应激条件下中枢胆碱能系统对颈动脉窦压力感受器反射的影响及其机制
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摘要
目的:
探讨中枢胆碱能系统在应激条件下对颈动脉窦压力感受器反射(Carotid sinus baroreceptor reflex, CSR)的影响及其可能的调节机制。
方法:
选择SD大鼠于应激态(足底随机电击,每次2小时,一天二次,持续一周,经应激标准筛选后用于实验)和常态下(处理、环境与应激态相同,但装置不通电,进行假应激),分别孤离其双侧颈动脉窦区(保留窦神经,切断主动脉神经和迷走神经),使之独立于体循环,同时在胆碱能纤维投射、受体分布的脑区之一:孤束核(NTS)和侧脑室,分别微量注射各种药物:人工脑脊液(ACSF)或选择性胆碱能受体拮抗剂(M1受体拮抗剂pirenzepine, PRZ或M2受体拮抗剂methoctramine, MTR或N1受体拮抗剂hexamethonium, HEX),以非应激常态下侧脑室或NTS注射ACSF后的CSR水平和应激态下侧脑室或NTS注射ACSF后的CSR水平分别作为实验的阴性对照组和阳性对照组。将不同窦内压(ISP)与其对应的平均动脉压(MAP)值进行Logistic五参数曲线方程拟合,构建二者函数关系,根据所得ISP-MAP关系曲线、ISP-增益(Gain)关系曲线以及CSR系列特征参数(均为实验的观察指标),解析应激条件下中枢胆碱能系统对CSR的调制作用及其机制。
结果:
1.应激对CSR的影响
在非应激组和应激组中,分别侧脑室或NTS内注射ACSF前、后,各自CSR水平和基础血压水平均无明显变化,实验以非应激常态下侧脑室或NTS注射ACSF后的CSR水平和应激态下侧脑室或NTS注射ACSF后的CSR水平分别作为实验的阴性对照组和阳性对照组。与非应激基础CSR水平及阴性对照组CSR水平相比,应激基础CSR水平及阳性对照组CSR水平共同表现为:ISP-MAP关系曲线显著全面右上移位(P<0.05),ISP-Gain关系曲线中部明显下移(P<0.05),CSR机能参数调定点(Set Point)、饱和压(SP)和最大增益时窦内压(ISPGmax)明显升高(P<0.05),而反射最大增益(Gmax)和平均动脉压反射变动范围(MAP range)显著减小(P<0.05)。
2.侧脑室微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响及其与非应激对照水平的比较
2.1侧脑室微量注射不同胆碱能受体拮抗剂对非应激CSR的影响在非应激组分别侧脑室注射(intracerebroventricular injection, i. c. v.)M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX,均不引起各自ISP-MAP、ISP-Gain关系曲线和反射系列参数明显改变(P>0.05)。
2.2侧脑室微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响在应激组i. c. v.同非应激组相应剂量的PRZ或MTR后,均能不同程度的减弱应激对CSR的抑制性重调定,表现为:与阳性对照组相比,应激PRZ、MTR组各自ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(MTR组)(P<0.05);就缓解应激对CSR抑制的程度而言,MTR的缓解作用强于PRZ的作用,表现为ISP-Gain关系曲线中部明显上移(P<0.05),饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range增多(P<0.05),上述反应一般出现在应激组i.c.v. PRZ或MTR后15至20 min,可维持15 min左右。但应激HEX组则对应激所致CSR的变化没有明显影响(P>0.05),却与PRZ组、MTR组的效应相比,有着不同程度的显著差异(P<0.05)。
2.3侧脑室注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响与非应激对照水平的比较侧脑室微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR,均不能使应激的CSR水平完全恢复到相应的非应激对照水平(P<0.05)。
3. NTS微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响及其与非应激对照水平的比较
3.1 NTS微量注射不同胆碱能受体拮抗剂对非应激CSR的影响在非应激组分别NTS注射M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX,也均不引起各自ISP-MAP、ISP-Gain关系曲线和反射系列参数明显改变(P>0.05)。
3.2 NTS微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响在应激组NTS注射同非应激组相应剂量的PRZ或MTR后,同样均能不同程度的减弱应激对CSR的抑制性重调定,表现为:与阳性对照组相比,应激PRZ、MTR组各自ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),反射参数调定点Set Point(MTR组)、饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(MTR组)(P<0.05);就缓解应激对CSR抑制的程度而言,MTR的缓解作用依然强于PRZ的作用,表现为其ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(P<0.05),上述变化一般出现在应激组NTS注射PRZ或MTR后12 min,也可维持20 min左右。但应激HEX组则对应激所致CSR的变化没有明显影响(P>0.05),却与PRZ组、MTR组的效应相比,有着不同程度的显著差异(P<0.05)。
3.3 NTS注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响与非应激对照水平的比较NTS微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR,均不能使应激的CSR水平完全恢复至相应的非应激对照水平(P<0.05)。
结论:
1.应激引起颈动脉窦压力感受器反射(CSR)重调定,反射敏感性下降,反射机能受抑。
2.非应激常态下,在侧脑室或NTS分别微量注射所给剂量的选择性胆碱能受体拮抗剂(M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX),均不引起各自基础动脉血压水平的明显改变,也不影响CSR反射的敏感性和机能。
