目的 觀察SD大鼠重復(fù)ig給予單硝酸異山梨酯鹽酸伊伐布雷定（單硝伊伐）復(fù)方產(chǎn)生的毒性反應(yīng)，比較單硝酸異山梨酯、鹽酸伊伐布雷定兩藥合用后，毒性是否增加或產(chǎn)生新的毒性。方法 SPF級(jí)SD大鼠120只，隨機(jī)分為空白組，單硝酸異山梨酯組，鹽酸伊伐布雷定組，復(fù)方低、中、高劑量（35、128、465 mg/kg）組，每組20只，雌雄各半。按照10 mL/kg的給藥體積連續(xù)ig給藥1個(gè)月，停藥觀察2周，試驗(yàn)期間進(jìn)行一般體征觀察、體質(zhì)量、攝食量、血壓、心率、血液學(xué)、生化學(xué)及組織病理學(xué)檢查。結(jié)果 給藥組與空白對(duì)照組比較外觀體征、行為活動(dòng)、體質(zhì)量、攝食量、血液學(xué)均未見明顯異常。復(fù)方藥物可使大鼠心率呈劑量相關(guān)性的降低，停藥后恢復(fù)正常。給藥末期復(fù)方高劑量組收縮壓（SBP）、舒張壓（DBP）比空白組略低，恢復(fù)期結(jié)束后出現(xiàn)反彈性升高。生化檢測(cè)中給藥末期復(fù)方高劑量組丙氨酸氨基轉(zhuǎn)移酶（ALT）、堿性磷酸酶（ALP）和中劑量組ALT與空白組、單硝酸異山梨酯組、鹽酸伊伐布雷定組比較雖具有統(tǒng)計(jì)學(xué)差異（P<0.05），但無生物學(xué)意義，恢復(fù)期后恢復(fù)正常。病理學(xué)檢查發(fā)現(xiàn)：鹽酸伊伐布雷定組、復(fù)方組雄性大鼠均可見不同程度的心肌病變動(dòng)物數(shù)量增加或病變程度加重，單硝酸異山梨酯組、復(fù)方組均可見個(gè)別雌性大鼠脾臟內(nèi)含鐵血黃素的沉積，且以上病變動(dòng)物數(shù)量隨復(fù)方低、中、高劑量的增加有依次遞增現(xiàn)象，停藥后未見良好的可恢復(fù)性。結(jié)論 本試驗(yàn)條件下SD大鼠重復(fù)ig給予復(fù)方藥物，毒性靶器官為心臟、脾臟并有一定的性別差異，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 evaluate the toxicity of isosorbide 5-mononitrate (ISMN) and Ivabradine (ISMN-I) Compound on SD rats by continuous ig administration and to compare whether the toxicity increased or new toxicity generated after the combination of the two drugs. Methods SPF SD rats (120) were randomly divided into control, ISMN, Ivabradine, low-, mid-, and high-dose [35, 128, and 465 mg/kg] compound groups, 20 in each group, half male and half female. The rats were consecutively drenched at 10 mg/kg for 1 months and observed for 2 weeks after stopping drug administration. General condition, body weight, food consumption, blood pressure, heart rate, haematology, biochemical tests, and histopathology were performed during the experiment. Results The treated groups compared with the control group, there were no significant changes on appearance of the signs, behavior, body weight, food consumption, and haematology. Compound drugs could make the heart rate decreased in a dose dependent manner, but returned to normal after drug withdrawal. SBP and DBP in the high-dose group slightly lower than those in the control group during delivery stage, but increased reboundly after recovery period. Compared with the control group, ISMN and Ivabradine groups, ALT and ALP in the high-dose group and ALT in the mid-dose group had statistically difference, but no biological significance (P < 0.05), and returned to normal after recovery period. Obvious pathological changes were observed: different degrees of the increase in the number of animal disease or myocardial lesions were observed in Ivabradine and Compound groups of male rats, deposition of hemosiderin in the spleen was observed in ISMN and Compound groups of individual female rats, with the increasing dose of compound, the number of disease animal had the increasing order of phenomena, no good recovery after stopping drug administration. Conclusion By continuous ig compound to SD rats, there are the toxic target organs of heart and spleen and some sex differences. The toxicity is not increased or generated compared with the ingredients used alone.