Experimental and clinical evaluation of cardioprotective effects by adenosine and nitric oxide

腺苷和一氧化氮心脏保护作用的实验和临床评价

• 批准号: 16390225
• 负责人: HORIO Masatsugu
• 金额: $ 9.22万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390225/
• 关键词: myocardial infarction; heart failure; preconditioning; adenosine; nitric oxide

In the developed country, arrhythmia and subsequent heart failure after myocardial infarction have been major cause of cardiac death. This study was designed to elucidate the mechanism of cardiovascular injury after acute myocardial infarction and develop the novel method to protect myocardial damage after ischemic stress. We especially examined the ischemia preconditioning phenomenon and role of vasodilatation after brief ischemia using rat or canine ischemia model.In this study, we showed that production of NO and K channel opener mimicked ischemic preconditioning. Adenosine was also revealed to have cardioprotective effect after ischemia suggesting adenosine and NO pathway plays an important role of ischemia preconditioning phenomenon. Then we showed that common anti-hypertensive medicine carvedirol and amlodipine protect ischemic injury by vascular dilation via production of NO and adenosine. Intracellular signaling of adenosine and NO was also examined and revealed the involvement of PKC and PKA in this protective effect.Since we concluded that NO and adenosine are key molecules for protecting these ischemic damages, we started the clinical use of adenosine signal enhancer for heart failure. We will continue to examine the effect of adenosine for cardiovascular function in various conditions clinically and experimentally.

在发达国家，心肌梗死后心律失常和继发性心力衰竭已成为心源性死亡的主要原因。本研究旨在阐明急性心肌梗死后心血管损伤的机制，探索保护缺血应激后心肌损伤的新方法。我们利用大鼠或犬的缺血模型，重点研究了短暂缺血后的缺血预适应现象和血管扩张作用。在本研究中，我们发现NO和K通道开放剂的产生模拟了缺血预适应。腺苷在缺血后也有心脏保护作用，提示腺苷和NO途径在缺血预适应现象中起重要作用。我们发现，常见的降压药卡维地洛和氨氯地平通过产生NO和腺苷来扩张血管，从而保护缺血性损伤。我们还检测了腺苷和NO的细胞内信号转导，发现PKC和PKA参与了这一保护作用。由于我们得出结论，NO和腺苷是保护这些缺血性损伤的关键分子，因此我们开始了腺苷信号增强剂在心力衰竭治疗中的临床应用。我们将继续通过临床和实验研究腺苷在各种条件下对心血管功能的影响。

项目成果

Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts

• DOI: 10.1097/00005344-200404000-00013
• 发表时间: 2004-04-01
• 期刊: JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
• 影响因子: 3
• 作者: Asanuma, H;Sanada, S;Kitakaze, M
• 通讯作者: Kitakaze, M

Celiprolol, a vasodilatory bet-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice.

Celiprolol 是一种血管舒张阻滞剂，可抑制小鼠压力超负荷引起的心脏肥大，并通过一氧化氮依赖性机制防止向心力衰竭的转变。

• 发表时间: 2004
• 期刊: Circulation 110
• 作者: Kubo T;Kitaoka H;Okawa M;Matsumura Y;Hitomi N;Yamazaki N;Furuno T;Takata J;Nishinaga M;Kimura A;Doi YL;Liao Yulin
• 通讯作者: Liao Yulin

Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model

• DOI: 10.1161/01.cir.0000160350.20810.0f
• 发表时间: 2005-04-05
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Li, Y;Minamino, T;Kitakaze, M
• 通讯作者: Kitakaze, M

Beta-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemiccaninehearts.

β-肾上腺素受体阻滞剂卡维地洛通过腺苷依赖性机制在缺血性犬心脏中提供心脏保护作用。

• 发表时间: 2004
• 期刊: Circulation 109
• 作者: Inagaki N;Hayahsi T;Arimura T;Koga Y;Takahashi M;Shibata H;Teraoka K;Chikamori T;Yamashina A;Kimura A;Liao Yulin;Ogita Hisakazu;Ogita Hisakazu;Sanada Syoji;Sanada Syoji;Shintani Yasunori;Asanuma Hiroshi
• 通讯作者: Asanuma Hiroshi

Paloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart : role of phosphatidylinositol 3-kinase/Akt pathway.

帕洛昔芬改善缺血性心脏中的冠状动脉灌注、心肌收缩力和心肌代谢：磷脂酰肌醇 3-激酶/Akt 途径的作用。

• 发表时间: 2004
• 期刊: J Cardiovasc Pharmacol 43
• 作者: Inagaki N;Hayahsi T;Arimura T;Koga Y;Takahashi M;Shibata H;Teraoka K;Chikamori T;Yamashina A;Kimura A;Liao Yulin;Ogita Hisakazu
• 通讯作者: Ogita Hisakazu