A conscious rat model involving bradycardia and hypotension after oral administration: a toxicokinetical study of aconitine

Abstract

1. A model of aconitine-induced bradycardia and hypotension, which is similar to aconitine poisoning in humans, was constructed in conscious rats by oral administration.

2. Blood pressure (BP) and heart rate (HR) of Sprague-Dawley rats were measured using a volume pressure recording (VPR) system. The pharmacokinetics of toxic doses of aconitine and its metabolites were analyzed using UPLC-MS/MS.

3. The HR was significantly decreased by 29% at 2 h after oral administration of 200 μg/kg aconitine. When the dose was increased to 400 μg/kg, systolic BP and diastolic BP were significantly decreased by 11% and 12% at 2 h after the administration, except when bradycardia occurred at 2 h and 4 h. The drug concentration-time curve showed a double-peak phenomenon in rats administered a 400 μg/kg dose. The AUC_0–12 h value in the 400 μg/kg group significantly increased 0.8-fold compared to the 200 μg/kg group. Moreover, a high plasma concentration of 16-O-demethyaconitine was found in the rats that received two toxic doses.

4. In conclusion, bradycardia and hypotension are induced in conscious rats by a toxic dose of aconitine (400 μg/kg), and there was no significant difference in dose-normalized AUC_0–12 h values between oral administrations of 200 μg/kg and that of 400 μg/kg. However, the dose-normalized C_max and AUC_0–12 h values in 200 μg/kg and 400 μg/kg groups were significantly smaller than those in 100 μg/kg group. The metabolites of aconitine, 16-O-demethyaconitine, and benzoylaconitine may also contribute to the hypotensive response.

Keywords:

• Aconitine
• bradycardia
• conscious rat
• hypotension
• toxicokinetics

Declaration of interest

The authors declare that there are no conflicts of interest.

This work was supported by grant from the National Program on Key Basic Research Project of China (Program 973, No. 2012CB518601).