脑热清口服液对发热家兔清热化瘀机制的研究
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摘要
发热是颅脑术后常见的症状，常分为感染性和非感染性。有效的控制颅脑术后发热，可减少术后其他并发症甚至死亡的发生。脑热清(NRQ)口服液是在临床实践基础上，依据中医理论，由黄芩、藿香、人工牛黄、大黄等组方，其组方中的黄芩、大黄、人工牛黄等均具有一定的清热化瘀作用，在治疗该类发热时，其疗效明显优于西药常规治疗。鉴于温热病过程中热与瘀两者的密切联系，本实验旨在通过复制家兔内毒素(endotoxin，ET)和内生致热原(endogenous pyrogen，EP)性发热模型，观察NRQ对发热家兔的清热化瘀作用，并进一步探讨其机制，为NRQ的临床应用和推广提供实验资料，为中医药治疗颅脑术后发热提供科学依据。
实验分两部分
第一部分：脑热清对发热家兔体温正负调节的影响
实验分为九组：生理盐水组(NS)、NRQ组、阿司匹林组(ASP)、ET组、NRQ+ET组、ASP+ET组、EP组、NRQ+EP组、ASP+EP组。
用数字测温计记录直肠温度，观察NRQ对ET及EP性发热家兔平均体温变化曲线、最大体温上升高度(△T：发热时的体温与基础体温之差)、体温反应指数(thermal response index，TRI：体温曲线与基线之间的面积)的影响，同时运用放免法测定家兔脑脊液cAMP、下丘脑IL-1_β及cAMP、脑腹中隔区(Ventral septalarea，VSA)精氨酸加压素(AVP)的含量，观察NRQ对发热家兔体温中枢正负调节物质含量的影响。
实验结果：
1 NRQ对发热家兔直肠温度的影响
①NRQ组和NS组对家兔直肠温度影响不大(P＞0.05)。②EP组和ET组的△T及TRI明显高于NS对照组(P＜0.01)。③NRQ治疗组家兔的平均体温变化曲线、△T及TRI明显低于EP和ET组(P＜0.01)。④NRQ和阳性对照药ASP相比，从降低发热家兔体温曲线的高度上无明显差异，两者的△T及TRI相比亦无明显差异(P＞0.05)。
2 NRQ对发热家兔体温中枢正调节物质含量的影响
①NRQ组脑脊液cAMP、下丘脑IL-1_β及cAMP的含量与NS组接近(P＞0.05)。ET和EP组的含量与NS组相比则明显升高(P＜0.01)。②NRQ+ET和NRQ+EP组脑脊液cAMP、下丘脑IL-1_β及cAMP的含量亦分别明显低于盯和EP组(P＜0.01)，且含量变化与体温变化分别呈正相关(P＜0.01、P＜0.05)。③NRQ和阳性对照药ASP相比，在降低发热家
脑热清口服液对发热家兔清热化疲机制的研究
兔脑脊液cAMP、下丘脑工L一1。及cAMP的含量上，差异不显著(P>0.05)o
3 NRQ对发热家兔体温中枢负调节物质含量的影响
①ET和EP组的脑中隔区AVP含量与NS组相比明显升高(P<0.01)。②NRQ治疗组脑
中隔区AVP含量明显低于ET和EP组(P<0.01、P<0.05)。③NRQ和阳性对照药ASP相比，
两者对发热家兔脑中隔区AvP的含量影响不大(P>O.05)o
第二部分:脑热清对发热家兔清热化癖作用的影响
实验分为六组:生理盐水(Ns)组、NRQ组、清开灵(QKL)组、ET组、NRQ+ET
组、QKL+ET组。
直肠温度的测量同第一部分.
运用放免法测定家兔血浆血栓素BZ(TxBZ)、6一酮一前列腺素F，。(6一ket。一PGFI
。)、内皮素的含量以及血清肿瘤坏死因子(TNF)的含量，用发色底物法测定家兔
血浆组织纤溶酶原激活物(t一PA)和组织纤溶酶原激活物抑制剂(PAI)的活性，从这
些物质的含量或活性变化探讨NRQ的解热化疲作用，同时取肺、肾、肝、心组织
做形态学观察.
