清醒大鼠急性低血压兴奋前庭神经核的NMDA受体机制研究
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摘要
[目的]大量的研究报道,在麻醉动物用动脉放血或静脉注射硝普钠(Sodium nitroprusside, SNP)诱发急性低血压,可能通过外周前庭器官经前庭神经释放谷氨酸(Glutamate, Glu)兴奋前庭内侧核(medial vestibular nucleus, MVN)并且MVN区有c-Fos蛋白表达。但是在清醒动物是否也能出现相同的结果,尤其是关于急性低血压兴奋MVN的Glu-NMDA受体机制的研究甚少。本研究观察了清醒动物诱发急性低血压导致大鼠MVN神经元兴奋过程中,NMDA受体激动剂(NMDA)和阻断剂(MK-801)对MVN内c-Fos蛋白表达的影响。
[方法]选用体重在250±50g的清洁级Wistar系雄性大鼠60只。动物随机分成3个大组,即前庭器官正常组；单侧前庭器官损伤组；NMDA受体组。本实验首先利用免疫组化方法,观察了正常动物和药物(对氨基苯胂酸盐)破坏一侧外周前庭器官慢性期(2w),静脉注射SNP (20μg/kg/min,3min)诱发急性低血压(50%)时MVN区c-Fos蛋白的表达情况,接着结合药理学方法,进一步探讨了给侧脑室注入NMDA受体激动剂(NMDA)和阻断剂(MK-801)对上述效应的影响,借此探讨药物诱发急性低血压兴奋MVN的谷氨酸NMDA受体机制。
[结果]
1、在正常动物,利用静脉注射SNP诱发急性低血压使血压平均下降50%后30min、60min、120min时,MVN区c-Fos蛋白均有表达,而且在60min时c-Fos蛋白表达最明显。但是在静脉注射生理盐水的对照组则无明显的c-Fos蛋白表达,两组间相比差异非常显著(P<0.001)。
2、单侧前庭器官损伤2w后诱发急性低血压30min、60min、120min时,损伤侧MVN区未见c-fos蛋白的明显表达。但是损伤对侧MVN区c-Fos蛋白仍明显增多,与损伤侧的相应时间比较均有显著性差异(P<0.001),在急性低血压后60min时c-Fos蛋白表达最明显；而且与前庭器官正常动物相同。
3、前庭器官正常动物侧脑室注射NMDA阻断剂(MK-801, 1mmol/L) 60min后,再诱发急性低血压,未能在MVN区见到c-Fos蛋白的明显表达,与侧脑室注射人工脑脊液组相比无明显差异(P<0.001)。
4、前庭器官正常动物侧脑室注射NMDA激动剂(NMDA, 1mmol/L) 60min钟后,双侧MVN区c-Fos蛋白表达显著增加,与人工脑脊液组相比有显著性差异(P<0.001)。
[结论]
1.清醒动物静脉注射SNP诱发急性低血压,可以兴奋MVN；
2.破坏外周前庭器官可以阻断清醒动物诱发急性低血压兴奋MVN的作用；
3.急性低血压诱发清醒动物MVN兴奋效应中有Glu-NMDA受体参与。
Aim:
The acute hypotension induced by exsanguinations of arterial blood or intravenous injection of Sodium Nitroprusside (SNP), can evoke c-Fos protein expression and neuronal excitation in medial vestibular nucleus (MVN) probably via peripheral vestibular organ pathway in anesthetized animals. However, it is unknown whether the acute hypotension-evoked response in awake animals is similar to the previous studies, especially its mechanisms is related to NMDA receptor. In the present study, we observed the c-Fos protein expression induced by acute hypotension and studied the effects of damaged unilateral vestibular organ, NMDA receptor agonist (NMDA) and antagonist (MK-801) on the c-fos protein expression in MVN neurons in conscious rats.
