一氧化氮在雷贝拉唑对大鼠胃黏膜损伤保护中的作用
http://www.100md.com
乐桥良, 林克荣, 张志坚
一氧化氮;雷贝拉唑;胃黏膜损伤;细胞保护乐桥良,林克荣,张志坚.一氧化氮在雷贝拉唑对大鼠胃黏膜损伤保护中的作用. 世界华人消化杂志2006;14(28)2796-2800 各组
 |
| 第1页 |
参见附件(921KB，5页)。
乐桥良, 林克荣, 张志坚, 中国人民解放军南京军区福州总医院消化科 福建省福州市 350025
通讯作者: 乐桥良, 350025, 福建省福州市西二环北路156号, 中国人民解放军南京军区福州总医院消化科. leqliang@sohu.com
电话: 0591-87893856
收稿日期: 2006-06-02 接受日期: 2006-09-01
Role of nitric oxide in the protective effect of rabeprazole on gastric mucosal lesions in rats
Qiao-Liang Le, Ke-Rong Lin, Zhi-Jian Zhang
Qiao-Liang Le, Ke-Rong Lin, Zhi-Jian Zhang, Department of Gastroenterology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou 350025, Fujian Province, China
Correspondence to: Qiao-Liang Le, Department of Gastroenterology, Fuzhou General Hospital of Nanjing Military Command, 156 Xi'erhuan North Road, Fuzhou 350025, Fujian Province, China. leqliang@sohu.com
Received: 2006-06-02 Accepted: 2006-09-01
AbstractAIM:To explore the role of nitric oxide (NO) in the protective effect of rabeprazole on the gastric mucosal lesions in rats.
METHODS: Before gastric mucosal lesion was made in rats by pure alcohol, rabeprazole (20 mg/kg) was administered into the gastric chamber and Nw-nitro-l-arginine methyl ester (l-NAME, 4 mg/kg), l-arginine (250 mg/kg) and d-arginine (250 mg/kg) were injected into the vein. Gastric mucosal blood flow (GMBF) was assessed with laser Doppler flowmetry (LDF); gastric mucosal and serum NO-2/NO-3 were measured by cadmium granulation reduction and colorimetric method; and the changes of ulcer index and the severity of tissue necrosis as well as neutrophil infiltration were observed.
RESULTS: The Ulcer index of the rabeprazole group was markedly lower than that in the controls (5.5 ± 0.5 vs 25.2 ± 2.3, P < 0.01), and the degrees of tissue necrosis and neutrophil infiltration were significantly milder (necrosis ++ - +++/≤+: 1/9 vs 8/2, P < 0.01; infiltration ++ - +++/≤+: 3/7 vs 9/1, P < 0.01). The protective effect of rabeprazole was significantly decreased by prior administration of l-NAME. The inhibitory effect of l-NAME was antagonized by prior administration of l-arginine, but not d-arginine. Rabeprazole administered into the gastric chamber obviously increased GMBF, gastric mucosal and serum NO-2/NO-3, which was prevented by pretreatment with l-NAME, but the antisecretory effect of rabeprazole was not affected by l-NAME.
CONCLUSION: Rabeprazole can exert important protection against gastric mucosal lesions in rats mediated by nitric oxide, and the action of rabeprazole against gastric acid secretion contributes little to the protective effect.
Key Words: Nitric oxide; Rabeprazole; Gastric mucosal lesion; Cytoprotection
Le QL, Lin KR, Zhang ZJ. Role of nitric oxide in the protective effect of rabeprazole on gastric mucosal lesions in rats. Shijie Huaren Xiaohua Zazhi 2006;14(28):2796-2800
摘要
目的: 探讨一氧化氮(NO)在雷贝拉唑对大鼠胃黏膜损伤保护中的作用.
方法: 在乙醇诱导大鼠胃黏膜损伤前, 预先给予雷贝拉唑(20 mg/kg)灌胃, l-硝基-精氨酸甲酯(l-NAME, 4 mg/kg)、l-精氨酸(250 mg/kg)及d-精氨酸(250 mg/kg)iv. 采用激光多普勒血流计(LDF)测定胃黏膜血流量(GMBF), 采用镉粒还原和比色法测定胃黏膜和血浆NO-2/NO-3含量, 并观察胃黏膜损伤指数(UI)、溃疡坏死组织和中性粒细胞浸润严重程度的变化.
