Castañeda A A, Kim Y S, Chang L K, Cui Y, Mercer D W
Department of Surgery, University of Texas-Houston Medical School, Houston, USA.
Surgery. 2000 Sep;128(3):422-8. doi: 10.1067/msy.2000.107982.
Bombesin prevents gastric injury primarily by the release of endogenous gastrin. Gastroprotection by exogenous gastrin is negated by nitric oxide synthase inhibition, which implicates a role for nitric oxide as a protective mediator. Because both endothelial and inducible isoforms of this enzyme can play a role in mucosal defense, this study was done to examine the contrasting effects of 2 nitric oxide synthase inhibitors on bombesin-induced gastroprotection.
Rats were given subcutaneous saline or bombesin (10-100 microg/kg) 30 minutes before they received a 1-mL orogastric bolus of acidified ethanol (150 mmol/L of hydrochloric acid/50% ethanol) and rats were killed 5 minutes later for assessment of macroscopic injury (mm(2)). Gastric mucosal blood flow was measured by laser Doppler. Endothelial, neural, and inducible nitric oxide synthase were assessed by using Western immunoblot.
Bombesin decreased gastric mucosal damage, and dose-dependently increased blood flow when compared with saline-treated rats. Endothelial but not neural or inducible nitric oxide synthase immunoreactivity was increased by bombesin. In additional studies, intraperitoneal administration of N(G)-nitro-l-arginine methyl ester (l-NAME, 5-10 mg/kg), a nonselective nitric oxide synthase inhibitor, negated bombesin-induced gastroprotection and hyperemia, whereas the selective inducible inhibitor aminoguanidine (45 mg/kg) did not. Subcutaneous (SC) l-arginine (300 mg/kg), but not d-arginine, abolished the effects of l-NAME.
Taken together, these data suggest that nitric oxide produced by the endothelial isoform of nitric oxide synthase plays an important role in mediating the gastroprotective and hyperemic actions associated with bombesin.
蛙皮素主要通过释放内源性胃泌素来预防胃损伤。外源性胃泌素的胃保护作用可被一氧化氮合酶抑制所抵消，这表明一氧化氮作为一种保护介质发挥作用。由于该酶的内皮型和诱导型同工酶均可在黏膜防御中发挥作用，因此进行本研究以检测两种一氧化氮合酶抑制剂对蛙皮素诱导的胃保护作用的不同影响。
在大鼠接受1 mL经口酸化乙醇（150 mmol/L盐酸/50%乙醇）推注前30分钟，皮下给予生理盐水或蛙皮素（10 - 100 μg/kg），5分钟后处死大鼠以评估大体损伤（mm²）。通过激光多普勒测量胃黏膜血流量。使用蛋白质免疫印迹法评估内皮型、神经型和诱导型一氧化氮合酶。
与生理盐水处理的大鼠相比，蛙皮素减少了胃黏膜损伤，并剂量依赖性地增加了血流量。蛙皮素增加了内皮型一氧化氮合酶的免疫反应性，但未增加神经型或诱导型一氧化氮合酶的免疫反应性。在进一步的研究中，腹腔注射非选择性一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME，5 - 10 mg/kg）可抵消蛙皮素诱导的胃保护作用和充血，而选择性诱导型抑制剂氨基胍（45 mg/kg）则无此作用。皮下注射（SC）L-精氨酸（300 mg/kg）而非D-精氨酸可消除L-NAME的作用。
综上所述，这些数据表明一氧化氮合酶的内皮型同工酶产生的一氧化氮在介导与蛙皮素相关的胃保护作用和充血作用中起重要作用。
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