颈交感神经干离断对浸水大鼠胃粘膜血流量的影响
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摘要
前言
应激性溃疡(SU)是临床危重疾病的常见并发症。胃粘膜血流量(GMBF)是维持胃粘膜完整性的重要因子，也是众多粘膜保护因子发挥作用的共同机制。星状神经节阻滞(SGB)是一种较常用的神经阻滞技术，在国内外的疼痛治疗中被广泛应用。实验证明：大鼠颈交感神经干离断(TCST)可以模拟人类的SGB，星状神经节切除可减弱应激性溃疡的严重程度。但有关其内在的作用机制尚未见报道。本实验以经典的浸水应激造成大鼠急性胃粘膜损伤，观察颈交感神经干离断对应激大鼠胃粘膜血流量、血浆内皮素-1(ET-1)、血清一氧化氮(NO)含量的变化，初步探讨星状神经节阻滞对胃粘膜血流量的影响及其可能的作用机制。
材料与方法
雄性SD大鼠30只，体重200-250克。随机分为3组每组10只：Ⅰ组为正常对照组；Ⅱ组为应激对照组；Ⅲ组为颈交感神经干离断后应激组。首先制备鼠颈交感神经干离断模型：各组大鼠均禁食24h，禁水1h。2.5％戊巴比妥钠40mg／kg腹腔注射将大鼠麻醉。在显微镜下于颈总动脉分叉处的背侧面找到颈上神经节，Ⅰ、Ⅱ组只将颈交感神经干暴露、分离，不离断；Ⅲ组距其下3mm处离断颈交感神经干并将断端结扎。然后进行浸水束缚应激：以上大鼠均于术后禁食24h后乙醚轻度麻醉，Ⅱ、Ⅲ组大鼠束缚四肢于木板上，待其清醒后将动物垂直浸水(水温23±1℃)至剑突水平，浸水6h取出。
后进行各项指标的的观察及标本的采集：2.5％戊巴比妥钠腹腔注射再次将大鼠麻醉，于剑突下沿正中线剖腹并游离出胃，在胃
幽门前壁少血管处切一 snun ／J’口。插人激光多普勒血流仪探头
分别于胃窦、胃体部的大小弯处4点测GMBF，取其平均值。后抽
取腹主动脉血4mL，取ZrnL注人含抗凝剂的试管中，混匀，离心
后，分高血浆。另取ZInL静置、离心、取上清。以上标本均置
一20 t保存。放免法测定血浆ET一二浓度。硝酸还原酶法测定
血清中亚硝酸盐浓度以间接反映NO含量。切除全胃，沿胃大弯
切开，经生理盐水漂洗后，按Gllth标准评定粘膜损伤指数（UI人
剪取1小块胃体上部粘膜，福尔马林固定，常规石蜡切片，y染色
后，进行组织学观察。
实验结果应用SPSS V10．0专业统计软件进行数据处理，数据
均以 k。S表示，两样本间均数比较用 t检验（tUdent引叫 人两
变量间关系用直线相关分析。P＜0．05为统计学差异显著，
P＜0．of为统计学差异非常显著。
结 果
各组大鼠的体重无显著差异。I组中1只大鼠因戊巴比妥钠
腹腔注射再次麻醉时死于呼吸抑制，被排除本研究。I组大鼠未
见应激性溃疡发生＊组和＊组大鼠可见胃粘膜的点状或／和线
条状的出血。11组中少数表现为粘膜水肿及糜烂。Ill组的UI明
显低于＊组。光镜下＊组的粘膜损伤程度明显轻于＊组。与互
组相比11组和Ill组GMBF均明显降低，但Ill组与11组比较
GMBF明显升高，11组和 Ill组 GMBF与＊呈高度负相关。11组
和 Ill组血浆的 ET－1值均明显高于 1组，但 Ill组与 11组比较明
显减少。11组血清的 NO值明显高于 1组；Ill组与 11组比较明显
减少。三组血浆ET人与GMBF呈中度负相关。三组血浆ETJ
与血清NO呈中度正相关。
·2·
讨 论
胃粘膜微循环障碍是应激性溃疡发生的最主要的病理生理过
程。胃粘膜血流量对胃粘膜的保护有重要作用。胃粘膜血流量的
调节机制十分复杂，其中ETJO起着重要作用。
星状神经节具有交感神经的生理作用，交感神经的活动大部
分通过交感肾上腺髓质系统的兴奋产生交感反应。啮齿类动物的
颈交感神经干一下颌下腺神经内分泌轴在应激情况下起着重要作
用，其各种多肽的释放是受交感神经控制的。文献报道大鼠颈交
感神经干离断可以模拟人类的星状神经节阻滞，且是模拟人类
SGB的较好的模型。本实验结果表明，大鼠应激后胃粘膜血流量
明显下降，出现急性胃粘膜损伤，而行颈交感神经于离断后胃粘膜
血流量的下降较单纯应激组明显减少，溃疡指数亦明显减少，提示
颈交感神经干离断可以通过增加胃粘膜血流量来减轻胃粘膜的损
伤。
本实验还发现颈交感神经干离断在增加胃粘膜血流量的同
时，血中ET刁JO含量下降，提示颈交感神经于离断可通过调节
血中ETJO的含量起到增加胃粘膜血流量，保护胃粘膜的作用。
现已证明：ET人主要是通过收缩血管及增加渗出、减少循环血量
等途径来降低GMBF进而引起胃粘膜损伤川O具有扩张血管的
作用，它可以通过升高GMBF来保护胃粘膜。大多数研究者认为
ET／NO的胃粘膜损伤／保护作用主要是通过调节GMBF而实现。
本研究也初步证实了大鼠浸水应激时GMBF明显下降，血中的
ET－lJO含量明显升高，而颈交感神经于离断后ET－lJO均
下降说明其粘膜保护作用与调节血中的ETJO有关。各种应激
状态下，ETJJO通过相互影响共同对GMBF进行平衡调节，从
而影响胃粘膜的损伤和修复。NO释放增加可能是血管内皮细胞
对ET升高的一种代偿性的反应。这也可解释本实验中血中ET一
·
Introduction
Stress ulcer is a frequent occurrence in critically ill patients. GMBF is not only an important factor to maintain integrity of gastric mucosa, but also the common mechanism of numerous mucosa protec-ting factors to role in . Stellate ganglion blockade (SGB) is a common technique in clinical nerve block , which is widely used in pain thera-py. Imitating stellate ganglion blockade in human being by TCST in rats has been founded. It has been reported that TCST can weaken the severity of experimental stress ulcer, but nobody reports its mecha-nism. We investigated the changes of plasma ET - 1 and serum NO and GMBF in water immersion restrain rats after TCST.