3.侧脑室微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ(M1受体拮抗剂)或MTR(M2受体拮抗剂),可明显减弱应激对CSR的抑制性重调定;而M2受体拮抗剂的缓解作用大于M1受体拮抗剂;N1受体拮抗剂则无明显作用。提示室周核团的M1、M2受体尤为M2受体参与介导应激对CSR的抑制性重调定。
4. NTS内微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ(M1受体拮抗剂)或MTR(M2受体拮抗剂),对应激所致CSR重调定的影响与结论3类似,NTS处M2受体拮抗剂的缓解作用大于M1受体;N1受体拮抗剂则同样无明显作用。提示NTS的M1、M2受体尤为M2受体也参与介导应激对CSR的抑制性重调定,下丘脑-NTS的胆碱能通路可能是应激影响CSR机能的下行通路之一。
5.侧脑室或NTS微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR后,均不能使应激的CSR水平完全恢复到相应的非应激对照水平。表明除了中枢胆碱能系统参与应激对CSR的抑制机制外,尚有其他神经机制的参与作用。
Objective:
To determine the roles of the central cholinergic system in the stress-induced carotid sinus baroreceptor reflex (CSR) resetting and its mechanism.
Methods:
Sprague?Dawley rats were divided into two groups at random: unstressed (n=48) and stressed groups (n=48). According to the site of microinjection of the selective cholinergic receptor antagonists, each group was subdivided into a group of intracerebroventricular injection (i.c.v.) and a group of microinjection into the nucleus tractus solitarius (NTS). Stressed groups were subjected to unavoidable electric foot-shock twice daily for a week, each session of foot-shock lasted 2 hours and unstressed groups followed by the same handling and environment but no electric stimulation for fake stresss. The left and right carotid sinus regions were isolated from the systemic circulation with the undamaged sinus nerve, cutting off the aortic nerve and off the vagus nerve under anesthesia with pentobarbital sodium in all rats. The artificial cerebrospinal fluid (ACSF), the selective muscarinic M1 cholinoceptor antagonist pirenzepine (PRZ), the selective M2 cholinoceptor antagonist methoctramine (MTR) and the selective nicotinic N1 cholinoceptor antagonist hexamethonium (HEX) was respectively administrated into the lateral ventricle or the NTS which is one of the brain regions of cholinergic fibers projection and cholinoceptors distribution in both stressed and unstressed groups. The ACSF into the lateral ventricle or the NTS in the stressed and unstressed groups was respectively served as a positive control (stressed) and a negative control (unstressed) in all experiment.
After the isolated carotid sinus preparation wae conducted, the intracarotid sinus pressure (ISP) was altered in a stepwise manner to trigger CSR from 0 to 280 mmHg at every step of 40 mmHg and 4 sec, and then returned to 0 mmHg in similar steps. ISP and mean femoral arterial pressure (MAP) were recorded simultaneously. ISP-MAP and ISP-Gain relationship curves were constructed by fitting to the logistic function with five parameters. The CSR functional characteristic parameters, the ISP-MAP and the ISP-Gain relationship curves were separately examined and compared statistically in order to observe the effects of central cholinergic system on CSR and its mechanism in mammalian under the stress state.
