Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root.

Effects of higenamine on nitric oxide (NO) production and inducible NO synthase (iNOS) mRNA expression (RAW 264.7 cells), on vascular reactivity in vitro and in vivo (rats), and on survival rates (mice) and serum nitrite/nitrate levels (rats) were investigated by using last lipopolysaccharide (LPS) plus interferon (IFN)-gamma. Higenamine concentration-dependently inhibited NO production and inducible NO synthase mRNA in RAW 264.7 cells, in which the IC(50) was 53 microM. Higenamine (10 mg/kg i.p.) administered 90 min before LPS (5 mg/kg i.v.) prevented not only LPS-induced hypotension but also pressor response to norepinephrine (1 microgram/kg) in rats. Incubation of thoracic aorta with LPS (300 ng/ml) for 8 h in vitro resulted in suppression of the vasoconstrictor effects to phenylephrine, which was prevented by coincubation with higenamine. The survival rate to endotoxin in mice was significantly (P <.01) increased by the presence of higenamine in the LPS-treated group up to 48 h. Serum nitrite/nitrate levels were significantly (P <.05) reduced by higenamine in LPS-treated rats. Finally, higenamine inhibited the activation of nuclear factor kappaB in RAW 264.7 cells due to LPS + IFN-gamma by mobility shift assays. Taken together, these data strongly suggest that higenamine inhibits iNOS expression by inhibiting nuclear factor kappaB activation by LPS + IFN-gamma, which may be beneficial in inflammatory diseases in which enhanced formation of NO is the main causative factor. Furthermore, due to positive inotropic action, higenamine may be more effective in a condition where myocardial contractility is likely to depress, such as in septic shock and/or endotoxin-induced inflammatory disorders.

Inhibition of rat hippocampal excitability by the Aconitum alkaloid, 1-benzoylnapelline, but not by napelline.

The effects of the two structurally related Aconitum alkaloids, 1-benzoylnapelline and napelline, were investigated by extracellular recording of the stimulus-evoked population spike in the CA1 region of rat hippocampal slices in vitro. 1-Benzoylnapelline (1-100 microM) exerted a depressant action on the orthodromic as well as on the antidromic population spike. Napelline failed to evoke a significant effect at concentrations up to 100 microM. The inhibitory action induced by 1-benzoylnapelline was enhanced when the frequency of electrical stimulation was increased. In contrast, reversal of the inhibitory effect was accelerated when stimulation frequency was decreased. The activity-dependent mode of action of 1-benzoylnapelline raised the question of whether the drug is effective to suppress epileptiform activity. The results obtained from experiments on epileptiform hippocampal slices revealed a reduction of the burst duration and of the number of spikes in the burst as well as attenuation of the amplitude of the population spikes. These data support the conclusion that 1-benzoylnapelline, in contrast to the structurally related compound, napelline, has an activity-dependent inhibitory action on central neurons.

[Experimental comparison of the analgesic action of Aconitum and its processed products].

This paper deals with the effects of crude Aconitum and Aconitum processed by a new method of moistening and steaming, and by method of pharmacopoeial stipulation on the analgesic action with writhing test and hot plate test in mice. The result shows that the Aconitum processed by new method No 1, which applies moistening in water for 48h and then heating with high pressure steam (68.65kPa, 115 degrees C) for 2h has an advantage over that processed according to pharmacopoeial routine (P < 0.05).

Gating and selectivity of aconitine-modified sodium channels in neuroblastoma cells.

Currents through normal and aconitine-modified sodium channels in perfused neuroblastoma cells were measured under voltage-clamp conditions. Aconitine is shown to induce changes in channel selectivity so that channels become more permeable to NH4+ than to Na+. Aconitine induces the shift of voltage dependence of channel activation toward more negative potentials by about 20 mV. Aconitine-modified channels inactivate practically completely with a time-course similar to that for normal channels. Aconitine is effective when applied to either side of the membrane. Steady-state characteristics of the gating machinery of aconitine-modified channels are discussed in terms of three-state model. According to the model, aconitine increases the probability of finding the channel in open state, which is reflected in negative shift of the voltage dependence of activation. The model predicts that the larger this shift, the higher is the level of steady-state sodium conductance. The comparison of respective properties of aconitine-modified channels in neuroblastoma cell and frog nerve confirms this prediction. Aconitine is assumed to reach its receptor through the lipophilic part of the membrane.

Arrow poisons in China. Part II. Aconitum--botany, chemistry, and pharmacology.

The botany of Chinese Aconitum species is briefly reviewed. Five species have been identified as sources of arrow poison: A. carmichaelii, A. nagarum, A. ouvrardianum, A. stylosum, and A. episcopale. The most important one, A. carmichaelii, has long served, together with A. kusnezoffii, as the main source of the Chinese medicinal aconite drugs--ts'ao wu (wu t'ou), the parent tuber, and fu tzu (ch 'uan wu), the daughter tuber. Two other aconite drugs have now been accepted into the Chinese materia medica: hsüeh shang i chih hao, from A. brachypodum, A. pendulum, and A. nagarum, and kuan pai fu, from A. coreanum. The folk-medicinal use of Aconitum species throughout China is also discussed. The alkaloid content and composition of Aconitum species known to occur in China are surveyed; and the effects of "processing", practised in order to diminish the toxicity of aconite drugs, are noted. Also the pharmacology of the aconites and their alkaloids is examined, in order to determine to what extent there may be a basis for the numerous medicinal properties attributed to the plants. Current understanding of the effectiveness of the drugs is incomplete and further study is required.