目的 观察Beagle犬连续6个月po单硝酸异山梨酯、缬沙坦、螺内酯复方（ISMN-V-S）降压药物所产生的毒性反应，比较3种药物联合应用后，毒性是否增加或产生新的毒性。方法 健康Beagle犬40只，雌雄各半，分为5组，空白对照组、单缬螺复方15、50、150 mg/(kg?d)及缬沙坦对照组，每组8只动物。给药体积为5 mL/kg，每日ig给药1次，每周给药6 d，连续给药26周，停药观察4周。实验期间，每日进行一般状态观察，每周测定1次体质量及摄食量，并于给药前、给药第13、26周及停药恢复期第4周，分别对眼科、体温、尿常规、心电图、血液学及血液生化学进行检查，在给药期结束前及恢复期结束前测量动物血压，末次给药后及恢复期结束后分两批对动物剖检并进行病理组织学检查。结果 各组动物行为活动、饮食、饮水正常。动物体质量、摄食量组间无差异。试验进行过程中进行的眼科、体温、尿常规、心电图、血液学及血液生化学等指标的检查，未见异常。各给药组动物血压同空白对照组比较明显降低，停药后恢复正常。组织病理学检查，除个别动物肾脏发生自发性病变，其他动物未见明显病理器官改变。结论 本试验条件下，单缬螺复方降压药物除药理作用延伸引起的血压降低外，未出现药物的蓄积现象，同各成分单独使用相比，未见毒性增加或产生新的毒性。

Objective To observe the toxicity of (ISMN), Valsartan, and Isosorbide Mononitrate Valsartan Spironolactone (ISMN-V-S) Compound in Beagle’s dogs for 6 months by oral administration, and to compare wether the toxicity increased or new toxicity was generated after three ingredients combined application. Methods Forty healthy Beagle’s dogs, half male and half female, were randomly disvided into control, Valsartan, low-, mid-, and high-dose [15, 50, and 150 mg/(kg?d)] ISMN-V-S Compound groups, eight in each group. Dose volume was 5 mL/kg, with ig administration for 26 weeks once daily, 6 d per week, and observed for 4 weeks after the last administration. During the experiment, the general conditions of animals were observed daily. Body weight and food consumption were weighed weekly. The related indexes including ophthalmology, body temperature,urinary routine, electrocardiogram, blood routine, and blood biochemistry were detected at different time points such as before administration, weeks 13 and 26 of administration, and week 4 in recovery period. Blood pressure were measured at the end of administration and at the end of recovery period, then the dogs were dissected and histopathologic examination was carried out. Results The states of behavior, food and drink intake in each group were normal. No significant differences in weight and food consumption among groups were observed. The indexes of ophthalmology, body temperature, urinary routine, electrocardiogram, blood routine, and biochemistry during the experiment were normal. The blood pressure in all the drug groups declined obviously compared with the control group, but returned to normal after drug withdrawal. No obvious pathological changes in organs were observed except spontaneous lesions in kidney appeared in few animals. Conclusion No accumulative antihypertensive effect is observed in ISMN-V-S Compound groups. The toxicity was not increased or generated compared with all ingredients used alone.