Cardioprotective Effect of SEA0400, a Selective Inhibitor of the Na+/Ca2+ Exchanger, on Myocardial Ischemia-Reperfusion Injury in Rats

Yoshiyama, Minoru; Nakamura, Yasuhiro; Omura, Takashi; Hayashi, Toshio; Takagi, Yasuhiro; Hasegawa, Takao; Nishioka, Hiroki; Takeuchi, Kazuhide; Itoh, Hiroshi; Yoshikawa, Junichi

doi:10.1254/jphs.fpj03101x

Cited by 19 publications

(14 citation statements)

References 21 publications

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“…In the determination of mouse cardiac function using an echocardiographic system, a combination of ketamine and xylazine is generally used for anesthesia (6,11,15). This anesthesia is convenient for the determination of cardiac parameters because of an appreciable reduction in HR of the experimental animals, which can determine several echocardiographic measures more conveniently.…”

Section: Discussionmentioning

confidence: 99%

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Preferable Anesthetic Conditions for Echocardiographic Determination of Murine Cardiac Function

et al. 2005

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Abstract. Ketamine and xylazine are routinely used for measurement of hemodynamics of mice and rats by echocardiography. The anesthetic agents produce low heart rate (HR) in the animals, which may result in misleading data in the hemodynamic profiles of the small animals. The purpose of the present study was to select an appropriate anesthetic condition in the evaluation of mouse and rat cardiac function by echocardiography. Echocardiographic measurement was performed in male C57BL6 mice anesthetized with an intraperitoneal injection of 30 or 40 mg/ kg pentobarbital (P30 or P40) or a combination of 60 mg / kg ketamine and 6 mg / kg xylazine (KX) and in male Wistar rats with an intraperitoneal injection of 40 or 50 mg / kg pentobarbital (P40 or P50) or a combination of 100 mg / kg ketamine and 10 mg / kg xylazine (KX). Basal HR of P30-anesthetized mice and P40-anesthetized were comparable to those in the conscious state, whereas KX-anesthetized mice and rats were 38% and 74% of those of the conscious animals, respectively. Fractional shortening (FS) and cardiac output index (COI) of the P30-anesthetized mice or the P40-anesthetized rats were greater than those of KX-anesthetized animals. Intraperitoneal injection of dobutamine at 0.3 and 1 mg / kg increased HR, FS, and COI of the P30-anesthetized mice and the P40-anesthetized rats, respectively, whereas the percent responses of these parameters in KX animals were greater than those in pentobarbitalanesthetized ones due to the lower basal values for the cardiac functional parameters. Anesthesia with P30 for the mouse and P40 for the rat rather than ketamine / xylazine may be relevant to the evaluation of cardiac function using echocardiography.

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Section: Discussionmentioning

confidence: 99%

“…In the measurement of cardiac function in experimental animals, various anesthetic agents such as pentobarbital (1,11), urethane (12 -14), and ketamine (1,5,6,10,13,15) have been employed to induce sedation and immobility. Apparently, the anesthetic agents directly and indirectly affect cardiac performance and hemodynamics (5,11,15).…”

Section: Introductionmentioning

confidence: 99%

Preferable Anesthetic Conditions for Echocardiographic Determination of Murine Cardiac Function

et al. 2005

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“…KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, 17,18) and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury [19][20][21][22] (Fig. 1).…”

Section: 2)mentioning

confidence: 99%

“…10,11) Recently, quinazoline derivatives 12) and a series of benzyloxyphenyl derivatives [13][14][15][16] have been identified as NCX inhibitors. KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, 17,18) and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury [19][20][21][22] (Fig. 1).…”

Section: Intracellular Camentioning

confidence: 99%

Discovery of N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacetamide as a Potent and Selective Reverse NCX Inhibitor

