Department of Cardiac Surgery, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szeged, Hungary.
J Surg Res. 2019 Dec;244:241-250. doi: 10.1016/j.jss.2019.06.053. Epub 2019 Jul 10.
Ischemic preconditioning (IPC) can provide a defense against ischemia-reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR.
Intestinal IR was induced in sodium pentobarbital-anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined.
Ischemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects.
Our data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.
缺血预处理（IPC）可以为许多器官的缺血再灌注（IR）诱导的急性炎症和屏障功能障碍提供防御。因为一氧化氮（NO）已被牵连为 IPC 机制中的触发或介质，并且神经元型一氧化氮合酶（nNOS）是胃肠道中 NOS 的主要同工酶，所以我们的目的是研究 nNOS 在 IPC 诱导的肠系膜 IR 后保护中的作用。
在戊巴比妥钠麻醉的狗中通过夹闭肠系膜上动脉 60 分钟来诱导肠道 IR，然后再进行 2 小时的再灌注（IR 组；n=7）。在进一步的组中，在存在或不存在选择性抑制 nNOS 的情况下使用 IPC（三个 5 分钟缺血/5 分钟再灌注周期），用 7-硝基吲唑（IPC 前 15 分钟静脉内给予 5mg/kg ，静脉内推注），每组 n=6。监测肠系膜血管阻力、黏膜内 pH 值（pHi）和小肠蠕动的变化。还测定了血浆亚硝酸盐/硝酸盐水平、肠道 NO 合酶活性、白细胞积聚、肥大细胞脱颗粒和组织学损伤。
缺血显着降低肠系膜血管阻力和 pHi，而 IR 诱导短暂的肠道蠕动亢进和急性炎症反应。IPC 促进 pHi 恢复，减轻运动功能障碍，增加 NOS 依赖性 NO 产生，并减少白细胞积聚、肥大细胞脱颗粒和黏膜损伤。用 7-硝基吲唑预处理阻止了 IPC 诱导的 NO 可用性增加、pHi 恢复以及抗炎和形态学作用。
我们的数据表明，由肠道 nNOS 产生的 NO 通过抑制与 IR 相关的急性炎症反应，在 IPC 相关的组织保护中起着关键作用。