Results:
1. The effects of stress on CSR function
In the stressed and unstressed groups, the ACSF into the lateral ventricle or the NTS did not obviously change each CSR base level, which was respectively served as a positive control (stressed groups) and a negative control (unstressed groups) in all experiment. In comparison with the unstressed CSR baseline and the CSR level of the negative control, the stressed CSR baseline and the CSR level of the positive control showed significant changes that the ISP-MAP relationship curves were remarkably shifted upwards (P<0.05) and the middle parts of ISP-Gain relationship curves were moved downwards (P<0.05), and the value of the MAP range and maximum gain (Gmax) were decreased (P<0.05), but the set point, saturation pressure (SP) and ISP at Gmax (ISPGmax) were increased (P<0.05).
2. Effects of the microinjection of different cholinergic receptor antagonists into the lateral cerebroventricle on the changes in CSR induced by stress and comparison between these effects and the corresponding control level of CSR in the unstressed group
2.1 Effects of microinjection of different cholinergic receptor antagonists into the lateral ventricle on the CSR level in the unstressed groups.
Microinjection of the selective cholinergic receptors antagonists, PRZ or MTR or HEX with given dose into the lateral ventricles in the unstressed groups, had no obvious effects on both ISP-MAP and ISP-Gain relationship curves and CSR functional parameters, respectively (P>0.05).
2.2 Effects of the microinjection of different cholinergic receptor antagonists into the lateral cerebroventricle on the changes in CSR induced by stress
Microinjection of the selective muscarinic M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the lateral cerebroventricle in the stressed groups with the corresponding doses used in the unstressed groups, significantly diminished the above-mentioned changes in CSR performance induced by stress, which remarkably moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters such as the MAP range (only for MTR) and Gmax (P<0.05), but decreased parameters like SP and ISPGmax (P<0.05), compared with the positive control. The alleviative effects of MTR were remarkably stronger than those of PRZ in the stressed group, which significantly shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and decreased parameters SP and ISPGmax (P<0.05), but increased parameters Gmax and the MAP range (P<0.05), compared with the stressed group of PRZ. The responses of CSR level in stressed groups to M1 or M2 cholinoceptor antagonists generally occurred 20 min after the administration and lasted approximately for 15 min. Microinjection of the selective nicotinic N1 cholinoceptor antagonist HEX into the lateral cerebroventricle in the stressed group, however, displayed no significant effects on the stressed CSR baseline and the CSR level of the positive control (P>0.05) but exhibited significant difference from the CSR levels in the stressed groups of the MTR and PRZ (P<0.05).
2.3 Comparison between the CSR levels treated by i.c.v. different cholinoceptor antagonists in stressed groups and the corresponding control level of CSR in the unstressed groups
Microinjection of PRZ or MTR or HEX into the lateral cerebroventricle in the stressed groups could not completely abolish the stress-induced changes in CSR (P<0.05).
3. Effects of the microinjection of different cholinergic receptor antagonists into the NTS on the changes in CSR induced by stress and comparison between these effects and the corresponding control level of CSR in the unstressed group
3.1 Effects of microinjection of different cholinergic receptor antagonists into the NTS on the CSR level in the unstressed groups.
Microinjection of the selective cholinergic receptors antagonists, PRZ or MTR or HEX with given dose into the NTS in the unstressed groups, had no obvious effects on both ISP-MAP and ISP-Gain relationship curves and CSR functional parameters, respectively (P>0.05).
3.2 Effects of the microinjection of different cholinergic receptor antagonists into the NTS on the changes in CSR induced by stress
Microinjection of the selective muscarinic M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the NTS in the stressed groups with the corresponding doses used in the unstressed groups, also significantly diminished the above-mentioned changes in CSR performance induced by stress, which remarkably moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters such as the MAP range (only for MTR) and Gmax (P<0.05), but decreased parameters like SP, ISPGmax and set point (only for MTR) (P<0.05), compared with the positive control. The alleviative effects of MTR were also remarkably stronger than those of PRZ in the stressed group, which significantly moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters Gmax and the MAP range (P<0.05), compared with the stressed group of PRZ. The responses of CSR level in stressed groups to M1 or M2 cholinoceptor antagonists generally occurred 12 min after the administration and lasted approximately for 20 min. Microinjection of the selective nicotinic N1 cholinoceptor antagonist HEX into the NTS in the stressed group, however, displayed no significant effects on the stressed CSR baseline and the CSR level of the positive control (P>0.05) but exhibited significant difference from the CSR levels in the stressed groups of the MTR and PRZ (P<0.05).
