多沙唑嗪及其光学异构体对兔离体肠肌收缩活动的影响

Effects of doxazosin and its enantiomers on contraction activity in isolated rabbit intestinal muscle

目的:观察左旋多沙唑嗪[(-)DOX]、右旋多沙唑嗪[(+)DOX]和消旋多沙唑嗪[(±)DOX]对兔离体回肠和十二指肠收缩活动的影响,为其消化系统不良反应的发生提供实验依据。方法:制备兔离体回肠、回肠纵肌、回肠环肌和十二指肠标本各10份,各标本两端分别固定于麦氏浴槽和张力换能器。实验分4组:(-)DOX组、(+)DOX组、(±)DOX组和蒸馏水对照组。(-)DOX、(+)DOX和(±)DOX各有3种不同浓度(3、10、30μmol/L),蒸馏水为15、35、100μl。将3种浓度的(-)DOX、(+)DOX和(±)DOX及3种容量的蒸馏水分别加入浴槽中,测量3种药物对回肠、回肠纵肌和十二指肠收缩频率和幅度的影响。另外,将(-)DOX、(+)DOX、(±)DOX和蒸馏水各150μl加入浴槽,20 min后,加入卡巴胆碱20μmol/L。在给予卡巴胆碱后30 min内记录回肠环肌收缩频率和幅度。结果:3种药物均抑制回肠收缩频率。(-)DOX、(+)DOX和(±)DOX在30μmol/L浓度时,回肠收缩频率分别为(8.2±1.6)、(7.1±1.5)和(6.8±1.4)次/min,与用药前的收缩频率[(11.0±1.5)、(10.3±1.7)和(10.6±2.1)次/min]或蒸馏水的收缩频率[(10.6±1.6)次/min]相比,差异均有统计学意义(均P<0.01)。3种药物均抑制回肠纵肌收缩频率。(-)DOX、(+)DOX和(±)DOX在30μmol/L浓度时,回肠纵肌收缩频率分别为(10.1±1.5)、(9.7±2.1)和(9.0±2.2)次/min,与用药前的收缩频率[(12.9±2.8)、(13.9±1.7)和(13.0±1.8)次/min]相比,差异有统计学意义(均P<0.01)。3种药物均不影响卡巴胆碱诱发的回肠环肌收缩活动,与蒸馏水相比,差异无统计学意义(均P>0.05)。3种药物均抑制十二指肠收缩频率和收缩力。(-)DOX、(+)DOX和(±)DOX在30μmol/L浓度时,十二指肠收缩频率分别为(11.9±1.2)、(14.2±2.6)和(12.5±1.8)次/min,与用药前的收缩频率[(16.5±1.4)、(17.5±1.8)和(15.1±1.5)次/min]或蒸馏水的收缩频率[(16.0±2.2)次/min]相比,差异均有统计学意义(均P<0.01);此外,十二指肠收缩力分别为(0.75±0.44)、(0.71±0.22)和(0.87±0.58)g,与用药前收缩力[(3.81±0.66)、(4.12±0.66)和(3.96±0.74)g]或蒸馏水的收缩力[(3.87±0.70)g]相比,差异均有统计学意义(均P<0.01)。结论:多沙唑嗪及其光学异构体对回肠和回肠纵肌收缩频率及十二指肠收缩频率和幅度有显著抑制作用,其中左旋多沙唑嗪的抑制作用相对较弱。

Objective： To observe the effect of （ - ） doxazosin[ （ - ）DOX], （ ＋ ） doxazosin[ （ ＋ ）DOX], and （ ± ） doxazosin [ （± ） DOX ] on the contraction activity in isolated rabbit ileum and duodenum in order to provide the experimental basis for doxazosin- induced digestive system disorders. Methods： The isolated preparations of rabbit ileum, ileal longitudinal muscle, ileal circular muscle, and duodenum were prepared. The ends of each preparation were fixed in the Magnus bath and tension converter, respectively. The experiments were divided into four groups ： the （ - ） DOX group, the （ ＋ ） DOX group, the （ ± ） DOX group, and the distilled water control group. Each of （ - ） doxazosin, （ ＋ ） doxazosin, and （ ± ） doxazosin had three concentrations of 3, 10, and 30μmol/L; 15, 35, and 100μl of distilled water served as controls. Three different concentrations of （ - ）DOX, （ ＋ ）DOX, and （ ±）DOX, as well as 15, 35, and 100 μl of distilled water were added into the Magnus bath. The contraction frequency and amplitude of ileum, ileal longitudinal muscle, duodenum were measured. In addition, 150 μl of （ - ） DOX, （ ＋ ） DOX, （± ） DOX, and distilled water was added into to the bath, respectively. Twenty minutes later, carbaehol was added into to the bath. The contraction frequency and amplitude were recorded after carbachol administration. Results：The 3 drugs all inhibited the ileum contraction frequency. At （ - ） DOX, （ ＋ ） DOX, and （± ） DOX concentrations of 30 μmoL/L, ileum contraction frequency was（8.2 ±1.6）/rain, （7.1 ±1.5 ）/min and（6.8±1.4）/min, respectively; the differences were statistically significant compared with the contraction frequency before drug administration [ （ 11.0±1.5 ）/min, （ 10.3 ±1.7 ）/min and （ 10.6 ± 2.1 ）/min ] or the contraction frequency of distilled water [ （ 10.6 ± 1.6 ）/min ] （ all P 〈 0.01 ）. The 3 drugs all inhibited the contraction frequency of ileal longitudinal muscle. At （ - ） DOX, （ ＋ ） DOX, and （±）DOX concentrations of 30μmol/L, the contraction frequency of ileal longitudinal muscle was （ 10. 1±1.5 ）/min, （9.7± 2. 1 ）/min and（9.0 ±2.2）/min, respectively; the difference were statistically significant compared with the contaction frequency before drug administration [ （ 12.9 ± 2.8 ）/min, （ 13.9±1.7 ）/min and（ 13.0 ± 1.8 ）/min] （ all P 〈 0.01 ）. The 3 drugs all did not affect the carbachol-induced contraction activity of ileal circular muscle. The differences were not statistically significant compared with distilled water （ all P 〉 0.05 ）. The 3 drugs all inhibited the contraction frequency and contractile force of duodenum. At （ - ） DOX, （ ＋ ）DOX, and （ ± ）DOX concentrations of 30μmol/L, the contraction frequency of duodenum was（ 11.9±1.2）/min, （ 14.2± 2. 6）/min and（ 12.5 ±1.8 ）/min, respectively; the differences were statistically significant compared with the contraction frequency before drug administration [ （ 16.5 ±1.4 ）/min, （ 17.5 ±1.8 ）/min and （ 15.1 ±1.5 ）/min ] or the contraction frequency of distilled water [ （ 16.0 ±2.2 ）/min ] （ all P 〈 0.01 ）. In addition, the contractile force of duodenum was （0.75 ± 0.44 ） g, （0.71 ±0. 22 ） g and （0. 87 ± 0. 58 ） g, respectively ; the difference were statistically significant compared with the contractile force before drug administration [ （ 3.81 ±0.66 ） g, （4. 12 ± 0. 66 ） g and （ 3.96 ±0.74 ） g ] or the contratile force of distilled water [ （ 3.87 ± 0.70 ） g ] （ all P 〈 0. 01 ）. Conclusion： Doxazosin and its enantiomers all have inhibitory action on contraction frequency of ileum and ileal longitudinal and contraction frequency and amplitude of duodenum; of them, the inhibitory action of （ - ） doxazosin is relatively weak.