Methods:
A total of 60 SPF male Wistar Rats (250±50g) were randomly divided into three groups:normal vestibular organ group, damaged unilateral vestibular organ group, NMDA receptor group. The acute hypotension (50%) of rats was induced by intravenous injection of SNP (20μg/kg/min,3min). The unilateral peripheral vestibular organ was damaged by treatment of arsanilic acid, and experiments were performed during the chronic phase (2-week later) of unilateral peripheral vestibular organ damage. The c-Fos protein expression in MVN neurons during the acute hypotension (50%) was studied by immunohistochemical methods. Furthermore, we examined the effects of NMDA receptor agonist (NMDA) and antagonist (MK-801) on acute hypotension-induced c-fos protein expression by intracerebroventricular injection techniques.
Result:
1, Intravenous injection of SNP (20μg/kg/min,3min) induced acute hypotension in normal rats, accompanied with an increase in c-fos protein expression in MVN region at the 30 min,60 min, and 120 min after blood pressure fell to an average of 50%percent, the peak expression of c-fos protein was observed at 60 min after the acute hypotension. The c-Fos protein expression was not induced by intravenous injection of saline in the control group. Difference between the two groups was significant (P< 0.001);
2, Two weeks later after the damage of the unilateral peripheral vestibular organ, the increase of c-fos protein expression was not observed in the ipsilateral MVN region at the 30 min,60 min, and 120 min after induction of acute hypotension, the peak expression of c-fos protein was observed at 60 min after acute hypotension. But, the c-fos protein expression was indeed increased in the contralateral MVN region, significant higher than its expression in ipsilateral MVN region (P< 0.001).
3, After 60 mins of intracerebroventricular injection of NMD A receptor blocker (MK-801, 1mmol/L), acute hypotension failed to induce an increase in c-Fos protein expression in MVN region in normal vestibular organ animals, the level of c-Fos protein expression was significant lower than the group of artificial cerebrospinal fluid (P< 0.001).
4, After 60 mins of intracerebroventricular injection of NMD A receptor agonist (NMDA, 1mmol/L), the c-Fos protein expression was increased in MVN region in normal vestibular organ animals, the level of c-Fos protein expression was significant higher than the group of artificial cerebrospinal fluid (P< 0.001).
Conclusion:
1. SNP-induced acute hypotension could evoke c-Fos over expression in MVN in the conscious rat.
2. UL prevented the c-Fos over expression in ipsilateral MVN without change the c-Fos expression in the contralateral MVN.3. Acute hypotension-induced c-Fos over expression involed the activation of NMD A receptor.
[方法]选用体重在250±50g的清洁级Wistar系雄性大鼠60只。动物随机分成3个大组,即前庭器官正常组；单侧前庭器官损伤组；NMDA受体组。本实验首先利用免疫组化方法,观察了正常动物和药物(对氨基苯胂酸盐)破坏一侧外周前庭器官慢性期(2w),静脉注射SNP (20μg/kg/min,3min)诱发急性低血压(50%)时MVN区c-Fos蛋白的表达情况,接着结合药理学方法,进一步探讨了给侧脑室注入NMDA受体激动剂(NMDA)和阻断剂(MK-801)对上述效应的影响,借此探讨药物诱发急性低血压兴奋MVN的谷氨酸NMDA受体机制。
[结果]
1、在正常动物,利用静脉注射SNP诱发急性低血压使血压平均下降50%后30min、60min、120min时,MVN区c-Fos蛋白均有表达,而且在60min时c-Fos蛋白表达最明显。但是在静脉注射生理盐水的对照组则无明显的c-Fos蛋白表达,两组间相比差异非常显著(P<0.001)。
2、单侧前庭器官损伤2w后诱发急性低血压30min、60min、120min时,损伤侧MVN区未见c-fos蛋白的明显表达。但是损伤对侧MVN区c-Fos蛋白仍明显增多,与损伤侧的相应时间比较均有显著性差异(P<0.001),在急性低血压后60min时c-Fos蛋白表达最明显；而且与前庭器官正常动物相同。
3、前庭器官正常动物侧脑室注射NMDA阻断剂(MK-801, 1mmol/L) 60min后,再诱发急性低血压,未能在MVN区见到c-Fos蛋白的明显表达,与侧脑室注射人工脑脊液组相比无明显差异(P<0.001)。
4、前庭器官正常动物侧脑室注射NMDA激动剂(NMDA, 1mmol/L) 60min钟后,双侧MVN区c-Fos蛋白表达显著增加,与人工脑脊液组相比有显著性差异(P<0.001)。
[结论]
1.清醒动物静脉注射SNP诱发急性低血压,可以兴奋MVN；
2.破坏外周前庭器官可以阻断清醒动物诱发急性低血压兴奋MVN的作用；
