CHRONIC CORONARY ARTERY OCCLUSION--EFFECTS OF EXERCISE TRAINING

慢性冠状动脉闭塞——运动训练的影响

• 批准号: 6296876
• 负责人: JANET L PARKER
• 金额: $ 27.57万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6296876
• 关键词: adenosine diphosphate; bradykinin; calcium; calcium flux; cardiovascular pharmacology; collateral circulation; coronary occlusion /thrombosis; disease /disorder model; endothelin; environmental adaptation; exercise; fluorimetry; heart function; miniature swine; muscle contraction; nitric oxide; nitroferricyanide; norepinephrine; stimulant /agonist; substance P; vascular smooth muscle; vasoconstriction; vasomotion; vasopressins

Ischemic heart disease (IHD) remains the most common serious health problem of contemporary western society. However, patients with IHD enrolled in exercise-based rehabilitation programs experience lower mortality rates, and exercise training appears to be the key ingredient. Mechanisms involved in the beneficial effects of training are not fully understood. This proposal will focus on coronary effects of exercise training in an experimental model of chronic coronary artery occlusion and collateral perfusion. In vitro analyses of vascular smooth muscle (VSM) and endothelium function will be compared in normal coronary arteries and in arteries isolated distal to the coronary occlusion (collateral-dependent myocardial region). Our preliminary studies suggest that alpha-adrenergic vasoconstrictor responses are enhanced and endothelium-mediated coronary relaxation is impaired in collateral- dependent vasculature. On the other hand, exercise training decreases alpha-adrenergic vasoconstriction and enhances endothelium-mediated coronary vasorelaxation. Our overall hypothesis is that exercise training of animals exposed to chronic coronary artery occlusion produces beneficial adaptive responses of coronary VSM and endothelium function; functional alterations are dependent upon vascular site (normal vs. collateral-dependent myocardium) and on artery size (conduit, near- resistance, resistance arteries). Specific aims of the current project involve in vitro evaluation of 1) agonist (norepinephrine, vasopressin, endothelin)-mediated VSM contractile mechanisms and intracellular Ca2+ ([Ca]i) regulation; 2) endothelium-dependent (bradykinin, ADP, substance P, flow) and endothelium-independent (nitroprusside, adenosine) relaxation responses; 3) mechanisms of altered endothelium-dependent relaxation including synthesis/release of EDRF/nitric oxide and vasoactive prostanoids; 4) vasomotor responsiveness in the presence of reduced perfusate oxygen tension; and 5) blood flow responses of collateral-dependent myocardium in vivo. In vitro end points to be measured include: isometric contraction and relaxation; vessel luminal diameter (videotracking imaging techniques); radioisotope fluxes (42K) and [Ca]i (fura-2 microfluorometry). We anticipate that exercise training will have a beneficial effect upon intrinsic function of VSM and endothelium in coronary-occluded hearts, shifting the balance of vasoconstrictor/vasodilator influence toward increased vasorelaxation and optimization of myocardial blood flow to collateral dependent myocardium.

缺血性心脏病（IHD）仍然是最常见的严重健康问题 当代西方社会的问题。 然而，IHD 患者 参加基于运动的康复计划的经验较低 死亡率，而运动训练似乎是关键因素。 涉及培训有益效果的机制尚未充分发挥 明白了。 该提案将重点关注运动对冠状动脉的影响 慢性冠状动脉闭塞实验模型的训练 和侧支灌注。 血管平滑肌的体外分析 (VSM) 和内皮功能将在正常冠状动脉中进行比较 动脉和冠状动脉闭塞远端分离的动脉中 （侧支依赖性心肌区域）。 我们的初步研究 表明α-肾上腺素能血管收缩反应增强， 内皮介导的冠状动脉舒张在侧支循环中受损 依赖性脉管系统。 另一方面，运动训练减少 α-肾上腺素能血管收缩并增强内皮介导 冠状血管舒张。 我们的总体假设是锻炼 对暴露于慢性冠状动脉闭塞的动物进行训练会产生 冠状动脉 VSM 和内皮功能的有益适应性反应； 功能改变取决于血管部位（正常与非正常） 侧支依赖性心肌）和动脉大小（导管、近端 阻力、阻力动脉）。 当前项目的具体目标 涉及 1) 激动剂（去甲肾上腺素、加压素、 内皮素）介导的 VSM 收缩机制和细胞内 Ca2+ ([Ca]i) 调节； 2）内皮依赖性（缓激肽、ADP、物质 P，流量）和内皮依赖性（硝普钠，腺苷） 放松反应； 3）改变内皮依赖性的机制 弛豫包括 EDRF/一氧化氮的合成/释放和 血管活性前列腺素； 4) 存在血管舒缩反应 降低灌注液氧分压； 5) 血流反应 体内侧支依赖性心肌。 体外终点为 测量的内容包括：等长收缩和放松；血管腔 直径（视频跟踪成像技术）；放射性同位素通量 (42K) 和[Ca]i（fura-2显微荧光测定法）。 我们预计该演习 训练将对 VSM 的内在功能产生有益的影响 冠状动脉闭塞心脏中的内皮细胞，改变了平衡 血管收缩剂/血管舒张剂对增加血管舒张的影响 优化流向侧支依赖性心肌的心肌血流。