结果: 与模型损伤组比, 雷贝拉唑组大鼠UI明显降低(5.5±0.5vs 25.2±2.3, P<0.01), 溃疡坏死组织和中性粒细胞浸润程度明显减轻(坏死物质++ → +++/≤+: 1/9 vs 8/2, P<0.01; 中性粒细胞++ → +++/≤+: 3/7 vs 9/1, P<0.01). 预先用l-NAME处理后, 雷贝拉唑保护胃黏膜损伤作用明显减弱;l-NAME抑制作用可被l-精氨酸拮抗, 而不被d-精氨酸拮抗. 向胃内灌注雷贝拉唑, 可增加GMBF、胃黏膜和血浆NO-2/NO-3, l-NAME可逆转这种作用, 但对雷贝拉唑抑制酸分泌作用无明显影响.
结论: 雷贝拉唑对大鼠胃黏膜损伤保护作用与NO有关, 而与雷贝拉唑抑制酸分泌作用无关.
关键词: 一氧化氮; 雷贝拉唑; 胃黏膜损伤; 细胞保护
乐桥良, 林克荣, 张志坚. 一氧化氮在雷贝拉唑对大鼠胃黏膜损伤保护中的作用. 世界华人消化杂志 2006;14(28):2796-2800
各组大鼠胃黏膜损伤指数变化和组织学观察(n = 10)
2.2 胃组织学观察 损伤模型组大鼠溃疡底部可见大量坏死物质, 周围组织中中性粒细胞浸润明显;雷贝拉唑组溃疡底部坏死物质和周围组织中中性粒细胞浸润均比损伤模型组明显减轻(P<0.01); l-NAME组溃疡底部坏死物质和周围组织中中性粒细胞浸润与损伤模型组比均无明显差异(P>0.05),而比雷贝拉唑组严重(P<0.01); l-精氨酸组与损伤模型组和l-NAME组比二者均明显减轻(P<0.01),与雷贝拉唑组比无明显差异(P>0.05), d-精氨酸组与损伤模型组和l-NAME组比二者均无明显差异,而比雷贝拉唑组严重(P<0.01)(表1).
2.3 GMBF损伤模型组大鼠GMBF与正常对照组比明显降低(P<0.01),雷贝拉唑组与损伤模型组比明显升高(P<0.05),l-NAME组与损伤模型组比无明显差异(P>0.05),而比雷贝拉唑组明显降低(P<0.05)(表2).
表2 Ⅰ-Ⅳ组大鼠GMBF、胃黏膜和血浆NO-2/NO-3及胃液pH的变化(mean±SD,n = 10)
2.4 NO-2/NO-3含量 损伤模型组大鼠胃黏膜和血浆NO-2/NO-3比正常对照组均非常显著增加(P<0.01);雷贝拉唑组比正常对照组非常显著增加(P<0.01),亦比损伤模型组明显增加(P<0.05); l-NAME组与雷贝拉唑组比显著减少(P<0.01),而与正常对照组比无明显差异(P>0.05, 表2).
2.5 胃液pH损伤模型组大鼠胃液pH与正常对照组比明显降低(P<0.05),雷贝拉唑组与损伤模型组比明显升高(P<0.01),l-NAME组与雷贝拉唑组比无明显差异(P>0.05,表2).
3 讨论
雷贝拉唑是人工合成的质子泵抑制剂(proton pump inhibitor, PPI), 通过抑制胃壁细胞分泌小管的H+/K+-ATP酶, 使胃酸分泌的最终步骤阻断, 其抑制作用强而持久, 从而可以治疗消化性溃疡[1-3]. 有研究表明, 雷贝拉唑对胃黏膜损伤具有保护作用[4-13]; Watanabe et al[4]报道雷贝拉唑能有效预防乙醇引起大鼠胃体和胃窦的胃黏膜损伤, 在乙醇引起的溃疡模型中, 也能明显改善其UI; Suzuki et al[5]报道雷贝拉唑对H pylori引起的蒙古沙鼠胃黏膜损伤有细胞保护作用的同时能加强细胞保护适应, 预先给阿司匹林、氯化氨或应激造成的实验性胃黏膜损伤的大鼠胃内灌注雷贝拉唑, 能明显减轻胃黏膜损伤[6], 对胆原反流和应激引起的胃黏膜损害雷贝拉唑亦有很好的保护作用[7-8]; Laheij et al[9]报道雷贝拉唑能明显减轻阿司匹林引起的胃黏膜损伤及胃肠道反应, Shimatani et al[10]发现雷贝拉唑对NSAIDs引起十二指肠球部溃疡有明显防治作用, 雷贝拉唑对危重患者应激性胃黏膜损害及胃黏膜出血有很好的预防作用[11], 对于志愿者口服阿司匹林引起的胃黏膜损伤潘托拉唑也有保护作用[12-13]. 本实验结果显示, 预先用雷贝拉唑给由乙醇诱导胃黏膜损伤大鼠灌胃, 与损伤模型组比, 胃黏膜损伤指数明显降低, 病理组织观察, 其溃疡坏死物质和周围中性粒细胞浸润亦明显减少, 表明雷贝拉唑对大鼠胃黏膜损伤具有保护作用.