实验结果:
1 NRQ对发热家兔体温的影响
①NRQ对正常家兔体温无明显影响(P>0.05)。②ET组的△T及TRI明显高于NS
对照组(P<0.01).③NRQ治疗组家兔的平均体温变化曲线、△T及TRI明显低于ET组，
差异显著(P<0.01).④NRQ和QKL相比，从降低发热家兔体温曲线的高度上无明显
差异，两者的△T及TRI相比亦无明显差异(P>0.05)o
2 NRQ对发热家兔血浆TxBZ、6一keto一PGF，。含量的影响
①NRQ对正常家兔TXBZ、6一ket。一PGFI。含量影响不大，与NS组相比无明显差
异(P>0.05).②ET组与NS组相比TXBZ明显升高、6一keto一PGF，。明显下降、
TXBZ/6一keto一PGF:。比值升高，差异显著(P<0.01、p<0.05).③NRQ治疗组可明显降低
发热家兔血浆TxBZ的含量，还可升高血浆6一ke to一PGFt。的含量，差异显著(P<0.01)。
④NRQ和 QKL两种药在降低发热家兔血浆TxBZ的含量，升高血浆6一ket。一PGF.。的含
量上无明显差异(P>0.05)o
3 NRQ对发热家兔血浆t一P人和PAI活性的影响
①NRQ对正常家兔血浆t一PA和PAI活性影响不大，与NS组相比无明显差异
(P>0.05).②ET组PAI明显升高、t一PA明显降低，与NS组相比差异显著(P<0.01)。
③用NRQ治疗后PAI明显下降、t一PA明显升高，差异显著(P<0.01)。④NRQ和QKL两
中文摘要
种药在降低发热家兔血浆PAI的活性，升高血浆t一PA的活性上无明显差异
(P>0 .05)。
4 NRQ对发热家兔血浆内皮素和血清TNF含量的影响
①NRQ对正常家兔血浆内皮素和血清TNF含量影响不大，与NS组相比无明显差
异(P>0.05)。②ET组与NS组相比，血浆内皮素和血清TNF含量明显升高，差异显
著(P<0.01)。③ET+NRQ与ET组相比内皮素和TNF含量明显下降，差异显著(p<0.01)。
④NRQ和QKL两种药在降低发热家兔血浆内皮素和血清TNF含量上无明显差异
(P>0 .05)。
5形态观察及图像分析
Fever is the familiar symptom of skull and brain post-operation, including infective fever and non-infective fever. The control of post-operational fever of skull and brain can reduce syndrome and death. The curative effect of Naoreqing(NRQ) Oral Liquid on treating fever is superior to western medicine. According to the theory or traditional Chinese medicine and based on clinical practices, Naoreqing Oral Liquid compose of huangqin ,huoxiang,niuhuang, dahuang and so on. huangqin , niuhuang and dahuang have the effect of clearing away heat and dissipate blood stasis. To study the antifebrile mechanism and clearing away heat and dissipate blood stasis effect of NRQ, the ET and EP induced fever models were established.
The study consists of two parts, including the effect of clearing away heat and dissipate blood stasis , the mechanism of positive and negative adjusting in febrile rabbits.
The first part: the effect of NRQ on positive and negative adjusting in febrile rabbits. In experimental research, the pureblood New-zealand rabbit, were divided randomly into nine groups: normal saline solution (NS) group, NRQ group, aspirin(ASP) group, endotoxin (ET)group, NRQ+ET group, ASP+ET group, endogenous pyrogen (EP) group, NRQ+EP group, ASP+EP group.
The digital thermometer were used to register rectal temperature. The temperature curve, AT, thermal response index(TRI), of febrile rabbits were observed. At the same time, we also used the radioimmunoassay to determine the cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP, AVP content in Ventral septal area(VSA).The effect of NRQ on content of positive and negative adjusting substance were observed.
The results displayed as follow:
1 The effect of NRQ on rectal temperature of febrile rabbits: (1)NRQ and NS group have no effects on the temperature of normal rabbits (P>0. 05) . (2)The T, TRI of ET and EP group were higher than that of NS group(P<0. 01). (3)The temperature curve, AT, TRI of NRQ+ET and NRQ+EP were separately lower than that of ET and EP group (P<0. 01). (4)NRQ and ASP therapeutic group have no obvious differences in reducing the temperature curve, AT, TRI (P>0. 05) .
2 The effect of NRQ on content of positive adjusting matter in the thermoregulation nerve center of febrile rabbits: (1)The cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP of NS group have no distinguished differences than that of NRQ group (P>0. 05) , but lower than that of ET and EP group (P<0. 01) . ㏕he cAMP content of NRQ+ET and NRQ+EP group were separately lower than that of ET group and EP group (P<0.01). And The cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP were paralleled with the changes of temperature separately (P<0.01 or P<0. 05). (DNRQ and ASP have no obvious differences in reducing the content of cAMP in hypothalamus (HP) and CSF , IL-1B in HPof febrile rabbits
(P>0. 05) .
3 The effect of NRQ on content of negative adjusting matter in the thermoregulation nerve center of febrile rabbits:㏕he AVP content in VSA of NS group were lower than that of ET and EP group (P<0. 01) .(2)The AVP content of NRQ+ET and NRQ+EP group were separately lower than that of ET group and EP group (P<0. 01 or P<0. 05). (DNRQ and ASP have no obvious differences in reducing the content of AVP in VSA of febrile rabbits (P>0. 05).
The second part: the effect of NRQ on clearing away heat and dissipate blood stasis of febrile rabbits. In experimental research, the pureblood New-zealand rabbit, were divided randomly into six groups: normal saline solution (NS) group, NRQ group, QKL group, ET group, NRQ+ET group, QKL+ET
group.
