Treatment and prevention of microvascular disorders

微血管疾病的治疗和预防

• 批准号: 07557346
• 负责人: EGASHIRA Kensuke
• 金额: $ 1.22万
• 依托单位: KYUSHU UNIVERSITY FACULTY OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557346/
• 关键词: angina pectoris; nitric oxide; endothelial cells; coronary circulation; serotonin; angiotensin-converting enzyme inhibitor; angiotensin receptors; 血管病変; 心筋虚血; 病理学

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.

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^<omega>-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）。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，但在对照猪中没有。血管对5-羟色胺的反应在两组之间相似。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。我们还研究了血管紧张素II受体拮抗剂的加入是否改善冠状动脉微血管结构变化的发展，从而减少罂粟碱诱导的心肌缺血。我们发现，血管紧张素II 1型受体拮抗剂防止微血管结构的变化和罂粟碱诱导的心肌缺血的发展。

项目成果

Itoh A.et al: "Chronic.inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs" Circulation. 92. 2636-2644 (1995)

Itoh A.等人：“内皮源性一氧化氮合成的慢性抑制会导致猪冠状动脉微血管结构变化和对血清素的高反应性”循环。

Katsuda Y Egashira K Akatsuka Y Narishige T Shimokawa H Takeshita A.: "Endothelium-derived nitric oxide does not modulate metabolic coronary vasodilation induced b tachycardia in dogs." J Cardiovasc Pharmac. 26. 437-444 (1995)

Katsuda Y Egashira K Akatsuka Y Narishige T Shimokawa H Takeshita A.：“内皮源性一氧化氮不会调节狗的代谢性冠状血管舒张引起的心动过速。”

Egashira K et al: "Effects of L-arginine on endothelium-dependent..." Circulation. 94. 130-134 (1996)

Egashira K 等人：“L-精氨酸对内皮依赖性......的影响”循环。

Egashira K Hirooka Y Kai H Sugimachi M Suzuki S Inou T Takeshita A.: "Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasodilation in patients with hypercholesterolemia." Circulation. 89. 2519-2524 (1994)

Egashira K Hirooka Y Kai H Sugimachi M Suzuki S Inou T Takeshita A.：“用普伐他汀降低血清胆固醇可改善高胆固醇血症患者的内皮依赖性冠状血管舒张。”

Takemoto M Egashira K Usui M Numaguchi K Tomita H Tsutsui H Shimokawa H Sueishi K Takeshita A.: "Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-ter

Takemoto M Egashira K Usui M Numaguchi K Tomita H Tsutsui H Shimokawa H Sueishi K Takeshita A.：“组织血管紧张素转换酶活性在长期运动引起的冠状血管和心肌结构变化的发病机制中的重要作用