Material and Methods
Male Sprague - Dawleys rats ( n = 30 ) which were fasting 24h , were allocated into three groups in random. All animals (200 ~250g) were anesthetized with sodium pentobarbital (40mg/kg, intraperitone-ally) , then we found the superior cervical ganglion at the dorsal sur-face of common cervical artery crotch under the microscope, and cut off the cervical sympathetic nerve truck 3mm inferior to the superior cervical ganglion before terminal ligation and suture of incision in the
group 3, while the nerves were simply exposed and separated in the group land 2. After being fasting 24h,all the rats were slightly anes-thetized with ether . The rats in group 2 and 3 were restrained. When the restrained rats awake, they were immersed into water ( 23 ?1~(?)C ) vertically with xiphoid process above water. Six hours later the im-mersed rats were taken out of water. All animals were anesthetized with sodium pentobarbital once more. Then we cut open their abdomen along the midline and separated stomach from surroundings. The probe of laser Doppler blood stream meter was inserted into stomach to detect GMBF of the gastric antrum and corpus in greater and lesser curvature respectively. Blood in abdominal aorta was drawed to measure NO and ET - 1 in plasma. Then stomach was cut open along greater curva-ture. We evaluated ulcer index ( UI) in stomach according to Guth score after washing stomach with saline. Then a piece of mucosa in gastric corpus was cut to be observed in histology after paraffin section and HE stain. ET - 1 was determined by radio - immunity technique while NO was determined by nitrate reductase technique.
The datas was presented as the mean ?standard deviation ( x ?s). Statistical significance was determined by students t - test for in-ter ?groups comparison. The relationship between two variances was determined by linear - regression analysis. P values less than 0. 05 were considered as statistically significant (SPSS statistic).
Results
There are no difference on body weights in three groups. One rats in group 1 died of respiratory depression by pentobarbital. There was no stress ulcer in gastric mucosa of group 1. Mucosa bleeding in point and line could be observed in group 2 and group 3. In the minority of
group 2, we could see mucosa edema and erosion. UI in group 3 was less than that in group 2. GMBF in groups 3 were more than that in group 2 and less than that in group 1. GMBF had a significant nega-tive correlation with UI in stress groups. ET - 1 in plasma in stress groups was higher than that in control group, but it was lower in group 3. NO value was higher in group 2 than that in goup 3. ET - 1 in plasma had a moderate negative - correlation with GMBF. ET - 1 in plasma had a moderate positive - correlation with NO in plasma.