The measure of rectal temperature were equal to the first part. The thromboxin B2 (TXB2), 6-keto-prostaglandin F1a (6-keto-PGF1a)and endothelin content in blood plasma, and tumor necrosis factor (TNF) in blood serum were determined by radioimmunoassay. The activity of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in blood plasma were measured by the assay of chromogenic substrate. The pathology of lung
实验分两部分
第一部分：脑热清对发热家兔体温正负调节的影响
实验分为九组：生理盐水组(NS)、NRQ组、阿司匹林组(ASP)、ET组、NRQ+ET组、ASP+ET组、EP组、NRQ+EP组、ASP+EP组。
用数字测温计记录直肠温度，观察NRQ对ET及EP性发热家兔平均体温变化曲线、最大体温上升高度(△T：发热时的体温与基础体温之差)、体温反应指数(thermal response index，TRI：体温曲线与基线之间的面积)的影响，同时运用放免法测定家兔脑脊液cAMP、下丘脑IL-1_β及cAMP、脑腹中隔区(Ventral septalarea，VSA)精氨酸加压素(AVP)的含量，观察NRQ对发热家兔体温中枢正负调节物质含量的影响。
实验结果：
1 NRQ对发热家兔直肠温度的影响
①NRQ组和NS组对家兔直肠温度影响不大(P＞0.05)。②EP组和ET组的△T及TRI明显高于NS对照组(P＜0.01)。③NRQ治疗组家兔的平均体温变化曲线、△T及TRI明显低于EP和ET组(P＜0.01)。④NRQ和阳性对照药ASP相比，从降低发热家兔体温曲线的高度上无明显差异，两者的△T及TRI相比亦无明显差异(P＞0.05)。
2 NRQ对发热家兔体温中枢正调节物质含量的影响
①NRQ组脑脊液cAMP、下丘脑IL-1_β及cAMP的含量与NS组接近(P＞0.05)。ET和EP组的含量与NS组相比则明显升高(P＜0.01)。②NRQ+ET和NRQ+EP组脑脊液cAMP、下丘脑IL-1_β及cAMP的含量亦分别明显低于盯和EP组(P＜0.01)，且含量变化与体温变化分别呈正相关(P＜0.01、P＜0.05)。③NRQ和阳性对照药ASP相比，在降低发热家
脑热清口服液对发热家兔清热化疲机制的研究
兔脑脊液cAMP、下丘脑工L一1。及cAMP的含量上，差异不显著(P>0.05)o
3 NRQ对发热家兔体温中枢负调节物质含量的影响
①ET和EP组的脑中隔区AVP含量与NS组相比明显升高(P<0.01)。②NRQ治疗组脑
中隔区AVP含量明显低于ET和EP组(P<0.01、P<0.05)。③NRQ和阳性对照药ASP相比，
两者对发热家兔脑中隔区AvP的含量影响不大(P>O.05)o
第二部分:脑热清对发热家兔清热化癖作用的影响
实验分为六组:生理盐水(Ns)组、NRQ组、清开灵(QKL)组、ET组、NRQ+ET
组、QKL+ET组。
直肠温度的测量同第一部分.
运用放免法测定家兔血浆血栓素BZ(TxBZ)、6一酮一前列腺素F，。(6一ket。一PGFI
。)、内皮素的含量以及血清肿瘤坏死因子(TNF)的含量，用发色底物法测定家兔
血浆组织纤溶酶原激活物(t一PA)和组织纤溶酶原激活物抑制剂(PAI)的活性，从这
些物质的含量或活性变化探讨NRQ的解热化疲作用，同时取肺、肾、肝、心组织
做形态学观察.
实验结果:
1 NRQ对发热家兔体温的影响
①NRQ对正常家兔体温无明显影响(P>0.05)。②ET组的△T及TRI明显高于NS
对照组(P<0.01).③NRQ治疗组家兔的平均体温变化曲线、△T及TRI明显低于ET组，
差异显著(P<0.01).④NRQ和QKL相比，从降低发热家兔体温曲线的高度上无明显
差异，两者的△T及TRI相比亦无明显差异(P>0.05)o
2 NRQ对发热家兔血浆TxBZ、6一keto一PGF，。含量的影响
①NRQ对正常家兔TXBZ、6一ket。一PGFI。含量影响不大，与NS组相比无明显差
异(P>0.05).②ET组与NS组相比TXBZ明显升高、6一keto一PGF，。明显下降、
TXBZ/6一keto一PGF:。比值升高，差异显著(P<0.01、p<0.05).③NRQ治疗组可明显降低
发热家兔血浆TxBZ的含量，还可升高血浆6一ke to一PGFt。的含量，差异显著(P<0.01)。
④NRQ和 QKL两种药在降低发热家兔血浆TxBZ的含量，升高血浆6一ket。一PGF.。的含
量上无明显差异(P>0.05)o
3 NRQ对发热家兔血浆t一P人和PAI活性的影响
①NRQ对正常家兔血浆t一PA和PAI活性影响不大，与NS组相比无明显差异
(P>0.05).②ET组PAI明显升高、t一PA明显降低，与NS组相比差异显著(P<0.01)。
③用NRQ治疗后PAI明显下降、t一PA明显升高，差异显著(P<0.01)。④NRQ和QKL两
中文摘要
种药在降低发热家兔血浆PAI的活性，升高血浆t一PA的活性上无明显差异
(P>0 .05)。
4 NRQ对发热家兔血浆内皮素和血清TNF含量的影响
①NRQ对正常家兔血浆内皮素和血清TNF含量影响不大，与NS组相比无明显差
异(P>0.05)。②ET组与NS组相比，血浆内皮素和血清TNF含量明显升高，差异显
著(P<0.01)。③ET+NRQ与ET组相比内皮素和TNF含量明显下降，差异显著(p<0.01)。
④NRQ和QKL两种药在降低发热家兔血浆内皮素和血清TNF含量上无明显差异
(P>0 .05)。
5形态观察及图像分析
Fever is the familiar symptom of skull and brain post-operation, including infective fever and non-infective fever. The control of post-operational fever of skull and brain can reduce syndrome and death. The curative effect of Naoreqing(NRQ) Oral Liquid on treating fever is superior to western medicine. According to the theory or traditional Chinese medicine and based on clinical practices, Naoreqing Oral Liquid compose of huangqin ,huoxiang,niuhuang, dahuang and so on. huangqin , niuhuang and dahuang have the effect of clearing away heat and dissipate blood stasis. To study the antifebrile mechanism and clearing away heat and dissipate blood stasis effect of NRQ, the ET and EP induced fever models were established.
