Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury
Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury
复制标题
DOI：
10.1161/01.hyp.0000092440.52239.39
复制
发表时间：
2003-10-01
期刊：
影响因子：
8.3
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Chen, R;Iwai, M;Horiuchi, M
为了研究缓激肽-NO 系统在 ACE 抑制剂作用中的可能作用，我们通过使用 AT(1)a 受体缺陷 (AT(1)aKO) 小鼠研究了 ACE 抑制剂咪达普利对炎症性血管损伤的影响。将聚乙烯袖带放置在 AT(1)aKO 小鼠和野生型（WT；C57BL/6J）小鼠的股动脉周围。放置袖带14天后测量动脉横截面的新内膜面积。通过灌胃给予低剂量的咪达普利（每天 1 mg/kg），不影响血压。术后7天采用免疫组化染色和逆转录聚合酶链反应（RT-PCR）检测单核细胞趋化蛋白（MCP）-1和肿瘤坏死因子（TNF）-α的表达。与 WT 小鼠相比，AT(1)aKO 小鼠受损动脉中的新内膜形成、血管平滑肌细胞增殖以及 MCP-1 和 TNF-α 的表达减弱。咪达普利抑制 AT(1)aKO 小鼠以及 WT 小鼠中的新内膜形成、血管平滑肌细胞的 DNA 合成以及 MCP-1 和 TNF-α 的表达。此外，咪达普利在放置袖带后增加了组织 cGMP 含量。在 WT 和 AT(1)aKO 小鼠中，缓激肽受体拮抗剂 Hoechst 140 或 NO 合酶抑制剂 L-NAME 显着降低或消除了咪达普利的这些抑制作用。咪达普利治疗不会改变受损动脉中 AT(2) 受体和 RT-PCR 检测到的 ACE 表达。这些结果表明，咪达普利对血管重塑的有益作用不仅阻断血管紧张素 II 的产生，而且激活缓激肽-NO 系统也发挥着重要作用。
To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT(1)a-receptor-deficient (AT(1)aKO) mice. A polyethylene cuff was placed around the femoral artery of AT(1)aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT(1)aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT(1)aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT(1)aKO mice. Treatment with imidapril did not change AT(2) receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.