目的 采用代谢组学技术研究去甲乌药碱（HG）对阿霉素诱导的心力衰竭大鼠内源代谢物的影响，探讨其代谢途径及作用机制。方法 60只SPF级雄性SD大鼠，随机分为对照组、模型组、多巴酚丁胺组（DH，50 μg·kg^-1）组和HG低、中、高剂量（2.5、5、10 mg·kg^-1）组，每组10只。除对照组外，对各组大鼠ip阿霉素至累积剂量15 mg·kg^-1构建心力衰竭模型，造模成功后各组ip给予对应药物干预7 d。通过检测左心室血流动力学指标、血浆心肌损伤标志物水平及观察心肌组织病理形态，明确HG的抗心力衰竭药理作用；采用UPLC-Q/TOF-MS技术开展血浆非靶向代谢组学分析，筛选差异代谢物并进行代谢通路富集，探究其作用的代谢机制。结果 与对照组相比，模型组大鼠左心室收缩功能指标［左心室收缩压（LVSP）、左心室内压最大上升速率（＋dp/dtmax）］显著降低（P＜0.01），舒张功能指标［左心室舒张末压（LVEDP）、左心室内压最大下降速率（－dp/dt_max）］显著升高（P＜0.01），血浆B型利钠肽（BNP）、N末端B型利钠肽原（NT-proBNP）、肌酸激酶同工酶MB（CK-MB）、乳酸脱氢酶（LDH）水平均显著上调（P＜0.01），且心肌组织出现明显损伤；与模型组相比，HG各剂量组可不同程度逆转上述指标异常，其中高剂量组改善效果最显著（P＜0.05、0.01），且能明显减轻心肌纤维紊乱、炎症浸润等病理损伤。代谢组学分析共鉴定出14种差异代谢物，涉及谷胱甘肽、D-果糖、磷脂酰乙醇胺等，这些代谢物在模型组中呈现特征性紊乱，而HG高剂量可显著回调其水平；通路富集分析显示，HG主要调控半乳糖代谢、果糖和甘露糖代谢、甘油磷脂代谢、谷胱甘肽代谢等17条代谢通路。结论 HG可通过改善左心室血流动力学、降低心肌损伤因子水平、修复心肌组织病理损伤，同时调控糖代谢、脂代谢及抗氧化相关通路的代谢紊乱，发挥对阿霉素诱导心力衰竭的治疗作用。

Objective This study was aimed to investigate the effect of higenamine on endogenous metabolites in doxorubicin-induced heart failure (HF) rats using metabolomics technology, and to explore its metabolic pathways and mechanism of action. Methods Sixty SPF-grade male SD rats were randomly divided into control group, model group, dobutamine hydrochloride group (50 μg·kg^-1), and higenamine low-, medium-, and high-dose groups (2.5, 5.0, 10.0 mg·kg^-1), with 10 rats in each group. Except for the control group, rats in other groups were intraperitoneally injected with doxorubicin at a cumulative dose of 15 mg·kg^-1 to establish a heart failure model. After successful modeling, each group was intraperitoneally administered with the corresponding drug for 7 consecutive days. The anti-heart failure pharmacological effects of higenamine were clarified by detecting left ventricular hemodynamic indexes, plasma myocardial injury marker levels, and observing myocardial histopathological morphology; UPLC-Q/TOF-MS technology was used to conduct plasma non-targeted metabolomics analysis, screen differential metabolites and perform metabolic pathway enrichment to explore the metabolic mechanism of its action. Results Compared with the control group, the left ventricular systolic function indicators [left ventricular systolic pressure (LVSP), maximum rate of increase of left ventricular pressure (+dp/dt_max)] of the model group rats were significantly decreased (P<0.01), and the diastolic function indicators [left ventricular end-diastolic pressure (LVEDP), maximum rate of decrease of left ventricular pressure (-dp/dt_max)] were significantly increased (P<0.01). The levels of plasma B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase isoenzyme MB (CKMB), and lactate dehydrogenase (LDH) were all significantly elevated (P<0.01), and obvious myocardial damage was observed. Compared with the model group, the different doses of HG could reverse the above abnormal indicators to varying degrees, with the high-dose group showing the most significant improvement (P<0.05, 0.01), and could significantly alleviate myocardial fiber disorder, inflammatory infiltration and other pathological damages. Metabolomics analysis identified a total of 14 differential metabolites, including glutathione, D-fructose, phosphatidylethanolamine, etc. These metabolites showed characteristic disorders in the model group, while higenamine high-dose could significantly restore their levels; Pathway enrichment analysis showed that higenamine mainly regulated 17 metabolic pathways such as galactose metabolism, fructose and mannose metabolism, glycerophospholipid metabolism, and glutathione metabolism. Conclusion Higenamine can exert a therapeutic effect on doxorubicin-induced heart failure by improving left ventricular hemodynamics, reducing myocardial injury factor levels, repairing myocardial histopathological damage, and regulating metabolic disorders of pathways related to glucose metabolism, lipid metabolism, and antioxidation.

R965

国家自然科学基金资助项目（82304738）；四川省科技计划资助（2024NSFSC1835）；云南省基础研究计划项目资助（202501AT070333)；西华大学研究生科创竞赛项目（YK20240261,YK20240271）