The study consists of two parts, including the effect of clearing away heat and dissipate blood stasis , the mechanism of positive and negative adjusting in febrile rabbits.
The first part: the effect of NRQ on positive and negative adjusting in febrile rabbits. In experimental research, the pureblood New-zealand rabbit, were divided randomly into nine groups: normal saline solution (NS) group, NRQ group, aspirin(ASP) group, endotoxin (ET)group, NRQ+ET group, ASP+ET group, endogenous pyrogen (EP) group, NRQ+EP group, ASP+EP group.
The digital thermometer were used to register rectal temperature. The temperature curve, AT, thermal response index(TRI), of febrile rabbits were observed. At the same time, we also used the radioimmunoassay to determine the cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP, AVP content in Ventral septal area(VSA).The effect of NRQ on content of positive and negative adjusting substance were observed.
The results displayed as follow:
1 The effect of NRQ on rectal temperature of febrile rabbits: (1)NRQ and NS group have no effects on the temperature of normal rabbits (P>0. 05) . (2)The T, TRI of ET and EP group were higher than that of NS group(P<0. 01). (3)The temperature curve, AT, TRI of NRQ+ET and NRQ+EP were separately lower than that of ET and EP group (P<0. 01). (4)NRQ and ASP therapeutic group have no obvious differences in reducing the temperature curve, AT, TRI (P>0. 05) .
2 The effect of NRQ on content of positive adjusting matter in the thermoregulation nerve center of febrile rabbits: (1)The cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP of NS group have no distinguished differences than that of NRQ group (P>0. 05) , but lower than that of ET and EP group (P<0. 01) . ㏕he cAMP content of NRQ+ET and NRQ+EP group were separately lower than that of ET group and EP group (P<0.01). And The cAMP content in hypothalamus (HP) and CSF , IL-1B content in HP were paralleled with the changes of temperature separately (P<0.01 or P<0. 05). (DNRQ and ASP have no obvious differences in reducing the content of cAMP in hypothalamus (HP) and CSF , IL-1B in HPof febrile rabbits
(P>0. 05) .
3 The effect of NRQ on content of negative adjusting matter in the thermoregulation nerve center of febrile rabbits:㏕he AVP content in VSA of NS group were lower than that of ET and EP group (P<0. 01) .(2)The AVP content of NRQ+ET and NRQ+EP group were separately lower than that of ET group and EP group (P<0. 01 or P<0. 05). (DNRQ and ASP have no obvious differences in reducing the content of AVP in VSA of febrile rabbits (P>0. 05).
The second part: the effect of NRQ on clearing away heat and dissipate blood stasis of febrile rabbits. In experimental research, the pureblood New-zealand rabbit, were divided randomly into six groups: normal saline solution (NS) group, NRQ group, QKL group, ET group, NRQ+ET group, QKL+ET
group.
The measure of rectal temperature were equal to the first part. The thromboxin B2 (TXB2), 6-keto-prostaglandin F1a (6-keto-PGF1a)and endothelin content in blood plasma, and tumor necrosis factor (TNF) in blood serum were determined by radioimmunoassay. The activity of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in blood plasma were measured by the assay of chromogenic substrate. The pathology of lung
引文
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7．徐方云，李楚杰．家兔内生致热原性发热时血浆、脑脊液和不同脑区组织cAMP化．中国病理生理杂志，1997，13(1)：52-54
8．屈洋，张怡，李楚杰，等．TNF性发热时家兔血浆、脑脊液PGE2及cAMP含量的变化[J]．中国病理生理杂志，1993，9(2)：165-169
9. Strijbos PJ, Hardwick AJ, Relton JK, et al, Inhibiton of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRH, Am J Physioi, 1992,263:E632-E633