3.3 Comparison between the CSR levels treated by different cholinoceptor antagonists into the NTS in stressed groups and the corresponding control level of CSR in the unstressed groups
Microinjection of PRZ or MTR or HEX into the NTS in the stressed groups could not completely abolish the stress-induced changes in CSR (P<0.05).
Conclusion:
1. Stress results in a resetting of CSR , a decrease in reflex sensitivity.
2. Microinjection of selective cholinergic receptor antagonist PRZ or MTR or HEX into the lateral ventricle or the NTS with given respective dose under the unstressed state, has neither effects on the CSR function and nor on the arterial blood pressure basal level.
3. Microinjection of the selective M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the lateral ventricle with given respective dose could obviously attenuate the stress-induced CSR inhibitory resetting, and the alleviative effects of MTR are more stronger than those of PRZ in the stressed group, but the selective N1 cholinoceptor antagonist, HEX into the lateral ventricle may have no effects on the CSR resetting resulted from the stress, which suggest that the M1 and M2 cholinoceptors, especially M2 cholinoceptors, in brain ventricle peripheral nuclei may participate in mediating stress-induced CSR resetting.
4. Microinjection of the selective M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the NTS with given respective dose could also remarkably diminish the stress-induced CSR inhibitory resetting, and the alleviative effects of MTR are more stronger than those of PRZ in the stressed group, but the selective N1 cholinoceptor antagonist, HEX into the NTS may also have no effects on the CSR resetting resulted from the stress, which indicate that the M1 and M2 cholinoceptors, especially M2 cholinoceptors, in the NTS may also involve in regulating stress-induced CSR resetting, and the descending cholinergic pathway from the hypothalamus to NTS may be involved in mechanisms of the stress-inhibited CSR function.
5. Microinjection of PRZ or MTR or HEX into the lateral ventricle or the NTS with given respective dose in the stressed state can not completely abolish the stress-induced changes in CSR, which denote that other neuromechanisms may also contribute to effects of the stress on CSR besides central cholinergic system.
探讨中枢胆碱能系统在应激条件下对颈动脉窦压力感受器反射(Carotid sinus baroreceptor reflex, CSR)的影响及其可能的调节机制。
方法:
选择SD大鼠于应激态(足底随机电击,每次2小时,一天二次,持续一周,经应激标准筛选后用于实验)和常态下(处理、环境与应激态相同,但装置不通电,进行假应激),分别孤离其双侧颈动脉窦区(保留窦神经,切断主动脉神经和迷走神经),使之独立于体循环,同时在胆碱能纤维投射、受体分布的脑区之一:孤束核(NTS)和侧脑室,分别微量注射各种药物:人工脑脊液(ACSF)或选择性胆碱能受体拮抗剂(M1受体拮抗剂pirenzepine, PRZ或M2受体拮抗剂methoctramine, MTR或N1受体拮抗剂hexamethonium, HEX),以非应激常态下侧脑室或NTS注射ACSF后的CSR水平和应激态下侧脑室或NTS注射ACSF后的CSR水平分别作为实验的阴性对照组和阳性对照组。将不同窦内压(ISP)与其对应的平均动脉压(MAP)值进行Logistic五参数曲线方程拟合,构建二者函数关系,根据所得ISP-MAP关系曲线、ISP-增益(Gain)关系曲线以及CSR系列特征参数(均为实验的观察指标),解析应激条件下中枢胆碱能系统对CSR的调制作用及其机制。
结果:
1.应激对CSR的影响
