Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species
Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species
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DOI：
10.1055/s-2006-957359
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发表时间：
1998-02-01
期刊：
影响因子：
2.7
通讯作者：
Schule, A
中科院分区：
文献类型：
--
作者：
Heubach, JF;Schule, A
目前正在研究中的镇痛药和抗炎药主要是飞燕草和飞燕草的生物碱。据报道，镇痛化合物高乌甲素（lappaconitine，LA）是一种C-19位的二萜生物碱，是河豚毒素敏感的电压依赖性钠通道的抑制剂。本实验观察了LA及其代谢产物N-脱乙酰基乌甲素（DLA）对豚鼠离体左心房和右心房的电刺激效应。在所有实验中，DLA的等效浓度均大于LA，在2.5 Hz的刺激频率下，LA效应开始的时间常数（tau = 56 +/- 29 min）明显大于DLA效应的时间常数（tau = 14 +/- 8 min）。化合物在0.06 μ M（LA）和0.2 μ M（DLA）时表现出显著的负性肌力作用，在4.5 μ M（LA）和10 μ M（DLA）时出现右心房收缩停止。因此，与乌头碱相比，LA和DLA的心脏毒性要低得多，乌头碱在我们的模型中在10 nM时引起心律失常。对于两种生物碱，可以证明使用依赖性作用模式。此外，与0.3 μ M LA预孵育可以防止乌头碱或哇巴因引起的心律失常。我们得出结论，高乌甲素是具有1类抗心律失常作用的天然化合物。
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.