10．吴其夏，余应年，卢建．新编病理生理学．北京：中国协和医科大学出版社，1999，216-218
11. Cooper KE, Malkinson TJ, Monda M, et al. New neurobiological conceptsof the genesis of fever and of antipyresis. In:Bartfai T, Ottoson D, eds. Neuroimmunology of fever. NewYork:Pergamon Press, 1992, 225-234
12. Trautwein C, Boker K, Nanns MP. Acute Phase reaction as a contribution to early mechanisms. Gut, 1994,35:1163-1174
13. Long NC, Otterness I, Kunkel SL, et al. Roles of interleukin 1β and tumor necrosis factor in lipopolysaccharide fever in rats. Am J physiol, 1990,259:724-728
14．杨惠玲，潘景轩，吴伟康，主编．高级病理生理学[M]．第1版．北京科学出版社，1998，86-112
15. Shapiro L, Xi-Xian Zhang, Rupp RRG, et al. Ciliary neurotrophic factor is an endogenous pyrogen. Pro Natl Acad Sci 1993, 90:8614-8621
16. Coceani F, Akarsu E. Prostaglandin E2 in the pathogenesis of fever an
update. Ann NY Acad Sci, 1998,850:76-82
17. Stitt J .Prostaglandin E as the neural mediator of the febrile response [J].Yale J Biol Med, 1986,59(2):137-149
18. Blatteis C M, Sehic E,Fever:How May circulating pyrogens signal the brain[J].News Phusiol Sci, 1997,12(2):1-9
19. Ushikubi F, Segi E, Sugimoto Y, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP1. Nature, 1998,395:281
20．齐云，李沧海，郭淑英等．桂枝汤对体温双向调节作用机理探讨——对发热及低体温大鼠下丘脑PGE_2含量及COX影响．中药药理与临床2001，17(6)：1-3
21. Li S, Wang Y, Matsumura K, et al. The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2, but not in cyclooxygenase-1 mic. Brain Res, 1999, 17:825(1-2):86-94
22. Cao CY, Matsumura K, Yamagata K, et al. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain: its possible role in the febrile response. Brain Res, 1995, 697:187-196
23. Cao CY, Matsumura K, Yamagata K, et al. Endothelial cell of the rat brain vasculature express site of prostaglandin systhesis responsible for fever. Brain Res, 1996, 733:263-272
24. Dinarello CA, et al.New concepts on the pathogenesis of fever, Rev Inf Dis, 1988, (10):168
25. Willies GH, Matic G, Kipic J, et al. The effects of sodium salicylate on dibutyryl cyclic AMP fever in the conscious rabbit[J].Neuropharmacology, 1976,10(2):15-19
26．徐方云，李楚杰．家兔EP性发热时血浆、脑脊液和不同脑区组织cAMP含量的变化．中国病理生理杂志1997；13(1)：52-55
27．胡景新，李楚杰．内毒素发热时家兔不同脑区组织、脑脊液及血浆中cAMP含量变化的比较[J]．中国病理生理杂志，1990，6(1)：9-13
28．邢德君，杜葵琴，计国义，等．大鼠内毒素性发热时不同脑区cAMP含量和腺苷酸环化酶的变化[J]．中国病理生理杂志，1992，8(2)：147-149
29. Strijbos PJ, Hardwick AJ, Relton JK, et al, Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF[J]. AM J Physiol, 1992,263(4):632-636
30. Rothwell NJ, Cooper A, Cytokines, CRF and BAT in fever [M],New York: Pergamon Press, 1992,6:257-266
31．王华东 王彦平 李楚杰等 α-helica 1CRH(9-41)与消炎痛联用对家兔内毒素性发热的解热作用中国病理生理杂志 1999，15(2)：147-150
32. Bernardi GL, Richards DB, lipton JM. Antipyretic effect of centrally
administered CRH[J].Peptides, 1984,5:57-59
33. Opp M, Obal F Jr, Krueger JN. Corticortropin-releasing factorattenuates intrleukin 1-induced sleep and fever in rabbits[J].Am J Physiol, 1989,257(3):R528-R535
34. Linthorst AC, Flachskamm C, Hopkins SJ, et al. Long-term intracerebroventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neurochemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge[J].J Neurosci, 1997,17(11):4448-4460
35．王华东，屈洋，王彦平中枢CRH在大鼠应激性体温升高和LPS性发热机制中的作用．中国病理生理杂志 2001，17(2)：124-127
36. Feldberg W, Myers RD, Veale WL. Perfusions from cerebral ventricle to cisterna magna in the unanesthetized cat. Effect of calcium on body temperature [J]. J Physiol, 1970,207(2): 403-416
37. Myers RD, Veale WL, Fever: Reciprocal shift in brain sodium to calcium ration as the set-point temperature rise [J], Science, 1972,178:765-767.