Discussion
Disturbance of microcirculation in gastric mucosa is major patho-physiological process in the stress ulceration. GMBF plays an impor-tant role in gastric mucosa protection. The regulatory mechanisms are very complicated, in which ET ?1 and NO are crucial. Stellate gan-glion plays a part of sympathetic functions in physiology. For rodent, the neuroendocrine axis of cervical sympathetic trunk ?submandibular gland plays an important role in stress, which releases various kinds of polypeptide under control of sympathetic nerve. The present experi-m
应激性溃疡(SU)是临床危重疾病的常见并发症。胃粘膜血流量(GMBF)是维持胃粘膜完整性的重要因子，也是众多粘膜保护因子发挥作用的共同机制。星状神经节阻滞(SGB)是一种较常用的神经阻滞技术，在国内外的疼痛治疗中被广泛应用。实验证明：大鼠颈交感神经干离断(TCST)可以模拟人类的SGB，星状神经节切除可减弱应激性溃疡的严重程度。但有关其内在的作用机制尚未见报道。本实验以经典的浸水应激造成大鼠急性胃粘膜损伤，观察颈交感神经干离断对应激大鼠胃粘膜血流量、血浆内皮素-1(ET-1)、血清一氧化氮(NO)含量的变化，初步探讨星状神经节阻滞对胃粘膜血流量的影响及其可能的作用机制。
材料与方法
雄性SD大鼠30只，体重200-250克。随机分为3组每组10只：Ⅰ组为正常对照组；Ⅱ组为应激对照组；Ⅲ组为颈交感神经干离断后应激组。首先制备鼠颈交感神经干离断模型：各组大鼠均禁食24h，禁水1h。2.5％戊巴比妥钠40mg／kg腹腔注射将大鼠麻醉。在显微镜下于颈总动脉分叉处的背侧面找到颈上神经节，Ⅰ、Ⅱ组只将颈交感神经干暴露、分离，不离断；Ⅲ组距其下3mm处离断颈交感神经干并将断端结扎。然后进行浸水束缚应激：以上大鼠均于术后禁食24h后乙醚轻度麻醉，Ⅱ、Ⅲ组大鼠束缚四肢于木板上，待其清醒后将动物垂直浸水(水温23±1℃)至剑突水平，浸水6h取出。
后进行各项指标的的观察及标本的采集：2.5％戊巴比妥钠腹腔注射再次将大鼠麻醉，于剑突下沿正中线剖腹并游离出胃，在胃
幽门前壁少血管处切一 snun ／J’口。插人激光多普勒血流仪探头
分别于胃窦、胃体部的大小弯处4点测GMBF，取其平均值。后抽
取腹主动脉血4mL，取ZrnL注人含抗凝剂的试管中，混匀，离心
后，分高血浆。另取ZInL静置、离心、取上清。以上标本均置
一20 t保存。放免法测定血浆ET一二浓度。硝酸还原酶法测定
血清中亚硝酸盐浓度以间接反映NO含量。切除全胃，沿胃大弯
切开，经生理盐水漂洗后，按Gllth标准评定粘膜损伤指数（UI人
剪取1小块胃体上部粘膜，福尔马林固定，常规石蜡切片，y染色
后，进行组织学观察。
实验结果应用SPSS V10．0专业统计软件进行数据处理，数据
均以 k。S表示，两样本间均数比较用 t检验（tUdent引叫 人两
变量间关系用直线相关分析。P＜0．05为统计学差异显著，
P＜0．of为统计学差异非常显著。
结 果
各组大鼠的体重无显著差异。I组中1只大鼠因戊巴比妥钠
腹腔注射再次麻醉时死于呼吸抑制，被排除本研究。I组大鼠未
见应激性溃疡发生＊组和＊组大鼠可见胃粘膜的点状或／和线
条状的出血。11组中少数表现为粘膜水肿及糜烂。Ill组的UI明
显低于＊组。光镜下＊组的粘膜损伤程度明显轻于＊组。与互
组相比11组和Ill组GMBF均明显降低，但Ill组与11组比较
GMBF明显升高，11组和 Ill组 GMBF与＊呈高度负相关。11组
和 Ill组血浆的 ET－1值均明显高于 1组，但 Ill组与 11组比较明
显减少。11组血清的 NO值明显高于 1组；Ill组与 11组比较明显
减少。三组血浆ET人与GMBF呈中度负相关。三组血浆ETJ
与血清NO呈中度正相关。
·2·
讨 论
胃粘膜微循环障碍是应激性溃疡发生的最主要的病理生理过
程。胃粘膜血流量对胃粘膜的保护有重要作用。胃粘膜血流量的
调节机制十分复杂，其中ETJO起着重要作用。
星状神经节具有交感神经的生理作用，交感神经的活动大部
分通过交感肾上腺髓质系统的兴奋产生交感反应。啮齿类动物的
颈交感神经干一下颌下腺神经内分泌轴在应激情况下起着重要作
用，其各种多肽的释放是受交感神经控制的。文献报道大鼠颈交
感神经干离断可以模拟人类的星状神经节阻滞，且是模拟人类
SGB的较好的模型。本实验结果表明，大鼠应激后胃粘膜血流量
明显下降，出现急性胃粘膜损伤，而行颈交感神经于离断后胃粘膜
血流量的下降较单纯应激组明显减少，溃疡指数亦明显减少，提示
颈交感神经干离断可以通过增加胃粘膜血流量来减轻胃粘膜的损
伤。
本实验还发现颈交感神经干离断在增加胃粘膜血流量的同
时，血中ET刁JO含量下降，提示颈交感神经于离断可通过调节
血中ETJO的含量起到增加胃粘膜血流量，保护胃粘膜的作用。
现已证明：ET人主要是通过收缩血管及增加渗出、减少循环血量
等途径来降低GMBF进而引起胃粘膜损伤川O具有扩张血管的
作用，它可以通过升高GMBF来保护胃粘膜。大多数研究者认为
ET／NO的胃粘膜损伤／保护作用主要是通过调节GMBF而实现。
本研究也初步证实了大鼠浸水应激时GMBF明显下降，血中的
ET－lJO含量明显升高，而颈交感神经于离断后ET－lJO均
下降说明其粘膜保护作用与调节血中的ETJO有关。各种应激
状态下，ETJJO通过相互影响共同对GMBF进行平衡调节，从
而影响胃粘膜的损伤和修复。NO释放增加可能是血管内皮细胞
对ET升高的一种代偿性的反应。这也可解释本实验中血中ET一
·
Introduction
Stress ulcer is a frequent occurrence in critically ill patients. GMBF is not only an important factor to maintain integrity of gastric mucosa, but also the common mechanism of numerous mucosa protec-ting factors to role in . Stellate ganglion blockade (SGB) is a common technique in clinical nerve block , which is widely used in pain thera-py. Imitating stellate ganglion blockade in human being by TCST in rats has been founded. It has been reported that TCST can weaken the severity of experimental stress ulcer, but nobody reports its mecha-nism. We investigated the changes of plasma ET - 1 and serum NO and GMBF in water immersion restrain rats after TCST.
