Treatment and prevention of microvascular disorders

我们已经建立了微血管疾病的动物模型。长期给予一氧化氮抑制剂（N^< ω b> -硝基- l -精氨酸甲酯，L-NAME）对大鼠和猪的一氧化氮合酶的长期抑制可引起冠状动脉血管结构改变（内侧增厚和血管周围纤维化）。我们检查了猪模型中微血管对血清素的反应是否改变。麻醉后，我们将5 -羟色胺注入冠状动脉，发现药物显著降低了L-NAME治疗猪的冠状动脉血流量，而对照组猪没有。两组对血清素的血管舒缩反应相似。因此，这些数据表明，冠状动脉血液流向血清素的增强减少是由于微血管收缩增强。我们的目的是在猪模型中引起心肌缺血。我们将罂粟碱注入冠状动脉，发现该药物引起心肌缺血（心肌乳酸生成）。由于罂粟碱引起的心肌缺血与冠状动脉血流量增加有关，我们认为罂粟碱引起的心肌缺血是由局部心肌血流量分布的改变引起的。我们还研究了添加血管紧张素II受体拮抗剂是否能改善冠状动脉微血管结构变化的发展，从而减少罂粟碱引起的心肌缺血。我们发现血管紧张素II型1受体拮抗剂既可以阻止微血管结构改变的发展，也可以阻止罂粟碱引起的心肌缺血。

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 respons 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 also examined whether addition of angiotensin II receptor antagonists ameliorate the development of structural changes in coronary microvessels and thus reduce papaverine-induced myocardial ischemia. We found that the angiotensin II type 1 receptor antagonists prevented both the development of microvascular structural changes and papaverine-induced myocardial ischemia.