38．李平，李楚杰脑室灌注CaCl_2对家兔内毒素性发热及其血浆、脑脊液中cAMP含量的影响[J]．中国病理生理杂志，1992，8(1)：13-16
39．汤穗生，李楚杰．家兔侧脑室灌注EGTA后发热效应及脑脊液cAMP、PGE_2含量变化的观察[J]．中国病理生理杂志，1990，6(6)：451-455
40．杨永录，陈邦勇 隔区注射AVP和AVP抗血清对家兔温敏神经元放电的影响．生理学报．1994：46：141～143
41. Kasting N W.Criteria for establishing a physiologic role for brain peptides. A case in point:the role of Vaso-pressin in the regulation during fever and antipyre-sis. Brain ResRev, 1989,14:143-153
42. Horowitz M, Epstein Y, Shapiro Y. Vasopressin in thermoregulation competitive demands:experimental evidence and theoretical considerations. [J].Physiol Res, 1992,41(1):41-52
43. Pittman Q D, Wilkinson M F. Central arginine Vasopressin and endogenous antipresis. Can J Physiol Pharmacol, 1992,70(2):786-794
44. Bock M, Roth J, Kiuger M J, et al. Antipyres is caused by stimulation of vasopress inergic neuron and intraseptal or systemic infusions r-MSH. AmJphysiol, 1994,266:614-621
45．杨永录，孙喜庚，王岚．精氨酸加压素在家兔内毒素发热耐受性中的作用．兰州医学院学报，1994，20(2)：124-126
46. Cooper K E, Naylor A M, Veale W L. Evidence supporting a role for endogenous Vasopressin in ferver Suppression in the
rat. Jphysiol 1987,387:163-172
47. Kasting N W. Criteria for establishing a physiologic role for brain peptides. A case in point:the role of Vasopressin in thermoregulation during fever and antipyresis. Brain ResRev, 1989,14:143-153
48. Wilkinson M F, Kasting N W. The antipyretic effects of central administered arginine Vasopressin at different ambient temperature. BrainRes, 1987,415:275-280
49．杨永录，张犁，陈帮勇．精氨酸加压素诱生内生致热原生成及致热性的影响．中国人兽共患病杂志，1994，10(6)：32-35
50．杨永录，杨文辉．精氨酸加压素在体温调节与抗热中的作用．解放军医学情报，1995，9：302-304
51．杨永录，陈邦勇．隔区注射AVP和AVP抗血清对家兔温敏神经元放电活动的影响．生理学报，1994，46(2)：141-143．
52. Chiao H, Foster S, Yhomas R, et al. Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. J Olin Invest, 1996 97(9):2038-2044
53. Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administration α-melanocyte stimulating hormone. Science, 1983,221:192-202
54. Davidson J, Milton AS, Rotondo D. α-Melanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit. J Physiol. 1992,451:491-502
55. Clark WG, Holdeman M, Lipton JM. Analysis of the antipyretic action of α-melanocyte-stimulating hormone in rabbits. J Physiol. 1985, 359:459-465
56. Goelst K, et al. Effects of alpha-melanocyte stimulating hormone on fever caused by endotoxin in rabbits, J Physiol(London) 1991,441:469-476
57. Holdeman M, Khorram O, Samson WK, et al. Fever specific changes in centrao MSH and CRF concentrations. A m J Physiol, 1985,248:R125-R129
58. Martin LW, Lipton JM. hcute phase response to endotoxin: rise in plasma α-MSH and effect of α-MSH injection.Am J Physiol, 1990,259:R768-R772
59. Glyn Ballinger, Bernardini G1, Lipton J M. α-MSH injected into the septal region reduced fever in rabbits. Peptides, 1983,4:199-210
60. Shin ST, Khorram O, lipton JM, et al. Central administration of α-MSH antiserum augments fever in the rabbit. Am J Physiol. 1986, 250:R803-R 806
61. Martin SM, Malkinson TJ, V eale WL, et al. Depletion of brain α-MSH alters
prostaglandin and interleukin fever in rats. Brain Res, 1990, 526:351-354
62. Davidson J, Nilton aS, Rotondo D. α-Nelanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit. J Physiol. 1992,451:491-501
63．王达安 胡巢凤 杨皓庄．α-促黑素细胞激素对IL-1β刺激家兔离体下丘脑释放cAMP的抑制作用．中国病理生理杂志，1997，18(4)：360-363
64．胡巢凤 王华东 王彦平 -MSH对内毒素性发热效应及下丘脑cAMP含量的影响．中国病理生理杂志，1998，14(6)：576-578
65．王华东，胡巢凤，王彦平，李楚杰．α-MSH对家兔ET性发热反应及脑腹中隔区AVP含量的影响．中国病理生理杂志，1998，14(2)：130-132
66. Bock M, Roth J, Kluger M J, et al. Antipyres is caused by stimulation of vasopressin ergicneuron and intraseptal or systemic infusions r-MSH. Am J physiol, 1994, 266:614-621
67. Zeisberger E, Merker G.The role of OVLT in fever andantipyresis. Prog BrainRes, 1992, 91:403-411
68. Mitchell LD, Callahan MF, Wilkin L D, et al. Activition of supraoptic magnocellular neurons by γ 2-melanocyte stimulating hormone(γ 2-MSH). Brain Res, 1989,480:388-396
69．王树人主编．病理生理学，科学出版社，2001：91-100
2．董军，李楚杰，陆大祥，等．电刺激VSA对IL-1β作用下兔POAH温敏神经元放电的影响[J]．中国病理生理杂志，2000，16(4)：301—303
3. Zeisberger E, Roth J. Neurobiogical concepts of fever generation and suppression. Neuropsychobiology, 1993,28(1):106-109
