MECHANISMS OF CORONARY FLOW REGULATION BY ADENOSINE

腺苷调节冠状动脉血流的机制

• 批准号: 3339113
• 负责人: S. Jamal Mustafa
• 金额: $ 7.3万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-30 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339113
• 关键词: adenosine; aminophylline; calcium transporting ATPase; cellular pathology; coronary disorder; coronary vasodilator; dogs; electron microscopy; guinea pigs; heart circulation; heart pharmacology; hypertension; indomethacin; isolation perfusion; laboratory rat; molecular pathology; oxygen tension; prostaglandins; radiotracer; reactive hyperemia; scintillation counter; vascular resistance; vascular smooth muscle; vasoactive agent; ventricular hypertrophy; xanthines

It is widely accepted that adenosine plays an important role in the regulation of coronary blood flow. The cellular and subcellular mechanisms by which adenosine produces the relaxation of coronary smooth muscle have been investigated in this laboratory for the last several years but are still not completely understood. Several possibilities, including the existence of adenosine receptor (Ra subtype) from this laboratory, changes in the intracellular calcium and ion fluxes have been proposed but the direct evidence is lacking. The proposed studies which are the continuation of the earlier work are directed at some of these possibilities. A combination of models will be used for these studies. We propose to study the: (a) relaxation of precontracted coronary artery by adenosine and its analogs in the absence of calcium and its antagonism to define the receptor subtype; (b) intracellular calcium lowering effect of adenosine and its analogs by measuring the efflux of calcium in the absence of extracellular calcium and the direct effects on intracellular organelles using skinned muscle; (c) intracellular calcium lowering effect of adenosine and its analogs using 3, 4, diaminopyridine induced phasic contraction of the coronary artery and its comparison to calcium entry blockers; (d) effect of adenosine and its analogs on 42K, 24Na and 36C1 fluxes; (e) binding of 3H-NECA (Ra site) and 125I-HPIA (Ri site) in purified plasma membrane, coronary microvessels and isolated cells (vascular smooth, cardiac muscle, endothelial); (f) order of potency of the adenylate cyclase activation using adenosine analogs and the protein phosphorylation in coronary plasma membranes; (g) characterization of adenosine receptor in human coronary arteries; (h) isolation and purification of adneosine receptor binding protein from coronary plasma membrane fraction; (i) adenosine receptor in hypertensive rat aortae both in the presence and absence of calcium using isolated vascular rings and measure the adenosine receptor binding in coronary microvessel preparation of hypertensive rat hearts; and finally (j) release of adenosine in the presence of methylxanthine during reactive hyperemia and adenosine infusion using Langendorf hearts. The data obtained from these studies should represent a major advance in our understanding of the metabolic regulation of coronary flow at a cellular and subcellular level which can lead to the development of rationale therapeutic approaches for regional blood flow disorders.

人们普遍认为，腺苷在 调节冠状动脉血流。 细胞和亚细胞机制 通过其中，腺苷会产生冠状动脉平滑肌的放松 过去几年在该实验室进行了调查，但 仍然没有完全理解。 几种可能性，包括 来自该实验室的腺苷受体（RA亚型）的存在，变化 已经提出了细胞内钙和离子通量 缺乏直接证据。 提出的研究是 较早作品的延续针对其中一些 可能性。 这些研究将使用模型的组合。 我们 提议研究以下方面：（a）通过 腺苷及其在没有钙及其对拮抗作用的情况下的类似物 定义受体亚型； （b）细胞内钙的降低效应 腺苷及其类似物通过在不存在的情况下测量钙的排出 细胞外钙和对细胞内细胞器的直接影响 使用皮肤肌肉； （c）细胞内钙的降低效应 腺苷及其类似物使用3、4，二氨基吡啶诱导的阶段 冠状动脉的收缩及其与钙进入的比较 阻滞剂； （d）腺苷及其类似物对42K，24NA和36C1的影响 磁通； （e）3H-NECA（RA站点）和125i-HPIA（RI位点）的结合 纯化的质膜，冠状微血管和分离的细胞 （血管光滑，心肌，内皮）； （f）效力的顺序 使用腺苷类似物和蛋白质的腺苷酸环化酶激活 冠状动脉质膜的磷酸化； （g）表征 人冠状动脉中的腺苷受体； （h）隔离和 从冠状血浆中纯化辅助受体结合蛋白 膜分数； （i）高血压大鼠主动脉中的腺苷受体 在存在和不存在钙的情况下，使用孤立的血管环和 测量冠状微血管制剂中的腺苷受体结合 高血压大鼠心；最后（j）释放腺苷 反应性充血和腺苷输注期间存在甲基黄嘌呤 使用Langendorf心。 从这些研究中获得的数据应 代表了我们对代谢调节的理解的重大进步 在细胞和亚细胞水平上的冠状动脉流量 开发区域血流的理由治疗方法 疾病。