CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

儿茶酚和腺苷在心肌预处理中的作用

• 批准号: 6979789
• 负责人: MICHAEL Victor COHEN
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6979789
• 关键词: adenosine; biological signal transduction; calcium flux; cardiovascular agents; cardiovascular injury; cell morphology; chemoprevention; cytoprotection; drug screening /evaluation; heart disorder chemotherapy; laboratory rabbit; myocardial ischemia /hypoxia; neurotransmitter agonist; nonhuman therapy evaluation; purinergic receptor; reperfusion

DESCRIPTION (provided by applicant): Coronary artery disease kills more Americans than any other disease. Coronary revascularization with either catheters (PTCA), surgery (CABG), or thrombolytic agent (TPA) has reduced morbidity and mortality from coronary occlusion. Yet there is always a delay between onset of symptoms in acute myocardial infarction and re-establishment of coronary flow. And delay translates into myocardial necrosis. Although it is critical to revascularize the heart if myocardium is to be salvaged, it has now become apparent that the very act of resuming flow after a period of ischemia causes its own form of damage, so-called reperfusion injury. There are many possible causes: free radicals, leukocyte damage and capillary plugging, shifts of Na+ and Ca++, contracture, apoptosis. Histologic features and probably functional characteristics of reperfusion injury are distinct from those caused by ischemia. Treatment at reperfusion in an attempt to attenuate resulting inury has clinical potential. There is no consensus that treatment targeted at reperfusion injury in animal models has been effective. However, a novel adenosine A1/A2 agonist AMP 579 has shown promise. Because of the still proprietary nature of this agent, I will examine properties and mechanisms of protection of NECA, another A1/A 2 agonist. Oddly, A2A receptor blockade aborts protection, but it cannot be mimicked by A2A agonists. I will first define dosing requirements for NECA's protection against reperfusion injury and determine whether a combination of selective A1 and A2 agonists can mimic protection. I will explore NECA's signal transduction pathway leading to protection starting with the Gs and phosphatidylinositol 3-kinase pathways, but also including Gi and NO pathways. Because an AI/A2 agonist can attenuate contracture in ischemia/reperfusion, I plan to see if NECA interferes with accumulation of intracellular Ca++. I will also determine whether NECA decreases intracellular osmolytes and attenuates swelling. Finally, I will see if NECA's salvage of myocardium at reperfusion translates into rapid functional benefits. It is hoped that the potential of this new pharmacologic approach can be defined.

描述（由申请人提供）：冠状动脉疾病比任何其他疾病都要多。采用导管（PTCA）、手术（CABG）或溶栓剂（TPA）进行冠状动脉血运重建可降低冠状动脉闭塞的发病率和死亡率。然而，在急性心肌梗死的症状发作和冠状动脉血流重建之间总是有延迟。延迟就会导致心肌坏死。虽然如果要挽救心肌，使心脏再血管化是至关重要的，但现在已经清楚的是，在缺血一段时间后恢复血流的行为本身会导致其自身形式的损伤，即所谓的再灌注损伤。可能的原因有：自由基、白细胞损伤和毛细血管堵塞、Na+和Ca++移位、挛缩、细胞凋亡。再灌注损伤的组织学特征和可能的功能特征与缺血损伤不同。在再灌注时进行治疗以试图减轻所导致的损伤具有临床潜力。在动物模型中，针对再灌注损伤的治疗是否有效还没有达成共识。然而，一种新的腺苷A1/A2激动剂AMP 579已显示出希望。由于这种药物的专利性质，我将研究另一种A1/A2激动剂NECA的保护特性和机制。奇怪的是，A2 A受体阻断剂中止保护，但它不能被A2 A激动剂模拟。我将首先确定NECA对再灌注损伤的保护的剂量要求，并确定选择性A1和A2激动剂的组合是否可以模拟保护。我将探索NECA的信号转导途径，导致从Gs和磷脂酰肌醇3-激酶途径开始的保护，但也包括Gi和NO途径。因为AI/A2激动剂可以减轻缺血/再灌注中的挛缩，所以我计划观察NECA是否干扰细胞内Ca++的积累。我还将确定NECA是否减少细胞内渗透压和减轻肿胀。最后，我将观察NECA在再灌注时对心肌的挽救是否会转化为快速的功能性益处。希望这种新的药理学方法的潜力可以被定义。

项目成果

Cardioprotection with adenosine A2 receptor activation at reperfusion.

再灌注时腺苷 A2 受体激活的心脏保护作用。

• DOI: 10.1097/01.fjc.0000188161.57018.29
• 发表时间: 2005
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Xu,Zhelong;Mueller,RobertA;Park,Sung-Sik;Boysen,PhilipG;Cohen,MichaelV;Downey,JamesM
• 通讯作者: Downey,JamesM

Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits

• DOI: 10.1023/a:1006856124501
• 发表时间: 1998-09-01
• 期刊: MOLECULAR AND CELLULAR BIOCHEMISTRY
• 影响因子: 4.3
• 作者: Miki, T;Cohen, MV;Downey, JM
• 通讯作者: Downey, JM

Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase.

• DOI: 10.1152/ajpheart.00476.2002
• 发表时间: 2003-02
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Qining Qin;J. Downey;M. Cohen

Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism.

• DOI: 10.1152/ajpheart.00954.2003
• 发表时间: 2004-08
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Qining Qin;Xi-ming Yang;Lin Cui;S. Critz;M. Cohen;Natasha C. Browner;T. Lincoln;J. Downey

Infarct limitation of the second window of protection in a conscious rabbit model.

清醒兔子模型中第二保护窗的梗死限制。

• DOI: 10.1016/0008-6363(96)00026-0
• 发表时间: 1996
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Yang,XM;Baxter,GF;Heads,RJ;Yellon,DM;Downey,JM;Cohen,MV
• 通讯作者: Cohen,MV