目的 觀察Beagle犬連續(xù)6個月po單硝酸異山梨酯、纈沙坦、螺內(nèi)酯復(fù)方（ISMN-V-S）降壓藥物所產(chǎn)生的毒性反應(yīng)，比較3種藥物聯(lián)合應(yīng)用后，毒性是否增加或產(chǎn)生新的毒性。方法 健康Beagle犬40只，雌雄各半，分為5組，空白對照組、單纈螺復(fù)方15、50、150 mg/(kg?d)及纈沙坦對照組，每組8只動物。給藥體積為5 mL/kg，每日ig給藥1次，每周給藥6 d，連續(xù)給藥26周，停藥觀察4周。實(shí)驗(yàn)期間，每日進(jìn)行一般狀態(tài)觀察，每周測定1次體質(zhì)量及攝食量，并于給藥前、給藥第13、26周及停藥恢復(fù)期第4周，分別對眼科、體溫、尿常規(guī)、心電圖、血液學(xué)及血液生化學(xué)進(jìn)行檢查，在給藥期結(jié)束前及恢復(fù)期結(jié)束前測量動物血壓，末次給藥后及恢復(fù)期結(jié)束后分兩批對動物剖檢并進(jìn)行病理組織學(xué)檢查。結(jié)果 各組動物行為活動、飲食、飲水正常。動物體質(zhì)量、攝食量組間無差異。試驗(yàn)進(jìn)行過程中進(jìn)行的眼科、體溫、尿常規(guī)、心電圖、血液學(xué)及血液生化學(xué)等指標(biāo)的檢查，未見異常。各給藥組動物血壓同空白對照組比較明顯降低，停藥后恢復(fù)正常。組織病理學(xué)檢查，除個別動物腎臟發(fā)生自發(fā)性病變，其他動物未見明顯病理器官改變。結(jié)論 本試驗(yàn)條件下，單纈螺復(fù)方降壓藥物除藥理作用延伸引起的血壓降低外，未出現(xiàn)藥物的蓄積現(xiàn)象，同各成分單獨(dú)使用相比，未見毒性增加或產(chǎn)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.