3.急性低血压诱发清醒动物MVN兴奋效应中有Glu-NMDA受体参与。
Aim:
The acute hypotension induced by exsanguinations of arterial blood or intravenous injection of Sodium Nitroprusside (SNP), can evoke c-Fos protein expression and neuronal excitation in medial vestibular nucleus (MVN) probably via peripheral vestibular organ pathway in anesthetized animals. However, it is unknown whether the acute hypotension-evoked response in awake animals is similar to the previous studies, especially its mechanisms is related to NMDA receptor. In the present study, we observed the c-Fos protein expression induced by acute hypotension and studied the effects of damaged unilateral vestibular organ, NMDA receptor agonist (NMDA) and antagonist (MK-801) on the c-fos protein expression in MVN neurons in conscious rats.
Methods:
A total of 60 SPF male Wistar Rats (250±50g) were randomly divided into three groups:normal vestibular organ group, damaged unilateral vestibular organ group, NMDA receptor group. The acute hypotension (50%) of rats was induced by intravenous injection of SNP (20μg/kg/min,3min). The unilateral peripheral vestibular organ was damaged by treatment of arsanilic acid, and experiments were performed during the chronic phase (2-week later) of unilateral peripheral vestibular organ damage. The c-Fos protein expression in MVN neurons during the acute hypotension (50%) was studied by immunohistochemical methods. Furthermore, we examined the effects of NMDA receptor agonist (NMDA) and antagonist (MK-801) on acute hypotension-induced c-fos protein expression by intracerebroventricular injection techniques.
Result:
1, Intravenous injection of SNP (20μg/kg/min,3min) induced acute hypotension in normal rats, accompanied with an increase in c-fos protein expression in MVN region at the 30 min,60 min, and 120 min after blood pressure fell to an average of 50%percent, the peak expression of c-fos protein was observed at 60 min after the acute hypotension. The c-Fos protein expression was not induced by intravenous injection of saline in the control group. Difference between the two groups was significant (P< 0.001);
2, Two weeks later after the damage of the unilateral peripheral vestibular organ, the increase of c-fos protein expression was not observed in the ipsilateral MVN region at the 30 min,60 min, and 120 min after induction of acute hypotension, the peak expression of c-fos protein was observed at 60 min after acute hypotension. But, the c-fos protein expression was indeed increased in the contralateral MVN region, significant higher than its expression in ipsilateral MVN region (P< 0.001).
3, After 60 mins of intracerebroventricular injection of NMD A receptor blocker (MK-801, 1mmol/L), acute hypotension failed to induce an increase in c-Fos protein expression in MVN region in normal vestibular organ animals, the level of c-Fos protein expression was significant lower than the group of artificial cerebrospinal fluid (P< 0.001).
4, After 60 mins of intracerebroventricular injection of NMD A receptor agonist (NMDA, 1mmol/L), the c-Fos protein expression was increased in MVN region in normal vestibular organ animals, the level of c-Fos protein expression was significant higher than the group of artificial cerebrospinal fluid (P< 0.001).
Conclusion:
1. SNP-induced acute hypotension could evoke c-Fos over expression in MVN in the conscious rat.
2. UL prevented the c-Fos over expression in ipsilateral MVN without change the c-Fos expression in the contralateral MVN.3. Acute hypotension-induced c-Fos over expression involed the activation of NMD A receptor.
引文
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