生理遥测和全体积描记法联用观测清醒大鼠昼夜节律变化及其在多索茶碱安全药理学中的应用

目的 应用植入式生理信号遥测系统和全身体积描记法肺功能检测技术系统，观察清醒大鼠的昼夜节律变化，并用多索茶碱进行性能验证，为今后该技术系统用于药物安全药理学评价提供依据。方法 SD大鼠8只，雌雄各半，采用外科术将植入子植入大鼠腹腔建立遥测系统，并结合肺功能检测技术，在术后14 d观察清醒大鼠24 h的生理参数及昼夜节律的变化，包括心率（HR）、血压、心电图Q波到血压的舒张点的时间差（QA间期）、呼吸、活动、体温和肺功能等指标，分为正常对照组、多索茶碱40和80 mg/kg组（雾化吸入），观察给药后上述参数的变化情况。结果 术后14 d清醒大鼠的生理指标具有明显的昼夜节律变化。与正常对照组比较，多索茶碱40 mg/kg组大鼠HR、潮气量（TV）、每分钟通气量（MV）、50%呼气流量（EF50）、吸气流量峰值（PIF）和呼吸流量峰值（PEF）均明显增加（P<0.01），呼吸频率、QA间期和增强呼气间歇（PENH）均明显降低（P<0.05，P<0.01），但对血压、活动和体温变化不明显；多索茶碱80 mg/kg组大鼠HR、血压、TV、MV、EF50、PIF和PEF均明显增加（P<0.01），呼吸频率、QA间期和PENH均明显降低（P<0.01），但对活动和体温变化不明显。结论 本技术系统对大鼠的生理昼夜节律无明显影响，并可灵敏监测到心血管呼吸系统的相关变化，可用于清醒大鼠心血管呼吸系统安全药理学研究。

Application of implantable telemetry and whole-body plethysmography to observe the changes of circadian rhythm in conscious rats and its application in pharmacological safety evaluation of doxofylline

Objective To study the application of implantable telemetry and whole-body plethysmography to observe the changes of circadian rhythm in conscious rats and evaluate the pharmacological safety of doxofylline, and to provide a basis for the future application of this technological system for drug safety evaluation. Methods Eight healthy SPF Sprague-Dawley rats were used in this study, 4 males and 4 females. The rats were implanted with telemetry transmitters by surgery to establish a telemetry system combined with plethysmography to observe the changes of 24 h physiological parameters and circadian rhythm in conscious rats at 14 d after operation, including heart rate (HR), blood pressure, the time interval from the Q wave to point A in the ECG of the aortic pressure wave (QA interval), respiration, activity, body temperature and pulmonary function parameters. The rats were divided into 3 groups:normal control group, doxofylline 40 mg/kg and 80 mg/kg groups, and the performance was validated by aerosolizing saline, doxofylline 40 mg/kg and 80 mg/kg inhalation, respectively, to observe the changes in physiological parameters after the drug administration. Results The physiological parameters of rats showed obvious changes in circadian rhythms at 14 d after operation. Compared with the normal control group, the doxofylline 40 mg/kg-treated group showed significantly increased changes of HR, tidal volume (TV), minute ventilation (MV), 50% expiratory flow (EF50), peak inspiratory flow (PIF) and peak expiratory flow (PEF) (P<0.01), significantly decreased respiratory frequency, QA interval and enhance pause (Penh) (P<0.05, P<0.01), but no significant differences in the blood pressure, activity and body temperature (P>0.05). Compared with the normal control group, the group treated with doxofylline 80 mg/kg had significantly increased HR, blood pressure, TV, MV, EF50, PIF and PEF (P<0.01), significantly decreased respiratory frequency, QA interval and Penh not (P<0.01), but not significantly changed activity and body temperature (P>0.05). Conclusions The application of implantable telemetry and whole-body plethysmography in this study does not obviously affect the circadian rhythm, and can sensitively monitor the relevant cardiovascular and respiratory parameters in conscious rats. It can be used in drug safety pharmacological research of cardiovascular and respiratory systems in conscious rats.