【作者】 刘宜先；

【导师】 何瑞荣；

【作者基本信息】 河北医科大学 ， 生理学， 2004， 硕士

【摘要】 动脉压力感受器是分布在颈动脉窦和主动脉弓血管外膜下的牵张敏感性神经末梢。动脉血压的变化使血管壁受牵张而变形，刺激压力感受器，从而在传入神经纤维上引发放电，电信号传至中枢神经系统引起反射，其中传入冲动的发放频率与血管壁牵张程度呈线形相关。通过此反射来缓冲血压的变化，即压力感受器反射是调节血压变化的重要负反馈机制。有研究显示，压力感受器上存在牵张敏感性阳离子通道，很多药物就是通过影响了此通道，从而对其敏感性起调变作用。胆囊收缩素在中枢神经和外周器官广泛分布，参与体内的许多生理过程。大量证据表明CCK通过两种受体发挥作用，即CCK-A 受体 和CCK-B受体。许多研究发现八肽胆囊收缩素（cholecystokinin octapeptide，CCK-8）是胆囊收缩素的内源性活性功能片段，可在清醒或麻醉大鼠引发心血管功能的变化，引起剂量依赖性的血压升高和心率的双向改变；为排除神经系统的影响，Gaw等给毁髓鼠静脉注射CCK-8，可引起剂量依赖性动脉血压升高和明显心动过缓，使用选择性CCK-AR拮抗剂loxiglumide和devazepide可减弱CCK-8引起的上述反应，使用CCK-BR拮抗剂L-365，260对次变化无影响。但CCK-8是否通过影响动脉压力感受器起作用，目<WP=5>前报道较少。本研究的目的主要是通过颈动脉窦区隔离灌流，观察CCK-8对颈动脉窦压力感受器活动和反射的影响，并探讨其可能作用机制。八肽胆囊收缩素抑制麻醉大鼠颈动脉窦压力感受器反射八肽胆囊收缩素（Cholecystokinin octapeptide, CCK-8）是胆囊收缩素的活性功能片段。已有大量的研究表明，八肽胆囊收缩素可影响心血管的活动。本实验在36只隔离灌流颈动脉窦区的麻醉大鼠上，观察了八肽胆囊收缩素（CCK-8）对颈动脉窦压力感受器反射的影响。其结果如下：（1）颈动脉窦压力感受器反射机能曲线的参数如下：最大斜率（peak slope, PS）0.47±0.01，反射性血压下降幅度（reflex decrease, RD）47.67±3.21, 阈压（threshold pressure, TP）65.42±1.82，饱和压（saturation pressure, SP）168.87±1.58;（2）以CCK-8（0.1 μmol/L）隔离灌流颈动脉窦区时，压力感受器机能曲线向右上方移位，PS减小至0.35±0.02 (P<0.001), RD减少至36.50±2.76 (P<0.001), TP增至72.36±2.94 (P<0.01)，SP增至178.49±2.86(P<0.01)；以CCK-8（0.5μmol/L）隔离灌流颈动脉窦区时，压力感受器机能曲线进一步向右上方移位，PS减小至0.3±0.01 (P<0.001), RD减少至31.17±1.14 (P<0.001), TP增至75.84±1.56 (P<0.001)，SP增至183.79±3.19 (P<0.001)；以CCK-8（1.0 μmol/L）隔离灌流颈动脉窦区时，压力感受器机能曲线进一步向右上方移位，PS减小至0.21±0.01 (P<0.001), RD减少至22.10±2.68 (P<0.001), TP增至82.04±2.24 (P<0.001)，SP<WP=6>增至199.01±2.43 (P<0.001)；其中 RD、PS 和 TP 呈明显的剂量依赖性；（3）用CCK-8 的非特异性受体拮抗剂丙谷胺（100 μmol/L）预处理后，能明显减弱CCK-8 （0.5 μmol/L）对压力感受器反射的抑制， PS为0.41±0.02 (P<0.001), RD为43.67±1.95 (P<0.001), TP为71.19±1.47 (P<0.05)，SP为177.32±2.47 (P<0.05)；（4）预先灌流NO 合酶阻断剂（L-NAME，100 μmol/L），不能阻断CCK-8 （0.5 μmol/L）对压力感受器反射的影响；（5）用Ca2+ 通道激动剂 Bay K8644 (500 nmol/L) 预处理后，也能明显减弱CCK-8 （0.5 μmol/L）对压力感受器反射的抑制作用，其中PS为0.38±0.01 (P<0.001), RD为39.94±3.31 (P<0.001), TP为72.33±2.09 (P<0.05)，SP为175.67±3.24 (P<0.05)。以上结果提示，CCK-8 是通过作用于颈动脉窦压力感受器神经元末梢上的受体而起到抑制作用，其机制可能为抑制了牵张敏感性通道，致使Ca2+离子内流减少，而与内皮细胞释放NO无关。关键词：八肽胆囊收缩素；丙谷胺；Bay K 8644；压力感受器反射；L-NAME；平均动脉压2 八肽胆囊收缩素抑制麻醉大鼠颈动脉窦压力感受器活动八肽胆囊收缩素是胆囊收缩素的活性功能片段，许多文献报道CCK-8 可在清醒或麻醉大鼠引发心血管功能的改变。本实验目的是在麻醉雄性大鼠隔离灌流颈动脉窦区条件下，通过记录窦神经传入放电，观察八肽胆囊<WP=7>收缩素（CCK-8）对动脉压力感受器活动的影响。实验结果如下：（1）窦神经放电最大积分值（PIV）215.31±4.25 (P<0.05)，最大斜率（PS）2.57±0.04 (P<0.05)，阈压（TP）63.45±1.23 (P<0.05)，饱和压（SP）176.36±1.58 (P<0.05)；（2）CCK-8 （0.1 μmol/L）使压力感受器机能曲线向右下方移位，PS和PIV均明显减小至2.49±0.03和205.50±5.03，TP和SP分别升至66.17±1.99和183.17±2.63；CCK-8 （0.5 μmol/L）使压力感受器机能曲线继续向右下方移位，PS和PIV均明显减小至2.36±0.03 (P<0.01)和186.17±3.61 (P<0.05)，TP和SP分别升至73.00±2.90 (P<0.05)和189.01±1.86； CCK-8 （1.0 μmol/L）使压力感受器机能曲线继续向右下方移位，PS和PIV均明显减小至2.24±0.04 (P<0.05)和171.15±3.53 (P<0.05)，TP和SP分别升至79.67±1.43 (P<0.05)和200.83±3.73 (P<0.05)；以上结果表明CCK-8 可抑制颈动脉窦更多还原