在非应激组和应激组中,分别侧脑室或NTS内注射ACSF前、后,各自CSR水平和基础血压水平均无明显变化,实验以非应激常态下侧脑室或NTS注射ACSF后的CSR水平和应激态下侧脑室或NTS注射ACSF后的CSR水平分别作为实验的阴性对照组和阳性对照组。与非应激基础CSR水平及阴性对照组CSR水平相比,应激基础CSR水平及阳性对照组CSR水平共同表现为:ISP-MAP关系曲线显著全面右上移位(P<0.05),ISP-Gain关系曲线中部明显下移(P<0.05),CSR机能参数调定点(Set Point)、饱和压(SP)和最大增益时窦内压(ISPGmax)明显升高(P<0.05),而反射最大增益(Gmax)和平均动脉压反射变动范围(MAP range)显著减小(P<0.05)。
2.侧脑室微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响及其与非应激对照水平的比较
2.1侧脑室微量注射不同胆碱能受体拮抗剂对非应激CSR的影响在非应激组分别侧脑室注射(intracerebroventricular injection, i. c. v.)M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX,均不引起各自ISP-MAP、ISP-Gain关系曲线和反射系列参数明显改变(P>0.05)。
2.2侧脑室微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响在应激组i. c. v.同非应激组相应剂量的PRZ或MTR后,均能不同程度的减弱应激对CSR的抑制性重调定,表现为:与阳性对照组相比,应激PRZ、MTR组各自ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(MTR组)(P<0.05);就缓解应激对CSR抑制的程度而言,MTR的缓解作用强于PRZ的作用,表现为ISP-Gain关系曲线中部明显上移(P<0.05),饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range增多(P<0.05),上述反应一般出现在应激组i.c.v. PRZ或MTR后15至20 min,可维持15 min左右。但应激HEX组则对应激所致CSR的变化没有明显影响(P>0.05),却与PRZ组、MTR组的效应相比,有着不同程度的显著差异(P<0.05)。
2.3侧脑室注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响与非应激对照水平的比较侧脑室微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR,均不能使应激的CSR水平完全恢复到相应的非应激对照水平(P<0.05)。
3. NTS微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响及其与非应激对照水平的比较
3.1 NTS微量注射不同胆碱能受体拮抗剂对非应激CSR的影响在非应激组分别NTS注射M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX,也均不引起各自ISP-MAP、ISP-Gain关系曲线和反射系列参数明显改变(P>0.05)。
3.2 NTS微量注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响在应激组NTS注射同非应激组相应剂量的PRZ或MTR后,同样均能不同程度的减弱应激对CSR的抑制性重调定,表现为:与阳性对照组相比,应激PRZ、MTR组各自ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),反射参数调定点Set Point(MTR组)、饱和压SP和最大增益时的窦内压值ISPGmax下降(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(MTR组)(P<0.05);就缓解应激对CSR抑制的程度而言,MTR的缓解作用依然强于PRZ的作用,表现为其ISP-MAP关系曲线后半程显著下移(P<0.05),ISP-Gain关系曲线中部明显上移(P<0.05),反射最大增益Gmax及MAP反射变动范围MAP range加大(P<0.05),上述变化一般出现在应激组NTS注射PRZ或MTR后12 min,也可维持20 min左右。但应激HEX组则对应激所致CSR的变化没有明显影响(P>0.05),却与PRZ组、MTR组的效应相比,有着不同程度的显著差异(P<0.05)。
3.3 NTS注射不同胆碱能受体拮抗剂对应激所致CSR变化的影响与非应激对照水平的比较NTS微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR,均不能使应激的CSR水平完全恢复至相应的非应激对照水平(P<0.05)。
结论:
1.应激引起颈动脉窦压力感受器反射(CSR)重调定,反射敏感性下降,反射机能受抑。
2.非应激常态下,在侧脑室或NTS分别微量注射所给剂量的选择性胆碱能受体拮抗剂(M1受体拮抗剂PRZ或M2受体拮抗剂MTR或N1受体拮抗剂HEX),均不引起各自基础动脉血压水平的明显改变,也不影响CSR反射的敏感性和机能。
3.侧脑室微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ(M1受体拮抗剂)或MTR(M2受体拮抗剂),可明显减弱应激对CSR的抑制性重调定;而M2受体拮抗剂的缓解作用大于M1受体拮抗剂;N1受体拮抗剂则无明显作用。提示室周核团的M1、M2受体尤为M2受体参与介导应激对CSR的抑制性重调定。
4. NTS内微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ(M1受体拮抗剂)或MTR(M2受体拮抗剂),对应激所致CSR重调定的影响与结论3类似,NTS处M2受体拮抗剂的缓解作用大于M1受体;N1受体拮抗剂则同样无明显作用。提示NTS的M1、M2受体尤为M2受体也参与介导应激对CSR的抑制性重调定,下丘脑-NTS的胆碱能通路可能是应激影响CSR机能的下行通路之一。
5.侧脑室或NTS微量注射所给剂量的选择性胆碱能受体拮抗剂PRZ或MTR后,均不能使应激的CSR水平完全恢复到相应的非应激对照水平。表明除了中枢胆碱能系统参与应激对CSR的抑制机制外,尚有其他神经机制的参与作用。
Objective:
To determine the roles of the central cholinergic system in the stress-induced carotid sinus baroreceptor reflex (CSR) resetting and its mechanism.
