CHRONIC CORONARY ARTERY OCCLUSION--EFFECTS OF EXERCISE TRAINING

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，患有IHD的患者 参加以锻炼为基础的康复计划的体验较低 死亡率，而运动训练似乎是关键因素。 训练的有益效果所涉及的机制还不完全 明白了。这项提案将侧重于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 和侧支循环。血管平滑肌的体外分析 比较正常冠脉(VSM)和血管内皮功能 动脉和冠脉闭塞远端的孤立动脉 (侧支依赖的心肌区)。我们的初步研究 提示α-肾上腺素能血管收缩反应增强 血管内皮介导的冠状动脉松弛在侧支循环中受损- 依赖的血管系统。另一方面，运动训练减少 α-肾上腺素能血管收缩与增强血管内皮细胞介导 冠脉血管松弛。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产生 冠脉VSM和血管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 侧支依赖的心肌)和动脉大小(管道，近- 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收缩机制和细胞内钙离子 ([CA]I)调节；2)内皮依赖性(缓激肽，ADP，物质 P，Flow)和非内皮依赖性(硝普钠、腺苷) 松弛反应；3)内皮依赖性改变的机制 松弛包括合成/释放EDRF/一氧化氮和 血管活性前列腺素；4)血管运动反应性 降低灌流氧分压；5)血流反应 活体侧支依赖的心肌。体外试验终点为 测量包括：等长收缩和等长松弛；血管管腔 直径(视频跟踪成像技术)；放射性同位素通量(42K) 和[Ca]i(Fura-2微量荧光法)。我们期待着那次演习 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 血管紧张剂/血管扩张剂对增强血管舒张性和 优化侧支依赖心肌的心肌血流量。

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.