Material and Methods
Male Sprague - Dawleys rats ( n = 30 ) which were fasting 24h , were allocated into three groups in random. All animals (200 ~250g) were anesthetized with sodium pentobarbital (40mg/kg, intraperitone-ally) , then we found the superior cervical ganglion at the dorsal sur-face of common cervical artery crotch under the microscope, and cut off the cervical sympathetic nerve truck 3mm inferior to the superior cervical ganglion before terminal ligation and suture of incision in the
group 3, while the nerves were simply exposed and separated in the group land 2. After being fasting 24h,all the rats were slightly anes-thetized with ether . The rats in group 2 and 3 were restrained. When the restrained rats awake, they were immersed into water ( 23 ?1~(?)C ) vertically with xiphoid process above water. Six hours later the im-mersed rats were taken out of water. All animals were anesthetized with sodium pentobarbital once more. Then we cut open their abdomen along the midline and separated stomach from surroundings. The probe of laser Doppler blood stream meter was inserted into stomach to detect GMBF of the gastric antrum and corpus in greater and lesser curvature respectively. Blood in abdominal aorta was drawed to measure NO and ET - 1 in plasma. Then stomach was cut open along greater curva-ture. We evaluated ulcer index ( UI) in stomach according to Guth score after washing stomach with saline. Then a piece of mucosa in gastric corpus was cut to be observed in histology after paraffin section and HE stain. ET - 1 was determined by radio - immunity technique while NO was determined by nitrate reductase technique.
The datas was presented as the mean ?standard deviation ( x ?s). Statistical significance was determined by students t - test for in-ter ?groups comparison. The relationship between two variances was determined by linear - regression analysis. P values less than 0. 05 were considered as statistically significant (SPSS statistic).
Results
There are no difference on body weights in three groups. One rats in group 1 died of respiratory depression by pentobarbital. There was no stress ulcer in gastric mucosa of group 1. Mucosa bleeding in point and line could be observed in group 2 and group 3. In the minority of
group 2, we could see mucosa edema and erosion. UI in group 3 was less than that in group 2. GMBF in groups 3 were more than that in group 2 and less than that in group 1. GMBF had a significant nega-tive correlation with UI in stress groups. ET - 1 in plasma in stress groups was higher than that in control group, but it was lower in group 3. NO value was higher in group 2 than that in goup 3. ET - 1 in plasma had a moderate negative - correlation with GMBF. ET - 1 in plasma had a moderate positive - correlation with NO in plasma.