NO是由血管内皮细胞产生血管舒张因子[14-15], 近年来有报道, NO对胃黏膜损伤有保护作用[14-23]; Konturek et al[16]发现NO介导了vit C保护健康志愿者口服阿斯匹林诱导的胃黏膜损伤; NO抑制剂l-NAME能增加水应激的胃黏膜损伤, 而NO前体l-精氨酸能明显减轻这种胃黏膜损伤[17-19]; NO可减轻由乙醇诱导的实验性胃黏膜损伤的严重程度[20-23], Kalia et al[20]预先用l-NAME(NOS抑制剂)处理大鼠, 发现会加重由乙醇诱导的胃黏膜损伤, 并且这种胃黏膜损伤能被l-精氨酸逆转, 而不被d-精氨酸逆转, 另外, l-NAME能明显降低大鼠GMBF和胃黏膜血红蛋含量[21], 表明NO对胃黏膜损伤有保护作用. 我们用l-NAME预先处理大鼠, 能明显升高雷贝拉唑降低的胃黏膜损伤指数, 溃疡底部坏死物质增多, 周围中性粒细胞浸润也非常明显, 在l-NAME给药15 min前给予l-精氨酸则能抑制这种损伤作用, 表明NO介导了雷贝拉唑对胃黏膜的保护作用.
本实验结果显示, 向胃内灌注雷贝拉唑, 能明显增加胃黏膜和血浆NO-2/NO-3含量, 同时GMBF亦升高, 而在雷贝拉唑灌胃前20 min给予l-NAME则能逆转这种作用. 本实验结果还显示, 雷贝拉唑能著显提高胃液pH, 抑制胃酸分泌, 而l-NAME则对雷贝拉唑抑制胃酸分泌的作用无明显影响.
总之,雷贝拉唑对大鼠胃黏膜损伤具有保护作用, NO通过增加GMBF参与了这种保护作用,而与雷贝拉唑抑制胃酸分泌作用无关.
4 参考文献
1 Giannini EG, Bilardi C, Dulbecco P, Mamone M, Santi ML, Testa R, Mansi C, Savarino V. A study of 4- and 7-day triple therapy with rabeprazole, high-dose levofloxacin and tinidazole rescue treatment for Helicobacter pylori eradication. Aliment Pharmacol Ther 2006; 23: 281-287 PubMed
2 Hirano I, Zhang Q, Pandolfino JE, Kahrilas PJ. Four-day Bravo pH capsule monitoring with and without proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2005; 3: 1083-1088 PubMed
3 Shimatani T, Inoue M, Kuroiwa T, Horikawa Y. Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression. Aliment Pharmacol Ther 2004; 19: 113-122 PubMed
4 Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arakawa T. Cytoprotective effect of rabeprazole against ethanol-induced gastric mucosal damage: possible involvement of nitric oxide. Drugs Exp Clin Res 2000; 26: 41-45 PubMed
5 Suzuki H, Miyazawa M, Nagahashi S, Sato M, Bessho M, Nagata H, Miura S, Ishii H. Rabeprazole treatment attenuated Helicobacter pylori-associated gastric mucosal lesion formation in Mongolian gerbils. J Gastroenterol Hepatol 2003; 18: 787-795 PubMed
6 Jaworski T, Sarosiek I, Sostarich S, Roeser K, Connor M, Brotze S, Wallner G, Sarosiek J. Restorative impact of rabeprazole on gastric mucus and mucin production impairment during naproxen adminis-tration: its potential clinical significance. Dig Dis Sci 2005; 50: 357-365 PubMed
7 Santarelli L, Gabrielli M, Candelli M, Cremonini F, Nista EC, Cammarota G, Gasbarrini G, Gasbarrini A. Post-cholecystectomy alkaline reactive gastritis: a randomized trial comparing sucralfate versus rabeprazole or no treatment. Eur J Gastroenterol Hepatol 2003; 15: 975-979 PubMed
8 Swiatkowski M, Budzynski J, Klopocka M, Grad K, Pulkowski G, Augustynska B, Suppan K, Fabisiak J. The effect of eight weeks of rabeprazole therapy on nitric oxide plasma level and esophageal pH and motility and motility nitric oxide plasma level in patients with erosive esophagitis. Med Sci Monit 2004; 10: CR46-51 PubMed
9 Laheij RJ, Van Rossum LG, Jansen JB, Verheugt FW. Proton-pump inhibitor therapy for acetylsalicylic acid associated upper gastrointestinal symptoms: a randomized placebo-controlled trial. Aliment Pharmacol Ther 2003; 18: 109-115 PubMed
