Fukumoto Y, Shimokawa H, Kozai T, Kadokami T, Kuwata K, Yonemitsu Y, Kuga T, Egashira K, Sueishi K, Takeshita A
Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
Circulation. 1997 Nov 4;96(9):3104-11. doi: 10.1161/01.cir.96.9.3104.
We recently developed a porcine model in which chronic, local treatment with interleukin-1beta (IL-1beta) causes coronary arteriosclerotic changes and hyperconstrictive responses. Inflammatory cytokines are known to induce inducible NO synthase (iNOS) in the vascular smooth muscle. This study was designed to examine whether or not the production of NO by iNOS has a protective or deleterious effect on the coronary artery in vivo.
A segment of the porcine coronary artery was aseptically wrapped with cotton mesh absorbing IL-1beta suspension. We inhibited both eNOS and iNOS activity by cotreatment with L-NAME (a nonspecific inhibitor of NOS) and iNOS activity alone by aminoguanidine (a selective inhibitor of iNOS). Immunostaining showed that iNOS was absent in the normal coronary artery, whereas it was highly expressed 1 day after the application of IL-1beta and thereafter downregulated until 14 days. In contrast, eNOS was well maintained throughout the study period. Two weeks after the operation, hyperconstrictive responses to intracoronary serotonin and neointimal formation were noted at the IL-1beta-treated site, and both responses were significantly greater at the site cotreated with either L-NAME or aminoguanidine.
These results indicate that iNOS is transiently induced in vivo in response to local inflammation and that NO produced by iNOS exerts an inhibitory effect against the cytokine-induced proliferative/vasospastic changes of the coronary artery in vivo.
我们最近建立了一种猪模型，其中白细胞介素-1β（IL-1β）的慢性局部治疗会导致冠状动脉粥样硬化改变和过度收缩反应。已知炎症细胞因子可诱导血管平滑肌中的诱导型一氧化氮合酶（iNOS）。本研究旨在探讨iNOS产生的一氧化氮（NO）在体内对冠状动脉是具有保护作用还是有害作用。
用吸收IL-1β悬浮液的棉网无菌包裹一段猪冠状动脉。我们通过联合使用L-NAME（一种非特异性一氧化氮合酶抑制剂）抑制内皮型一氧化氮合酶（eNOS）和iNOS的活性，并单独使用氨基胍（一种iNOS的选择性抑制剂）抑制iNOS的活性。免疫染色显示，正常冠状动脉中不存在iNOS，而在应用IL-1β后1天iNOS高度表达，此后下调直至14天。相比之下，在整个研究期间eNOS保持良好。术后两周，在IL-1β处理部位观察到对冠状动脉内5-羟色胺的过度收缩反应和内膜增生，并且在联合使用L-NAME或氨基胍处理的部位，这两种反应都明显更大。
这些结果表明，iNOS在体内因局部炎症而被短暂诱导，并且iNOS产生的NO在体内对细胞因子诱导的冠状动脉增殖/血管痉挛性改变发挥抑制作用。
