Metabolic Behaviors of Aconitum Alkaloids in Different Concentrations of Aconiti Lateralis Radix Praeparata and Effects of Aconitine in Healthy Human and Long QT Syndrome Cardiomyocytes

Abstract

Aconiti Lateralis Radix Praeparata (Fu Zi) is the processed lateral root of Aconitum carmichaelii Debx, which is widely used in emergency clinics. Poisoning incidents and adverse reactions occur with the improper intake of Fu Zi. Metabolic characteristics of aconitum alkaloids of Fu Zi may vary, and the effects of Fu Zi in healthy and Long QT syndrome (LQTS) patients is unknown. In this experiment, 24 Sprague Dawley rats were randomly divided into three groups: 2.0, 1.0, and 0.5 g/kg dose groups, and blood samples were collected after the oral administration of Fu Zi extract. We used an ultra-high performance liquid chromatography-tandem mass spectrometry system to detect the concentrations of six aconitum alkaloids. Cell toxicity, calcium imaging, and patch-clamp recordings of human induced pluripotent stem cells-cardiomyocytes (hiPSC-CMs) of aconitine in healthy and LQTS were observed. We found that the AUC(0–48h), Cmax, and t1/2 of the six compounds increased with the multiplicative dosages; those in the high group were significantly higher than those in the low group. Aconitine concentration-dependently decreased the amplitude, which has no significant effect on the cell index of normal hiPSC-CMs. Aconitine at 5.0 μM decreased the cell index between 5–30 min for LQTS hiPSC-CMs. Meanwhile, aconitine significantly increased the frequency of calcium transients in LQTS at 5 μM. Aconitine significantly shortened the action potential duration of human cardiomyocytes in both normal and LQTS groups. These results show metabolic behaviors of aconitum alkaloids in different concentrations of Fu Zi and effects of aconitine in healthy and LQTS patients.

The known, unknown, and the intriguing about members of a critically endangered traditional medicinal plant genus Aconitum

“…Despite containing diverse poisonous compounds, several Aconitum spp. has been used in TCM for over 2,000 years, among which A. carmichaelii Debx is the most used (Zhao et al, 2021;Yang et al, 2022). Comprehensive information about the therapeutic index of its alkaloids is unavailable, which has led to several cases of poisoning and death.…”

Development of an ultra‐high‐performance liquid chromatography–tandem mass spectrometry method for the simultaneous determination of crassicauline A, fuziline, karacoline, and songorine in rat plasma and application in their pharmacokinetics

“…Several studies have demonstrated that alkaloids found in Fuzi have significant anti‐tumor effects (Dai et al, 2023; Fan et al, 2016; Fu et al, 2022; Li et al, 2022; Yu et al, 2021; Zhou et al, 2015). These alkaloids can be divided into three general categories based on structure: diester‐type alkaloids, such as aconitine, mesaconitine, and hypaconitine; monoester‐type alkaloids, such as benzoyl aconitine, benzoyl mesaconitine, and benzoyl hypaconitine; and alcohol amine‐type alkaloids, such as aconine, mesaconine, and hypaconine, among which diester‐type alkaloids are considered the active and toxic components of Fuzi (Gao et al, 2022; Jang et al, 2022; Jiang et al, 2022; Jin et al, 2022; Punia et al, 2022; Tian et al, 2022; Wang et al, 2022; Xin et al, 2022; Yang et al, 2022). The most abundant alkaloids found in Fuzi are crassicauline A, fuziline, karacoline, and songorine.…”