Methods:
Sprague?Dawley rats were divided into two groups at random: unstressed (n=48) and stressed groups (n=48). According to the site of microinjection of the selective cholinergic receptor antagonists, each group was subdivided into a group of intracerebroventricular injection (i.c.v.) and a group of microinjection into the nucleus tractus solitarius (NTS). Stressed groups were subjected to unavoidable electric foot-shock twice daily for a week, each session of foot-shock lasted 2 hours and unstressed groups followed by the same handling and environment but no electric stimulation for fake stresss. The left and right carotid sinus regions were isolated from the systemic circulation with the undamaged sinus nerve, cutting off the aortic nerve and off the vagus nerve under anesthesia with pentobarbital sodium in all rats. The artificial cerebrospinal fluid (ACSF), the selective muscarinic M1 cholinoceptor antagonist pirenzepine (PRZ), the selective M2 cholinoceptor antagonist methoctramine (MTR) and the selective nicotinic N1 cholinoceptor antagonist hexamethonium (HEX) was respectively administrated into the lateral ventricle or the NTS which is one of the brain regions of cholinergic fibers projection and cholinoceptors distribution in both stressed and unstressed groups. The ACSF into the lateral ventricle or the NTS in the stressed and unstressed groups was respectively served as a positive control (stressed) and a negative control (unstressed) in all experiment.
After the isolated carotid sinus preparation wae conducted, the intracarotid sinus pressure (ISP) was altered in a stepwise manner to trigger CSR from 0 to 280 mmHg at every step of 40 mmHg and 4 sec, and then returned to 0 mmHg in similar steps. ISP and mean femoral arterial pressure (MAP) were recorded simultaneously. ISP-MAP and ISP-Gain relationship curves were constructed by fitting to the logistic function with five parameters. The CSR functional characteristic parameters, the ISP-MAP and the ISP-Gain relationship curves were separately examined and compared statistically in order to observe the effects of central cholinergic system on CSR and its mechanism in mammalian under the stress state.
Results:
1. The effects of stress on CSR function
In the stressed and unstressed groups, the ACSF into the lateral ventricle or the NTS did not obviously change each CSR base level, which was respectively served as a positive control (stressed groups) and a negative control (unstressed groups) in all experiment. In comparison with the unstressed CSR baseline and the CSR level of the negative control, the stressed CSR baseline and the CSR level of the positive control showed significant changes that the ISP-MAP relationship curves were remarkably shifted upwards (P<0.05) and the middle parts of ISP-Gain relationship curves were moved downwards (P<0.05), and the value of the MAP range and maximum gain (Gmax) were decreased (P<0.05), but the set point, saturation pressure (SP) and ISP at Gmax (ISPGmax) were increased (P<0.05).
2. Effects of the microinjection of different cholinergic receptor antagonists into the lateral cerebroventricle on the changes in CSR induced by stress and comparison between these effects and the corresponding control level of CSR in the unstressed group
2.1 Effects of microinjection of different cholinergic receptor antagonists into the lateral ventricle on the CSR level in the unstressed groups.
Microinjection of the selective cholinergic receptors antagonists, PRZ or MTR or HEX with given dose into the lateral ventricles in the unstressed groups, had no obvious effects on both ISP-MAP and ISP-Gain relationship curves and CSR functional parameters, respectively (P>0.05).
2.2 Effects of the microinjection of different cholinergic receptor antagonists into the lateral cerebroventricle on the changes in CSR induced by stress
Microinjection of the selective muscarinic M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the lateral cerebroventricle in the stressed groups with the corresponding doses used in the unstressed groups, significantly diminished the above-mentioned changes in CSR performance induced by stress, which remarkably moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters such as the MAP range (only for MTR) and Gmax (P<0.05), but decreased parameters like SP and ISPGmax (P<0.05), compared with the positive control. The alleviative effects of MTR were remarkably stronger than those of PRZ in the stressed group, which significantly shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and decreased parameters SP and ISPGmax (P<0.05), but increased parameters Gmax and the MAP range (P<0.05), compared with the stressed group of PRZ. The responses of CSR level in stressed groups to M1 or M2 cholinoceptor antagonists generally occurred 20 min after the administration and lasted approximately for 15 min. Microinjection of the selective nicotinic N1 cholinoceptor antagonist HEX into the lateral cerebroventricle in the stressed group, however, displayed no significant effects on the stressed CSR baseline and the CSR level of the positive control (P>0.05) but exhibited significant difference from the CSR levels in the stressed groups of the MTR and PRZ (P<0.05).
