ROLE OF MICROVASCULAR DISORDERS IN THE PATHOGENESIS OF MYOCARDIAL ISCHEMIA

我们已经建立了微血管疾病的动物模型。对大鼠和猪长期给予一氧化氮抑制剂（N ^-硝基-L-精氨酸甲酯，L-NAME），长期抑制一氧化氮合酶，可引起冠状动脉血管结构变化（中膜增厚和血管周围纤维化）。<omega>我们研究了在猪模型中微血管对5-羟色胺的反应是否改变。麻醉后，我们向冠状动脉内注入5-羟色胺，发现L-NAME治疗组猪的冠状动脉血流量显著减少，而对照组猪的冠状动脉血流量则没有减少。因此，这些数据表明，冠状动脉血流量的5-羟色胺的增强减少是由于微血管的增强收缩。我们将罂粟碱注入冠状动脉，发现该药可引起心肌缺血（心肌乳酸盐生成）。由于罂粟碱诱导的心肌缺血与冠状动脉血流量增加有关，我们得出结论，罂粟碱诱导的心肌缺血是由局部心肌血流量分布改变引起的，我们研究了L-精氨酸给药对微血管性心绞痛患者内皮依赖性冠状动脉血管舒张的影响，发现补充L-精氨酸可改善这些患者的乙酰胆碱诱导的内皮依赖性血管舒张。本研究还探讨了缓激肽舒张冠状动脉的机制。我们发现，缓激肽诱导的冠状动脉血管舒张几乎完全抑制NO合成的抑制剂和血管紧张素转换酶抑制剂依那普利拉显着增强。

We have created animal models of microvascular disorders. Long-term inhibition of nitric oxide synthase with administering chronically an nitric oxide inhibitor (N^<omega>-nitro-L-arginine methyl ester, L-NAME) to rats and pigs caused coronary vascular structural changes (medial thickening and perivascular fibrosis). We examined whether microvascular responses to serotonin is altered in the pig model. After anesthesia, we infused serotonin into the coronary artery and found that the drug significantly decreased coronary blood flow in the L-NAME treated pigs but not in the control pigs.the vasomotor response to serotonin was similar between the two groups. Thus, these data suggest that the enhanced decrease in coronary blood flow to serotonin was due to augmented constriction of microvessels.We aimed to provoke myocardial ischemia in the pig model. We administered papaverine into the coronary artery and found that the drug induced myocardial ischemia (myocardial lactate production). Because the papaverine-induced myocardial ischemia was associated with increased coronary blood flow, we concluded that the papaverine-induced myocardial ischemia was caused by altered distribution of regional myocardial blood flow.We examined effects of L-arginine administration on endothelium-dependent coronary vasodilation in patients with microvascular angina and found that L-arginine supplementation improved acetylcholine-induced endothelium-dependent vasodilation in those patients. We also explored to determined the mechanism of bradykinin-induced coronary vasodilation in humans. We found that the bradykinin-induced coronary vasodilation was nearly completely inhibited by an inhibitor of NO synthesis and markedly augmented by an angiotensin-converting enzyme inhibitor enalaprilat.