Discussion
Disturbance of microcirculation in gastric mucosa is major patho-physiological process in the stress ulceration. GMBF plays an impor-tant role in gastric mucosa protection. The regulatory mechanisms are very complicated, in which ET ?1 and NO are crucial. Stellate gan-glion plays a part of sympathetic functions in physiology. For rodent, the neuroendocrine axis of cervical sympathetic trunk ?submandibular gland plays an important role in stress, which releases various kinds of polypeptide under control of sympathetic nerve. The present experi-m
引文
1．万军利．应激性溃疡的形成机制．中国病理生理杂志，1993；9(5)：664．
2. Shiraishi K, Otsuki M, Tase C, et al. The effect of cervical sympathectomy on the pituitary and pineal endocrine system. Masui, 1998;47(10): 1187-92.
3. Iwama H. Can superior cervical ganglionectomy be an experimental model of stellate ganglion block? Masui, 1997,46(4):565-567.
4．小川秀道．星状神经节阻滞的继发(中枢)性作用：家兔胃溃疡模型的实验研究．疼痛学杂志，1994，2(4)：152—3．
5. Guth PH. Topical aspirin plus HCL gastric lesion in rat. Gastroenterology, 1979;76(1):88-93.
6. Soto N, Kawano S, Tsuji S, et al. Gastric blood flow in ulcer disease. Scand J Gastroenterol. 1995;30 (suppl 208): 14-20.
7．林桂芳．麻醉与内分泌。北京：人民卫生出版社，1990：133。
8. Befus AD, Mathison R, Davision J. Integration of neuro-endocrine immune responses in defense of mucosal surfaces. Am J Trop Med Hyg, 1999;60 (4 suppl):26-34.
9. Rougeot C, Rosinski-Chupin I, Mathison R, et al. Rodent submandibular gland peptide hormones and other biologically active peptides. Peptides, 2000 Mar;21(3):443-55.
10. Masayuki M, Yoshinori T, Mitsuaki M et al. Change of blood flow in celiac artery and superior mesenteric artery after stellate ganglion block. Masui, 1993,42(12):1808-12.
11．郑方．探讨星状神经节阻滞疗法．疼痛学杂志，1996；4(2)：50—49。
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10. Masayuki M, Yoshinori T, Mitsuaki M et al. Change of blood flow in celiac artery and superior mesenteric artery after stellate ganglion block. Masui, 1993,42(12):1808-12.
11．郑方．探讨星状神经节阻滞疗法．疼痛学杂志，1996；4(2)：50—49。
12．李兆申，段义民，湛先保等．内皮素在大鼠冷束缚应激性溃疡中的作用．解放军医学杂志，1999；24(1)：15．
13. Hassan M, Kashimura H, Matsumaru K et al. Phosphoramidon, an endothelin converting enzyme inhibitor attenuates local gastric ischemia-reperfusion injury in rats. Life Sci, 1997,61:PL 141.
14. Whittle BJ, et al. Cardiopulmonary and gastric ulcerogenic actions of endothelin-1 in the guinea pig and rat. J Cardiovasc Phannacol, 1989; 13: S103.
15. Fukumura D, et al. Role of platelet-activating factor (RAF) in endothelin-induced microvascular disturbance in rat stomach. Intestinal Disorder, 1991; 100(5):211.
16. Michida T, Kawano S, Masude E, et al. Endothelin-1 in the gastric mucosa in stress ulcers of critically ill patients. An J Gastroenterol, 1997,92(7): 1177-81.
17．崔忠敏，李兆申，湛先保等．内源性NO对应激性胃粘膜损伤保护作用的实验研究．第二军医大学学报，2000；21(2)：153—5．
18. Brzozwski T, Konturek SJ, Sliwowski Z, et al. Role of Larginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing. J Gastroenterol 1998,32(4):442-52.
19. Ogle CW and Qiu BS. Nitric oxide inhibition intensifies coldrestraint induced gastric ulcers in rats. Experientia 1993;19:304.
20．张国锋，陈易人，张明璈．一氧化氮、内皮素与胃粘膜损伤．胃肠病学和肝病学杂志，1999；8(4)：293—6．
21．万军利，王昌留，崔胜忠．川芎嗪对大鼠浸水应激性溃疡的影响．中草药，2000；31(2)：115．