4. Hori TM, Shibata T, Nakashima M et al. Brain ResBull, 1988,20:75-82
5. Kozak W, Kluger MJ, Soszynski D, et al. IL-6 and IL-1beta in fever. Studies using cytokine-deficient (knockout)mice[J].Ann N Y Acad Sci, 1998,856:33-47
6. Dascombe MJ, Rothwell NS. Mechanisms of the early and late hypermetaglism and fever localized tissue injury in rats. Am J Physiol, 1989,256:E7-E11
7．徐方云，李楚杰．家兔内生致热原性发热时血浆、脑脊液和不同脑区组织cAMP化．中国病理生理杂志，1997，13(1)：52-54
8．屈洋，张怡，李楚杰，等．TNF性发热时家兔血浆、脑脊液PGE2及cAMP含量的变化[J]．中国病理生理杂志，1993，9(2)：165-169
9. Strijbos PJ, Hardwick AJ, Relton JK, et al, Inhibiton of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRH, Am J Physioi, 1992,263:E632-E633
10．吴其夏，余应年，卢建．新编病理生理学．北京：中国协和医科大学出版社，1999，216-218
11. Cooper KE, Malkinson TJ, Monda M, et al. New neurobiological conceptsof the genesis of fever and of antipyresis. In:Bartfai T, Ottoson D, eds. Neuroimmunology of fever. NewYork:Pergamon Press, 1992, 225-234
12. Trautwein C, Boker K, Nanns MP. Acute Phase reaction as a contribution to early mechanisms. Gut, 1994,35:1163-1174
13. Long NC, Otterness I, Kunkel SL, et al. Roles of interleukin 1β and tumor necrosis factor in lipopolysaccharide fever in rats. Am J physiol, 1990,259:724-728
14．杨惠玲，潘景轩，吴伟康，主编．高级病理生理学[M]．第1版．北京科学出版社，1998，86-112
15. Shapiro L, Xi-Xian Zhang, Rupp RRG, et al. Ciliary neurotrophic factor is an endogenous pyrogen. Pro Natl Acad Sci 1993, 90:8614-8621
16. Coceani F, Akarsu E. Prostaglandin E2 in the pathogenesis of fever an
update. Ann NY Acad Sci, 1998,850:76-82
17. Stitt J .Prostaglandin E as the neural mediator of the febrile response [J].Yale J Biol Med, 1986,59(2):137-149
18. Blatteis C M, Sehic E,Fever:How May circulating pyrogens signal the brain[J].News Phusiol Sci, 1997,12(2):1-9
19. Ushikubi F, Segi E, Sugimoto Y, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP1. Nature, 1998,395:281
20．齐云，李沧海，郭淑英等．桂枝汤对体温双向调节作用机理探讨——对发热及低体温大鼠下丘脑PGE_2含量及COX影响．中药药理与临床2001，17(6)：1-3
21. Li S, Wang Y, Matsumura K, et al. The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2, but not in cyclooxygenase-1 mic. Brain Res, 1999, 17:825(1-2):86-94
22. Cao CY, Matsumura K, Yamagata K, et al. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain: its possible role in the febrile response. Brain Res, 1995, 697:187-196
23. Cao CY, Matsumura K, Yamagata K, et al. Endothelial cell of the rat brain vasculature express site of prostaglandin systhesis responsible for fever. Brain Res, 1996, 733:263-272
24. Dinarello CA, et al.New concepts on the pathogenesis of fever, Rev Inf Dis, 1988, (10):168
25. Willies GH, Matic G, Kipic J, et al. The effects of sodium salicylate on dibutyryl cyclic AMP fever in the conscious rabbit[J].Neuropharmacology, 1976,10(2):15-19
26．徐方云，李楚杰．家兔EP性发热时血浆、脑脊液和不同脑区组织cAMP含量的变化．中国病理生理杂志1997；13(1)：52-55
27．胡景新，李楚杰．内毒素发热时家兔不同脑区组织、脑脊液及血浆中cAMP含量变化的比较[J]．中国病理生理杂志，1990，6(1)：9-13
28．邢德君，杜葵琴，计国义，等．大鼠内毒素性发热时不同脑区cAMP含量和腺苷酸环化酶的变化[J]．中国病理生理杂志，1992，8(2)：147-149
29. Strijbos PJ, Hardwick AJ, Relton JK, et al, Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF[J]. AM J Physiol, 1992,263(4):632-636
30. Rothwell NJ, Cooper A, Cytokines, CRF and BAT in fever [M],New York: Pergamon Press, 1992,6:257-266
31．王华东 王彦平 李楚杰等 α-helica 1CRH(9-41)与消炎痛联用对家兔内毒素性发热的解热作用中国病理生理杂志 1999，15(2)：147-150
32. Bernardi GL, Richards DB, lipton JM. Antipyretic effect of centrally
administered CRH[J].Peptides, 1984,5:57-59
33. Opp M, Obal F Jr, Krueger JN. Corticortropin-releasing factorattenuates intrleukin 1-induced sleep and fever in rabbits[J].Am J Physiol, 1989,257(3):R528-R535
34. Linthorst AC, Flachskamm C, Hopkins SJ, et al. Long-term intracerebroventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neurochemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge[J].J Neurosci, 1997,17(11):4448-4460
35．王华东，屈洋，王彦平中枢CRH在大鼠应激性体温升高和LPS性发热机制中的作用．中国病理生理杂志 2001，17(2)：124-127
36. Feldberg W, Myers RD, Veale WL. Perfusions from cerebral ventricle to cisterna magna in the unanesthetized cat. Effect of calcium on body temperature [J]. J Physiol, 1970,207(2): 403-416
37. Myers RD, Veale WL, Fever: Reciprocal shift in brain sodium to calcium ration as the set-point temperature rise [J], Science, 1972,178:765-767.
