Abstract
The transformation pathways of diterpenoid alkaloids have been clarified in the boiling and steaming process. Aconitine, a famous diterpenoid alkaloid, is successively transformed into benzoylaconine and aconine during the processes of boiling and steaming, but the transformation pathway remains to be determined in the sand frying process. The present study aims at investigating the transformation pathways of aconitine in the process of sand frying, as well as assessing the cardiotoxicity and antiarrhythmic activity of aconitine and its converted products. The parameters of temperature and time for the structural transformation of aconitine were confirmed by HPLC. The converted products were further separated and identified by column chromatography, NMR, and HR-ESI-MS. Furthermore, by observing the lead II electrocardiogram (ECG) changes in rats under an equivalent dose, the cardiotoxicity of aconitine and its converted products were compared. Ultimately, the antiarrhythmic effect of the converted products was investigated by employing the model of aconitine-induced arrhythmia. Consequently, the structure of aconitine was converted when processed at 120°C–200°C for 1–40 min. Two diterpenoid alkaloids, a pair of epimers, namely, pyroaconitine and 16-epi-pyroaconitine, were further isolated from processed aconitine. 0.03 mg/kg aconitine induced arrhythmias in normal rats, while the converted products did not exhibit arrhythmias under an equal dose. In the antiarrhythmic assay, 16-epi-pyroaconitine could dose-dependently delay the onset time of VPB, reduce the incidence of VT, and increase the arrhythmia inhibition rate, demonstrating comparatively strong antiarrhythmic activity. Conclusively, compared with the prototype compound aconitine, the converted products exhibited lower cardiotoxicity. Further investigations on the cardiotoxicity indicated that pyroaconitine with β configuration had a stronger cardiotoxicity than 16-epi-pyroaconitine with α configuration. Furthermore, 16-epi-pyroaconitine could antagonize the arrhythmogenic effect caused by the prototype compound aconitine; the antiarrhythmic effect of 16-epi-pyroaconitine was stronger than lidocaine and propafenone, which had the potential to be developed as antiarrhythmic drugs.
Highlights
Introduction ere are more than 300 species of Aconitum plants belonging to the family of Ranunculaceae worldwide, mainly distributed in the temperate regions of the northern hemisphere, of which over 200 species are distributed in China, most of them are found in Sichuan, Yunnan, and Tibet Autonomous Region [1,2,3,4]. 76 species are diffusely applied in traditional Chinese medicine and ethnomedicine [2], such as Aconitum pendulum Busch, A. carmichaelii
Two main methods are applied for the processing of Aconitum herbs in traditional Chinese medicine, namely, boiling with water for 4–6 hours and steaming for 6–8 hours. e processing mechanism of the above methods is that diester diterpenoid alkaloids are sequentially hydrolyzed into less toxic monoester- and alkanolamine-diterpenoid alkaloids
Validation. e obtained results of standard sample showed that aconitine exhibited good linearity within test ranges (Y 11461X-39.79, r 0.9995)
Summary
Introduction ere are more than300 species of Aconitum plants belonging to the family of Ranunculaceae worldwide, mainly distributed in the temperate regions of the northern hemisphere, of which over 200 species are distributed in China, most of them are found in Sichuan, Yunnan, and Tibet Autonomous Region [1,2,3,4]. 76 species are diffusely applied in traditional Chinese medicine and ethnomedicine [2], such as Aconitum pendulum Busch, A. carmichaeliiDebx., A. kusnezoffii Reichb., and A. coreanum 76 species are diffusely applied in traditional Chinese medicine and ethnomedicine [2], such as Aconitum pendulum Busch, A. carmichaelii. Two main methods are applied for the processing of Aconitum herbs in traditional Chinese medicine, namely, boiling with water for 4–6 hours and steaming for 6–8 hours. E processing mechanism of the above methods is that diester diterpenoid alkaloids are sequentially hydrolyzed into less toxic monoester- and alkanolamine-diterpenoid alkaloids. Aconitine is successively transformed into benzoylaconine and aconine during the processes of boiling and steaming [3, 10]. Different from boiling and steaming, the method of sand frying is a unique processing method for Aconitum herbs in ethnomedicine; it only takes 10–15 minutes of stir-frying with sand to achieve the purpose of detoxification. To clarify the specific structural transformation pathways of diterpenoid alkaloids, a classical and well-known diterpenoid alkaloid aconitine was chosen as the research object
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