Kuramochi

Kakefuda

Yamada

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Intracellular Ca2ϩ is of primary importance in the pathogenesis of ischemia and reperfusion injury in the myocardium. Recent studies have suggested that a massive Ca 2ϩ influx may occur as a consequence of Na ϩ -Ca 2ϩ exchange via the sodium-calcium exchanger (NCX) during reperfusion which, in turn, may be caused by an accumulation of Na ϩ via the sodium-hydrogen exchanger (NHE) during ischemia. 1,2)This results in an intracellular Ca 2ϩ overload, the detrimental effects of which include myocardial contracture, stunning, necrosis, and reperfusion arrhythmia.3-9) NCX functions in both reverse and forward modes, and it is well known that an overactive reverse NCX causes Ca 2ϩ overload. Inhibition of reverse NCX overactivity would effectively block this overload and prevent damage to the myocardium in ischemiareperfusion. Therefore, reverse NCX inhibitors are currently considered to be beneficial in treating disease states.10,11) Recently, quinazoline derivatives 12) and a series of benzyloxyphenyl derivatives [13][14][15][16] have been identified as NCX inhibitors. KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, 17,18) and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury [19][20][21][22] (Fig. 1). We have recently discovered reverse NCX inhibitors, such as 3, which we have reported elesewhere. 16,23,24) To create potent and selective reverse NCX inhibitors, we have now designed a novel class of NCX inhibitors based on 3, and in this paper describe the results of our work on the synthesis and structure-activity relationships (SAR) of this novel class of benzyloxyphenyl derivatives. ChemistryCompounds 4a-e were converted into compounds 5a-e via O-alkylation with 1-(bromomethyl)-3-fluorobenzene. Desired compounds 6a-e were prepared from 5a-e by condensation with pyridin-4-ylmethylamine as shown in Chart 1. Intermediate 4e was synthesized from 7 via S-alkylation with the corresponding alkylbromide. Compounds 9a-c were obtained by O-alkylation of 8 15) with the corresponding alkylbromides followed by hydrolysis of the ester group. Compounds 10a-c were afforded by condensation with 9a-c and pyridin-4-ylmethylamine. Compound 8 was converted into a compound whose amino group was protected with a phthaloyl group, followed by deprotection of the phthaloyl group with hydrazine to give compound 11. Compound 12 was afforded via condensation of 11 with pyridin-4-ylacetic acid. Compound 13 was prepared by O-alkylation of 8 with tert-butyl(2-bromoethyl)carbamate followed by deprotection of the tert-butoxycarbonyl group. Desired compound 14 was obtained from 8 via condensation with bis(trichloromethyl)carbonate and pyridin-4-ylmethylamine. Results and DiscussionIn order to measure the inhibitory effect of the synthesized compounds on the reverse mode of NCX activity, an Na ϩ -dependent Ca 2ϩ influx assay was performed according to reported protocols, using 45 Ca and CCL39 cells stably expr...

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“…AP: action potential APD: action potential duration APD 90 , APD 75 , APD 50 50 : plateau potential at 50% repolarization time RyR: ryanodine receptor SA node, SAN: sinoatrial node SERCA2a: myocardial sarcoplasmic reticulum Ca 2+ ATPase SR: sarcoplasmic reticulum Vmax: maximum rate of depolarization…”

Section: Acronyms and Abreviationsmentioning

confidence: 99%

Characterization of different aspects of selective NCX inhibition in the heart

Kohajda

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Cardioprotective Effect of SEA0400, a Selective Inhibitor of the Na+/Ca2+ Exchanger, on Myocardial Ischemia-Reperfusion Injury in Rats

Cited by 19 publications

References 21 publications

Preferable Anesthetic Conditions for Echocardiographic Determination of Murine Cardiac Function

Preferable Anesthetic Conditions for Echocardiographic Determination of Murine Cardiac Function

Discovery of N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacetamide as a Potent and Selective Reverse NCX Inhibitor

Characterization of different aspects of selective NCX inhibition in the heart

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