Hezi inhibits Tiebangchui-induced cardiotoxicity and preserves its anti-rheumatoid arthritis effects by regulating the pharmacokinetics of aconitine and deoxyaconitine

Tiebangchui (TBC, dried roots of Aconitum pendulum Busch. and Aconitum flavum Hand.-Mazz.) is a well-known Tibetan medicine for dispelling cold and relieving pain. In China, it is widely used in prevention and treatment of various diseases, such as rheumatoid arthritis (RA), traumatic injury, and fracture. However, its cardiotoxicity and neurotoxicity seriously restrict its clinical application. Traditionally, Hezi (HZ, dry ripe fruit of Terminalia chebula Retz. and Terminalia chebula Retz. var. tomentella Kurt.) is generally used in combination with TBC for the purpose of toxicity reducing and efficacy enhancing, but so far we still can’t clearly elucidate the compatibility effect and mechanism of the classical herbal pair. To investigate the compatibility effect and mechanism of TBC co-administered with HZ. In the present study, we clarified the cardioprotective role of HZ on the cardiotoxicity induced by TBC. The electrocardiogram, the levels of serum cardiac troponin T (cTnT), the activities of cardiac superoxide dismutase (SOD), malonaldehyde (MDA), and histopathology of heart tissue have been determined in each group. Meanwhile, the anti-RA effect of each group was investigated by paw swelling measurement and histopathological examination of synovial. To explore the underlying mechanism, we performed the pharmacokinetic studies of aconitine (AC) and deoxyaconitine (DE) in TBC group and TBC + HZ group by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) system. TBC co-administered with HZ could significantly inhibit the increased heart rate and the prolonged QTc interval induced by TBC (p