10 Shimatani T, Inoue M, Yokoya H, Daimaru Y. Evaluation of gastric acid secretion in two patients (each aged over 90 years) with Helicobacter pylori-negative nonsteroidal anti-inflammatory drug-caused duodenal ulcers. J Gastroenterol 2003; 38: 164-169 PubMed
11 Spirt MJ. Stress-related mucosal disease: risk factors and prophylactic therapy. Clin Ther 2004; 26: 197-213 PubMed
12 Itagaki F, Homma M, Yuzawa K, Nishimura M, Naito S, Ueda N, Ohkohchi N, Kohda Y. Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm Pharmacol 2004; 56: 1055-1059 PubMed
13 Mondal U, Ganesan M, Pal TK, Jayakumar M, Chattaraj TK, Roy K, Banerjee SN. Bioequivalence study of rabeprazole sodium on healthy human volunteers.J Indian Med Assoc 2004; 102: 26, 28, 30 PubMed
14 Uchida M, Matsueda K, Shoda R, Muraoka A, Yamato S. Nitric oxide donating compounds inhibit HCl-induced gastric mucosal lesions mainly via prostaglandin. Jpn J Pharmacol 2001; 85: 133-138 PubMed
15 Kwiecien S, Brzozowski T, Konturek PCh, Konturek SJ. The role of reactive oxygen species in action of nitric oxide-donors on stress-induced gastric mucosal lesions. J Physiol Pharmacol 2002; 53: 761-773 PubMed
16 Konturek PC, Kania J, Gessner U, Konturek SJ, Hahn EG, Konturek JW. Effect of vitamin C-releasing acetylsalicylic acid on gastric mucosal damage before and after Helicobacter pylori eradication therapy. Eur J Pharmacol 2004; 506: 169-177 PubMed
17 Ohta Y, Nishida K. Protective effect of L-arginine against stress-induced gastric mucosal lesions in rats and its relation to nitric oxide-mediated inhibition of neutrophil infiltration. Pharmacol Res 2001; 43: 535-541 PubMed
18 Samini M, Moezi L, Jabarizadeh N, Tavakolifar B, Shafaroodi H, Dehpour AR. Evidences for involvement of nitric oxide in the gastroprotective effect of bromocriptine and cyclosporin A on water immersion stress-induced gastric lesions. Pharmacol Res 2002; 46: 519-523 PubMed
19 乐桥良, 文晓冬. 大鼠应激性溃疡中一氧化氮的作用. 世界华人消化杂志 2000; 8: 815-816 WCJD
20 Kalia N, Bardhan KD, Reed MW, Jacob S, Brown NJ. L-Arginine protects and exacerbates ethanol-induced rat gastric mucosal injury. J Gastroenterol Hepatol 2000; 15: 915-924 PubMed
21 Ko JK, Cho CH, Lam SK. Adaptive cytoprotection through modulation of nitric oxide in ethanol-evoked gastritis. World J Gastroenterol 2004; 10: 2503-2508 PubMed
22 Sanchez S, Martin MJ, Ortiz P, Motilva V, Herrerias JM, Alarcon de la Lastra C. Role of prostaglandins and nitric oxide in gastric damage induced by metamizol in rats. Inflamm Res 2002; 51: 385-392 PubMed
23 Gallego-Sandin S, Novalbos J, Rosado A, Gisbert JP, Galvez-Mugica MA, Garcia AG, Pajares JM, Abad-Santos F. Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions. Dig Dis Sci 2004; 49: 1538-1544 PubMed
24 乐桥良,张志坚, 林克荣, 王雯.潘托拉唑对胃黏膜损伤保护作用及其机制.世界华人消化杂志 2005; 13: 2480-2484 WCJD
电编 张敏 编辑 张焕兰
您现在查看是摘要介绍页，详见PDF附件(921KB，5页)。