38．李平，李楚杰脑室灌注CaCl_2对家兔内毒素性发热及其血浆、脑脊液中cAMP含量的影响[J]．中国病理生理杂志，1992，8(1)：13-16
39．汤穗生，李楚杰．家兔侧脑室灌注EGTA后发热效应及脑脊液cAMP、PGE_2含量变化的观察[J]．中国病理生理杂志，1990，6(6)：451-455
40．杨永录，陈邦勇 隔区注射AVP和AVP抗血清对家兔温敏神经元放电的影响．生理学报．1994：46：141～143
41. Kasting N W.Criteria for establishing a physiologic role for brain peptides. A case in point:the role of Vaso-pressin in the regulation during fever and antipyre-sis. Brain ResRev, 1989,14:143-153
42. Horowitz M, Epstein Y, Shapiro Y. Vasopressin in thermoregulation competitive demands:experimental evidence and theoretical considerations. [J].Physiol Res, 1992,41(1):41-52
43. Pittman Q D, Wilkinson M F. Central arginine Vasopressin and endogenous antipresis. Can J Physiol Pharmacol, 1992,70(2):786-794
44. Bock M, Roth J, Kiuger M J, et al. Antipyres is caused by stimulation of vasopress inergic neuron and intraseptal or systemic infusions r-MSH. AmJphysiol, 1994,266:614-621
45．杨永录，孙喜庚，王岚．精氨酸加压素在家兔内毒素发热耐受性中的作用．兰州医学院学报，1994，20(2)：124-126
46. Cooper K E, Naylor A M, Veale W L. Evidence supporting a role for endogenous Vasopressin in ferver Suppression in the
rat. Jphysiol 1987,387:163-172
47. Kasting N W. Criteria for establishing a physiologic role for brain peptides. A case in point:the role of Vasopressin in thermoregulation during fever and antipyresis. Brain ResRev, 1989,14:143-153
48. Wilkinson M F, Kasting N W. The antipyretic effects of central administered arginine Vasopressin at different ambient temperature. BrainRes, 1987,415:275-280
49．杨永录，张犁，陈帮勇．精氨酸加压素诱生内生致热原生成及致热性的影响．中国人兽共患病杂志，1994，10(6)：32-35
50．杨永录，杨文辉．精氨酸加压素在体温调节与抗热中的作用．解放军医学情报，1995，9：302-304
51．杨永录，陈邦勇．隔区注射AVP和AVP抗血清对家兔温敏神经元放电活动的影响．生理学报，1994，46(2)：141-143．
52. Chiao H, Foster S, Yhomas R, et al. Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. J Olin Invest, 1996 97(9):2038-2044
53. Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administration α-melanocyte stimulating hormone. Science, 1983,221:192-202
54. Davidson J, Milton AS, Rotondo D. α-Melanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit. J Physiol. 1992,451:491-502
55. Clark WG, Holdeman M, Lipton JM. Analysis of the antipyretic action of α-melanocyte-stimulating hormone in rabbits. J Physiol. 1985, 359:459-465
56. Goelst K, et al. Effects of alpha-melanocyte stimulating hormone on fever caused by endotoxin in rabbits, J Physiol(London) 1991,441:469-476
57. Holdeman M, Khorram O, Samson WK, et al. Fever specific changes in centrao MSH and CRF concentrations. A m J Physiol, 1985,248:R125-R129
58. Martin LW, Lipton JM. hcute phase response to endotoxin: rise in plasma α-MSH and effect of α-MSH injection.Am J Physiol, 1990,259:R768-R772
59. Glyn Ballinger, Bernardini G1, Lipton J M. α-MSH injected into the septal region reduced fever in rabbits. Peptides, 1983,4:199-210
60. Shin ST, Khorram O, lipton JM, et al. Central administration of α-MSH antiserum augments fever in the rabbit. Am J Physiol. 1986, 250:R803-R 806
61. Martin SM, Malkinson TJ, V eale WL, et al. Depletion of brain α-MSH alters
prostaglandin and interleukin fever in rats. Brain Res, 1990, 526:351-354
62. Davidson J, Nilton aS, Rotondo D. α-Nelanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit. J Physiol. 1992,451:491-501
63．王达安 胡巢凤 杨皓庄．α-促黑素细胞激素对IL-1β刺激家兔离体下丘脑释放cAMP的抑制作用．中国病理生理杂志，1997，18(4)：360-363
64．胡巢凤 王华东 王彦平 -MSH对内毒素性发热效应及下丘脑cAMP含量的影响．中国病理生理杂志，1998，14(6)：576-578
65．王华东，胡巢凤，王彦平，李楚杰．α-MSH对家兔ET性发热反应及脑腹中隔区AVP含量的影响．中国病理生理杂志，1998，14(2)：130-132
66. Bock M, Roth J, Kluger M J, et al. Antipyres is caused by stimulation of vasopressin ergicneuron and intraseptal or systemic infusions r-MSH. Am J physiol, 1994, 266:614-621
67. Zeisberger E, Merker G.The role of OVLT in fever andantipyresis. Prog BrainRes, 1992, 91:403-411
68. Mitchell LD, Callahan MF, Wilkin L D, et al. Activition of supraoptic magnocellular neurons by γ 2-melanocyte stimulating hormone(γ 2-MSH). Brain Res, 1989,480:388-396
69．王树人主编．病理生理学，科学出版社，2001：91-100