Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species

Aconitum and Delphinium alkaloids are currently under investigation in search for new analgesic and anti-inflammatory drugs, It has been reported that the analgesic compound lappaconitine (LA), a C-19 diterpenoid alkaloid from Aconitum sinomontanum Nakai is an inhibitor of tetrodotoxin-sensitive, voltage-dependent sodium channels. In the present study we investigated the cardiac effects of LA and its metabolite N-deacetyllappaconitine (DLA) in electrically stimulated left and spontaneously beating right atria isolated from guinea-pig hearts, In all experiments, equieffective concentrations were larger with DLA than with LA, At a stimulation frequency of 2.5 Hz the time constant for the onset of LA effects (tau = 56 +/- 29 min) was markedly larger than the one for DLA effects (tau = 14 +/- 8 min). The compounds exerted a significant negative inotropic action at 0.06 mu M (LA) and 0.2 mu M (DLA), Asystolia of right atria occurred at 4.5 mu M (LA) and 10 mu M (DLA). Therefore, cardiotoxicity of LA and DLA was much lower compared to aconitine, which caused arrhythmia at 10 nM in our model, For both alkaloids a use-dependent mode of action could be demonstrated, In addition, preincubation with 0.3 mu M LA prevented arrhythmia induced by aconitine or ouabain, We conclude that lappaconitine is a naturally occurring compound with class-1 antiarrhythmic action.