【Abstract】 Arterial baroreceptors are mechanosensitive nerve endings that innervate adventitia of carotid sinuses and aortic arch. Changes in arterial blood pressure are sensed indirectly through the baroreceptors’ responsiveness to mechanical deformation during vascular stretch. Changes in the frequency of baroreceptor afferent discharge transmitted to the central nervous system trigger reflex adjustments that buffer or oppose the change in pressure; that is, the baroreceptor reflex provides a powerful negative feedback mechanism of blood pressure regulation. Many studies have shown there are mechanosensitive ion channels in baroreceptors, many drugs may act on the channels leading to modulation of baroreceptor activity.Cholecystokinin is widely distributed in the central and peripheral nervous systems. A considerable body of evidence indicates that CCK-8 exerts its effects via two distinct subtypes of receptors, CCK-AR and CCK-BR. Many studies showed that cholecystokinin octapeptide (CCK-8), the active fragment of endogenous CCK, had cardiovascular actions in both conscious and anesthetized animals, and elicited dose-dependent increase in arterial blood pressure and a variable change in heart rate. To <WP=10>exclude the effect of the central nervous system, Gaw et al reported that injection of CCK-8 caused a dose-dependent increase in arterial blood pressure and a bradycardia in pithed rats, and the above effects of CCK-8 were inhibited by administration of CCK-AR antagonists, loxiglumide and devazepide, while not by treatment with CCK-BR antagonist, L-365, 260. However, there are little reports on whether CCK-8 affects carotid sinus baroreflex which is of the most importance to the regulation of cardiovascular. So, the present work was undertaken to study the effects of CCK-8 on carotid sinus baroreflex and baroreceptor activity in anesthetized male rats with isolated carotid sinus perfusion in vivo. 1 Cholecystokinin octapeptide inhibits carotid sinus baroreflex in anesthetized ratsCCK-8 is an active functional fragment of CCK. It has been established that CCK-8 can alter cardiovascular functions on conscious or anesthetized animals. The purpose of this study was to determine the effect of cholecystokinin octapeptide (CCK-8) on carotid sinus baroreflex in 36 anesthetized male rats by isolated carotid sinus perfusion in vivo. The results obtained are as follows. (1) parameters of carotid sinus baroreflex are as follows: peak slope (PS) 0.47±0.01, reflex decrease（RD） is 47.67±3.21, threshold pressure（TP）is 65.42±1.82， saturation pressure（SP）is 168.87±1.58; (2) By perfusion with CCK-8 (0.1 μmol/L), the functional curve of baroreflex was shifted to the right and upward, PS was decreased to 0.35±0.02 and RD was <WP=11>decreased to 36.50±2.76（P<0.001）, while TP and SP were significantly increased to 72.36±2.94 and 178.49±2.86; By perfusion with CCK-8 (0.5 μmol/L), the functional curve of baroreflex was further shifted to the right and upward, PS and RD were decreased to 0.3±0.01（P<0.001）and 31.17±1.14（P<0.001）, TP and SP were increased to 75.84±1.56 （P<0.001）and 183.79±3.19（P<0.001）; By perfusion with CCK-8 (1.0 μmol/L), the functional curve of baroreflex was shifted to the right and upward further comparing to group CCK-8 (0.5 μmol/L), PS and RD were decreased to 0.21±0.01（P<0.001）and 22.10±2.68（P<0.001）, while TP and SP were increased to 82.04±2.24（P<0.01）and 199.01±2.43（P<0.001）; Among the functional parameters of carotide baroreflex, the changes in RD, PS and TP were dose-dependent. (2) Pretreatment with proglumide (100 μmol/L), a nonselective CCK receptor antagonist, the inhibitory effect of CCK-8 (0.5 μmol/L) on the baroreflex was significantly attenuated. PS and RD were increased to 0.41±0.02（P<0.001）and 43.67±1.95（P<0.001）; TP and SP were decreased to 71.19±1.47（P<0.05） and 177.32±2.47（P<0.05）. (3) Pretreatment with L-NAME (100 μmol/L), an inhibitor of NO synthase, did not affect the inhibitory effect of CCK-8 (0.5 μmol/L); (4) Preperfusion with B更多还原