rat model of myocardial ischemic infarction, sodium orthovanadate rescued cells from ischemia/reperfusion injuries. Rats underwent 30 min of myocardial ischemia by occluding the left coronary artery followed by 24 h of reperfusion. Posttreatment with orthovanadate reduced infarct size in a dosedependent manner. Orthovanadate treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. The cytoprotective action of orthovanadate treatment was closely associated with inhibition of fodrin breakdown. Since orthovanadate is a potent inhibitor for protein tyrosine phosphatases, thereby activating tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) pathways, we investigated activities of protein kinase B (Akt), a downstream target of PI3K in cardiomyocytes. Orthovanadate-induced cytoprotection was associated with partial restoration of reduced Akt activity following myocardial infarction. Restoration of Akt activity by orthovanadate treatment correlated positively with increased phosphorylation of glycogen synthase kinase-3␤ and Bad in cardiomyocytes. Furthermore, orthovanadate treatment inhibited caspase-3 activation induced by ischemia. Taken together, orthovanadate post-treatment rescued cardiomyocytes from ischemia/reperfusion injuries via Akt activation and inhibition of fodrin breakdown, thereby inhibiting apoptosis.

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Section: Methodsmentioning

confidence: 99%

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Takada

Hashimoto²,

Kasahara³

et al. 2004

J Pharmacol Exp Ther

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“…Importantly, the potency of cariporide and some other NHE inhibitors is related to the ionization state of the guanidine residues that depends on the pH to be positively charged: e.g. zoniporide (pK a ¼ 7.2), TY-12533 (pK a ¼ 6.93) and, especially, cariporide (pK a ¼ 6.28) [75,[80][81][82], making these compounds more efficient at inhibiting NHE1. Indeed, cariporide will be even more active at very low pH e (i.e.…”

Section: Mechanism Underlying Increased Nhe1 Activity and Alkalinizatmentioning

confidence: 99%

Role of pH_i, and proton transporters in oncogene-driven neoplastic transformation

Reshkin

Greco

Cardone

2014

Phil. Trans. R. Soc. B

118

119

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The change of a normal, healthy cell to a transformed cell is the first step in the evolutionary arc of a cancer. While the role of oncogenes in this ‘passage’ is well known, the role of ion transporters in this critical step is less known and is fundamental to our understanding the early physiological processes of carcinogenesis. Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the normal tissue intracellular to extracellular pH gradient (ΔpH i to ΔpH e ). When this perturbation in pH dynamics occurs during carcinogenesis is less clear. Very early studies using the introduction of different oncogene proteins into cells observed a concordance between neoplastic transformation and a cytoplasmic alkalinization occurring concomitantly with a shift towards glycolysis in the presence of oxygen, i.e. ‘Warburg metabolism’. These processes may instigate a vicious cycle that drives later progression towards fully developed cancer where the reversed pH gradient becomes ever more pronounced. This review presents our understanding of the role of pH and the NHE1 in driving transformation, in determining the first appearance of the cancer ‘hallmark’ characteristics and how the use of pharmacological approaches targeting pH/NHE1 may open up new avenues for efficient treatments even during the first steps of cancer development.

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“…Akzo Nobel has a NHE inhibitor, KB-R9032, at the preclinical stage as does Sanofi-Synthelabo (SL 59.1227) [Lorrain et al, 2000]. There are a number of other early stage NHE inhibitors: Mitsui have MS-31-038 [Banno et al, 1999] and Toa Eiyo have TY-12533 [Aihara et al, 2000] at the preclinical stage. The potential utility of these drugs remains to be proven clinically.…”

Section: Na + /H + Exchange Inhibitorsmentioning

confidence: 99%

Ventricular fibrillation, an uncontrolled arrhythmia seeking new targets

Beatch

Barrett

Plouvier

et al. 2002

Drug Development Research

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Ventricular antiarrhythmic drugs in current clinical use leave much to be desired in terms of safety and efficacy. With the exception of beta-adrenoreceptor blockers, none of the available antiarrhythmic drugs have significantly improved survival after myocardial infarction. Amiodarone has shown marginal benefit but has several safety limitations. As a result, there is a large unmet medical need for a safe and effective drug to treat lethal ventricular arrhythmias. Despite the difficulties in developing such a drug, there are a few research programs dedicated to solving this unmet medical need. These include drugs that are targeted to the pathological substrate responsible for initiating arrhythmias and drugs that block multiple ion channels in a manner similar to amiodarone. A few research programs are directed toward other molecular targets. This article briefly reviews the active research programs in the pharmaceutical industry currently that are pursuing ventricular antiarrhythmic drugs. Drug Dev. Res. 55:45-52, 2002.

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Cardioprotective effect of TY-12533, a novel Na+/H+ exchange inhibitor, on ischemia/reperfusion injury

Cited by 41 publications

References 27 publications

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Role of pH_i, and proton transporters in oncogene-driven neoplastic transformation

Ventricular fibrillation, an uncontrolled arrhythmia seeking new targets

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Cardioprotective effect of TY-12533, a novel Na+/H+ exchange inhibitor, on ischemia/reperfusion injury

Cited by 41 publications

References 27 publications

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Cytoprotective Effect of Sodium Orthovanadate on Ischemia/Reperfusion-Induced Injury in the Rat Heart Involves Akt Activation and Inhibition of Fodrin Breakdown and Apoptosis

Role of pHi, and proton transporters in oncogene-driven neoplastic transformation

Ventricular fibrillation, an uncontrolled arrhythmia seeking new targets

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Product

Resources

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Role of pH_i, and proton transporters in oncogene-driven neoplastic transformation