EFFECTS OF DRUGS UPON MYOCARDIAL HYPOXIA

本提案的长期目标是继续分析 药物对局部心肌血流量和心肌功能的作用 在不同的缺血模型中。 一个主要目标是确定 特定药理学药物增加冠状动脉粥样硬化的机制 侧支循环血流量及其对跨壁分布的影响 犬单冠状动脉和多冠状动脉内、外膜下 闭塞和/或狭窄。 未成熟或发育不良的犬 侧支血管（急性闭塞）和成熟或发育良好的侧支血管 将使用侧支血管（慢性闭塞）。 心肌节段 将在正常、部分缺血的 和中央缺血区域以及节段缩短的变化（% SS）将被 与局部血流变化相关（放射性微球）。 通过使用选择性β和α受体激动剂和拮抗剂， 特异性心动过缓药物和迷走神经刺激， 被认为影响侧支灌注的变量的数量， 也就是说，心率，非缺血心肌的小动脉阻力，α 1 和α 2肾上腺素能受体。 在多 闭塞研究，β受体阻滞剂的有效性， 迷走神经刺激和特定的心动过缓药物，以增加冠状动脉 部分闭塞的冠状血管远端的灌注压，从而 将研究增加完全闭塞区域的侧支血流 侧支血管不成熟或发育良好的犬。 第二主 目的将是确定不同的慢通道钙的作用， 进入阻滞剂对发育良好的犬的侧支功能的影响 侧支血管 此外，这些试剂的相对选择性 扩张冠状动脉阻力血管， 和侧支血管进行评估 放射性微球， 逆行压力和血流将被用作侧支功能的指标 并将不同钙通道阻滞剂的剂量反应曲线 通过冠状动脉内或静脉内输注获得。 硝酸甘油和 腺苷，已知选择性扩张侧支血管的药物，或 小动脉阻力血管，分别将用于目的， 对比 由于缺血性心脏病患者通常有多个 闭塞和/或狭窄，并具有广泛不同程度的侧支循环 发展，这些研究应该提供重要的见解，机制 某些药理学试剂通过其减轻心肌缺血。

The long term goal of the present proposal is to continue an analysis of drug actions on regional myocardial blood flow and cardiac muscle function in different models of ischemia. One major objective will be to determine mechanisms whereby specific pharmacological agents increase coronary collateral blood flow and influence its transmural distribution between subendocardium and subepicardium in dogs with single or multiple coronary occlusions and/or stenoses. Dogs with immature or poorly developed collateral vessels (acute occlusion) and ones with mature or well developed collateral vessels (chronic occlusion) will be used. Myocardial segment function (sonomicrometry) will be monitored in normal, partially ischemic and central ischemic areas and changes in segment shortening (% SS) will be correlated with changes in regional blood flow (radioactive microspheres). By using selective beta and alpha receptor agonists and antagonists, specific bradycardic agents and vagal stimulation, the importance of a number of variables which are thought to influence collateral perfusion, i.e., heart rate, arteriolar resistance in nonischemic myocardium, alpha1 and alpha2 adrenergic receptors, will be investigated. In the multiple occlusion studies, the effectiveness of beta receptor blocking agents, vagal stimulation and specific bradycardic drugs to increase coronary perfusion pressure distal to a partially occluded coronary vessel, thereby increasing collateral blood flow to a totally occluded area will be studied in dogs with immature or well-developed collateral vessels. A second major objective will be to determine the effect of different slow channel calcium entry blockers on collateral function in dogs with well developed collateral vessels. In addition, the relative selectivity of these agents to dilate coronary resistance vessels versus large epicardial conductance and collateral vessels will be assessed. Radioactive microspheres, retrograde pressure and flow will be used as indices of collateral function and dose-response curves to different calcium channel blockers will be obtained by intracoronary or intravenous infusion. Nitroglycerin and adenosine, agents known to selectively dilate collateral vessels or arteriolar resistance vessels, respectively, will be used for purposes of comparison. Since patients with ischemic heart disease often have multiple occlusion and/or stenoses and have widely varying degrees of collateral development, these studies should lend important insight as to mechanisms by which certain pharmacological agents relieve myocardial ischemia.