2.3 Comparison between the CSR levels treated by i.c.v. different cholinoceptor antagonists in stressed groups and the corresponding control level of CSR in the unstressed groups
Microinjection of PRZ or MTR or HEX into the lateral cerebroventricle in the stressed groups could not completely abolish the stress-induced changes in CSR (P<0.05).
3. Effects of the microinjection of different cholinergic receptor antagonists into the NTS on the changes in CSR induced by stress and comparison between these effects and the corresponding control level of CSR in the unstressed group
3.1 Effects of microinjection of different cholinergic receptor antagonists into the NTS on the CSR level in the unstressed groups.
Microinjection of the selective cholinergic receptors antagonists, PRZ or MTR or HEX with given dose into the NTS in the unstressed groups, had no obvious effects on both ISP-MAP and ISP-Gain relationship curves and CSR functional parameters, respectively (P>0.05).
3.2 Effects of the microinjection of different cholinergic receptor antagonists into the NTS on the changes in CSR induced by stress
Microinjection of the selective muscarinic M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the NTS in the stressed groups with the corresponding doses used in the unstressed groups, also significantly diminished the above-mentioned changes in CSR performance induced by stress, which remarkably moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters such as the MAP range (only for MTR) and Gmax (P<0.05), but decreased parameters like SP, ISPGmax and set point (only for MTR) (P<0.05), compared with the positive control. The alleviative effects of MTR were also remarkably stronger than those of PRZ in the stressed group, which significantly moved the posterior semi-parts of ISP-MAP relationship curves downwards (P<0.05), shifted the middle parts of ISP-Gain relationship curves upwards (P<0.05), and increased parameters Gmax and the MAP range (P<0.05), compared with the stressed group of PRZ. The responses of CSR level in stressed groups to M1 or M2 cholinoceptor antagonists generally occurred 12 min after the administration and lasted approximately for 20 min. Microinjection of the selective nicotinic N1 cholinoceptor antagonist HEX into the NTS in the stressed group, however, displayed no significant effects on the stressed CSR baseline and the CSR level of the positive control (P>0.05) but exhibited significant difference from the CSR levels in the stressed groups of the MTR and PRZ (P<0.05).
3.3 Comparison between the CSR levels treated by different cholinoceptor antagonists into the NTS in stressed groups and the corresponding control level of CSR in the unstressed groups
Microinjection of PRZ or MTR or HEX into the NTS in the stressed groups could not completely abolish the stress-induced changes in CSR (P<0.05).
Conclusion:
1. Stress results in a resetting of CSR , a decrease in reflex sensitivity.
2. Microinjection of selective cholinergic receptor antagonist PRZ or MTR or HEX into the lateral ventricle or the NTS with given respective dose under the unstressed state, has neither effects on the CSR function and nor on the arterial blood pressure basal level.
3. Microinjection of the selective M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the lateral ventricle with given respective dose could obviously attenuate the stress-induced CSR inhibitory resetting, and the alleviative effects of MTR are more stronger than those of PRZ in the stressed group, but the selective N1 cholinoceptor antagonist, HEX into the lateral ventricle may have no effects on the CSR resetting resulted from the stress, which suggest that the M1 and M2 cholinoceptors, especially M2 cholinoceptors, in brain ventricle peripheral nuclei may participate in mediating stress-induced CSR resetting.
4. Microinjection of the selective M1 cholinoceptor antagonist PRZ or the selective M2 cholinoceptor antagonist MTR into the NTS with given respective dose could also remarkably diminish the stress-induced CSR inhibitory resetting, and the alleviative effects of MTR are more stronger than those of PRZ in the stressed group, but the selective N1 cholinoceptor antagonist, HEX into the NTS may also have no effects on the CSR resetting resulted from the stress, which indicate that the M1 and M2 cholinoceptors, especially M2 cholinoceptors, in the NTS may also involve in regulating stress-induced CSR resetting, and the descending cholinergic pathway from the hypothalamus to NTS may be involved in mechanisms of the stress-inhibited CSR function.
5. Microinjection of PRZ or MTR or HEX into the lateral ventricle or the NTS with given respective dose in the stressed state can not completely abolish the stress-induced changes in CSR, which denote that other neuromechanisms may also contribute to effects of the stress on CSR besides central cholinergic system.
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