【作者】 王凤玉；

【导师】 任雷鸣；

【作者基本信息】 河北医科大学 ， 药理学， 2008， 硕士

【摘要】 目的:观察多沙唑嗪（rac-doxazosin, rac-DOX）及其光学异构体（S-DOX和R-DOX）对兔离体心房肌和心室肌收缩活动的影响,对兔离体回肠和十二指肠收缩活动的影响。方法:制备兔离体左心房、右心房、右心室肌标本。对于心房标本,累积给予3、10、30μmol·L^-1浓度的多沙唑嗪及其光学异构体。对于右心室标本,非累积给予3、10、30μmol·L^-1多沙唑嗪及其光学异构体。观察多沙唑嗪及其光学异构体对心率和心肌收缩力的影响。制备兔离体回肠、回肠纵肌、回肠环肌标本。对于回肠和回肠纵肌标本,累积给予3、10、30μmol·L^-1浓度的多沙唑嗪及其光学异构体。对于回肠环肌标本,先给予30μmol·L^-1的多沙唑嗪及其光学异构体,再给予20μmol·L^-1的卡巴胆碱。观察多沙唑嗪及其光学异构体对离体回肠肠肌收缩频率和收缩幅度的影响。制备兔离体十二指肠标本,累积给予3、10、30μmol·L^-1浓度的多沙唑嗪及其光学异构体,观察多沙唑嗪及其光学异构体对离体十二指肠自发收缩频率和收缩幅度的影响。结果:1 S-DOX、R-DOX及rac-DOX对兔离体右心房心率的影响R-DOX(30μmol·L^-1),使23%的实验标本发生停搏,rac-DOX和S-DOX未诱发停搏反应。S-DOX(30μmol·L^-1)对兔离体右心房心率无显著影响。R-DOX和rac-DOX(3、10、30μmol·L^-1)浓度依赖性地抑制兔右心房心率, 30μmol·L^-1时R-DOX组心率减慢（25.7±10.5）%,rac-DOX组心率减慢（23.6±7.7）%。2 S-DOX、R-DOX及rac-DOX对兔离体右心房收缩力的影响S-DOX(3、10、30μmol·L^-1)对兔离体右心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L^-1)浓度依赖性地抑制兔右心房心肌收缩力,30μmol·L^-1时R-DOX组心肌收缩力下降了（78.6±8.6）%,rac-DOX组心肌收缩力下降了（56.7±11.7）%。R-DOX的心肌收缩力抑制作用强于rac-DOX。3 S-DOX、R-DOX及rac-DOX对兔离体左心房收缩力的影响S-DOX(3、10、30μmol·L^-1)对兔离体左心房心肌收缩力无显著影响。R-DOX和rac-DOX(3、10、30μmol·L^-1)浓度依赖性地抑制兔左心房心肌收缩力,30μmol·L^-1时,R-DOX和rac-DOX对左心房心肌收缩力的抑制百分率分别为（89.9±4.9）%和（45.4±15.6）%。R-DOX的心肌收缩力抑制作用强于rac-DOX。4 S-DOX、R-DOX及rac-DOX对兔离体右心室肌收缩力的影响S-DOX(30μmol·L^-1)显著增强兔离体右心室肌收缩力,30μmol·L^-1时右心室肌收缩力增强了（26.7±21.5）%。R-DOX和rac-DOX(3、10、30μmol·L^-1)浓度依赖性地抑制兔右心室肌收缩力,30μmol·L^-1时,R-DOX和rac-DOX对右心室肌收缩力的抑制百分率分别为（38.1±28.1）%和（29.4±24.4）%。R-DOX的心肌收缩力抑制作用强于rac-DOX。5 S-DOX、R-DOX及rac-DOX对兔离体回肠、回肠纵肌和环肌收缩反应的影响S-DOX、R-DOX和rac-DOX(3、10、30μmol·L^-1)对兔离体回肠自发收缩幅度无显著影响。S-DOX仅在30μmol·L^-1浓度减慢回肠自发收缩频率。R-DOX和rac-DOX(10、30μmol·L^-1)显著抑制回肠自发收缩频率,30μmol·L^-1时R-DOX和rac-DOX使自发收缩频率分别减慢至7.1cycles·min-1和6.8cycles·min-1。S-DOX、R-DOX和rac-DOX(3、10、30μmol·L^-1)对兔离体回肠纵肌自发收缩幅度无显著影响。S-DOX仅在30μmol·L^-1浓度减慢自发收缩频率。R-DOX和rac-DOX(10μmol·L^-1、30μmol·L^-1)显著抑制兔离体回肠纵肌的自发收缩频率;30μmol·L^-1时R-DOX和rac-DOX使回肠纵肌自发收缩频率分别减慢至9.7cycles·min-1和9.0cycles·min-1。S-DOX、R-DOX和rac-DOX(3、10、30μmol·L^-1)对卡巴胆碱所诱发的兔离体回肠环肌收缩频率和收缩幅度均无显著影响。6 S-DOX、R-DOX及rac-DOX对兔离体十二指肠收缩反应的影响。S-DOX仅在30μmol·L^-1浓度显著抑制兔离体十二指肠自发收缩频率。R-DOX(10、30μmol·L^-1)、rac-DOX(10、30μmol·L^-1)显著抑制兔离体十二指肠自发收缩频率,30μmol·L^-1时两组标本的收缩频率分别由给药前的17.5cycles·min-1减慢至14.2cycles·min-1以及15.1cycles·min-1减慢至12.5cycles·min-1。S-DOX、R-DOX和rac-DOX(10、30μmol·L^-1 )均显著抑制兔离体十二指肠自发收缩幅度;30μmol·L^-1时十二指肠的收缩幅度分别被抑制至0.75g、0.71g和0.87g。结论:R-DOX抑制右心房心率的作用强于rac-DOX,甚至诱发停搏反应;S-DOX不影响心率。R-DOX对心房肌和心室肌收缩力的抑制作用强于rac-DOX;S-DOX不影响心房肌收缩力,对心室肌具有正性肌力作用。S-DOX、R-DOX及rac-DOX对兔离体回肠和回肠纵肌的收缩力无影响,对卡巴胆碱所诱发回肠环肌收缩反应亦无明显影响,但显著抑制离体十二指肠收缩力。S-DOX、R-DOX及rac-DOX显著抑制兔离体回肠、回肠纵肌和十二指肠的自发收缩频率,其中S-DOX的抑制作用相对较弱。更多还原

【Abstract】 Objective: To study the effects of rac-doxazosin （rac-DOX） and its enantiomers （S-doxazosin, S-DOX and R-Doxazosin, R-DOX） on the rabbit isolated atrial and ventricular strips and ileum and duodenal smooth muscle.Methods: The strips of the rabbit isolated right atrium, left atrium and right ventricle were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively administered into the organ bath containing the rabbit isolated atrial strips, but they were non-cumulatively administered into the organ bath containing the rabbit isolated right ventricular strips. The effects of doxazosin and its enantiomers on contractile force and heart rate were observed.The rabbit isolated ileum, ileum longitudinal muscle strips and circular muscle strips were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively given into the organ bath containing the rabbit isolated ileum, ileum longitudinal muscle. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively administered into the organ bath containing the rabbit isolated ileum circular muscle, then carbachol at 20μmol·L^-1 was applied. Effects of doxazosin and its enantiomers on the contractile force, contractile frequency and carbachol-induced responses were observed in the rabbit isolated ileum preparations.The rabbit isolated duodenal smooth muscle preparations were prepared, and doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively given into the organ bath containing the rabbit isolated duodenum. Effects of doxazosin and its enantiomers on the contractile force and contractile frequency were observed in the rabbit isolated duodenal smooth muscle.Results:1 Effects of doxazosin and its enantiomers on the heart rate in the rabbit isolated right atriumIn 23% of the used atrial preparations, the cardiac arrest was induced by R-DOX at 30μmol·L^-1, but S-DOX and rac-DOX at the same concentration did not induce the same effect. S-DOX at 30μmol·L^-1 did not affect the heart rate of the rabbit isolated right atrium, R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the heart rate. R-DOX and rac-DOX at 30μmol·L^-1 decreased the heart rate by 25.7±10.5% and 23.6±7.7%, respectively.2 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right atrium S-DOX did not affect the contractile force of the rabbit isolated right atrium. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the contractile force of the rabbit isolated right atrium and both of them at 30μmol·L^-1 decreased the contractile force by 78.6±8.6% and 56.7±11.7%, respectively. The negative inotropic effect in the right atrium by R-DOX was stronger than that by rac-DOX.3 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated left atriumS-DOX did not affect the contractile force of the rabbit isolated left atrium. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the contractile force of the rabbit isolated left atrium and both of them at 30μmol·L^-1 decreased the contractile force by 89.9±4.9% and 45.4±15.6%, respectively. The negative inotropic effect in the left atrium by R-DOX was stronger than that by rac-DOX.4 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right ventricular stripsS-DOX at 30μmol·L^-1 increased the contractile force of the rabbit isolated right ventricular strips, and S-DOX at 30μmol·L^-1 increased the contractile force by 26.7±21.5%. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration -dependently decreased the contractile force of the rabbit isolated right ventricular strips and both of them at 30μmol·L^-1 decreased the contractile force by 38.1±28.1% and 29.4±24.4%, respectively. The negative inotropic effect in the ventricular strips by R-DOX was stronger than that by rac-DOX.5 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated ileum smooth muscleDoxazosin and its enantiomers (3³0μmol·L^-1) did not affect the spontaneous contractile force in the rabbit isolated ileum. S-DOX only at 30μmol·L^-1 decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum, R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frequency from 10.3cycles·min-1 to 7.1cycles·min-1 and from 10.6cycles·min-1 to 6.8cycles·min-1, respectively.Doxazosin and its enantiomers (3³0μmol·L^-1) did not affect the spontaneous contractile force in the rabbit isolated ileum longitudinal muscle strips. S-DOX only at 30μmol·L^-1 decreased the contractile frequency from 12.9cycles·min-1 to 10.1cycles·min-1 in the rabbit isolated ileum longitudinal muscle. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum longitudinal muscle strips, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frequency from 13.9cycles·min-1 to 9.7cycles·min-1 and from 13.0cycles·min-1 to 9.0cycles·min-1, respectively.Doxazosin and its enantiomers (3³0μmol·L^-1) did not affect the contractile force and contractile frequency of the contraction induced by carbachol in the rabbit isolated ileum circular muscle strips.6 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated duodenal smooth muscleS-DOX only at 30μmol·L^-1 decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenum. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenal smooth muscle, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frquency from 17.5cycles·min-1 to 14.2cycles·min-1 and from 15.1cycles·min-1 to 12.5cycles·min-1, respectively.Doxazosin and its enantiomers (10³0μmol·L^-1) all decreased the spontaneous contractile force in the rabbit isolated duodenal muscle. S-DOX at 30μmol·L^-1 decreased the spontaneous contractile force from 3.81g to 0.75g, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the spontaneous contractile force from 4.12g to 0.71g and from 3.96g to 0.87g, respectively.Conclusion: R-DOX produces a negative chronotropic effect in the rabbit isolated right atrium more potently than rac-DOX, and it even causes cardiac arrest at higher concentration. S-DOX does not affect the heart rate. R-DOX produces a negative inotropic effect in the rabbit isolated atrial and ventricular strips more potently than rac-DOX. On the contrary, S-DOX produces the positive inotropic effect.Doxazosin and its enantiomers do not affect the spontaneous contractile force in the rabbit isolated ileum and ileum longitudinal muscle, and do not affect the contraction induced by carbachol in the rabbit isolated ileum circular muscle, but decrease the spontaneous contractile force in the rabbit duodenal muscle. Doxazosin and its enantiomers decrease the spontaneous contractile frequency in the rabbit isolated ileum, ileum longitudinal muscle and duodenum muscle, and the inhibitory effect by S-DOX is weaker.更多还原