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PubMed1990

Blocking effects of hypaconitine and aconitine on nerve action potentials in phrenic nerve-diaphragm muscles of mice.

The mechanisms of neuromuscular blockade by hypaconitine and aconitine were investigated electrophysiologically in isolated phrenic nerve-diaphragm muscles of mice. Hypaconitine (0.08-2 microM) and aconitine (0.3-2 microM) depressed the nerve-evoked twitch tension, without affecting the contraction evoked by stimulation of the muscle. At the concentrations of hypaconitine (up to 5 microM) and aconitine (up to 2 microM) that depressed the nerve-evoked twitch tension, the resting membrane potential of the muscle cells was unchanged. Hypaconitine (0.1-2 microM) and aconitine (2 microM) blocked the end-plate potential (epp), without affecting the amplitude of the miniature epp (mepp). The quantal content of end-plate potentials was decreased by these agents in parallel with the decrement in amplitude. The nerve compound action potential was inhibited by hypaconitine (5 microM) and aconitine (2-10 microM), as well as by 1 microM tetrodotoxin (TTX). When the nerve compound action potential was completely blocked by 2 microM aconitine, the muscle action potential was unaffected, although 1 microM TTX suppressed both potentials to the same degree. These results indicate the neuromuscular blockade produced by hypaconitine and aconitine were caused by reducing the evoked quantal release. The mechanism of this effect was attributed mainly to blocking of the nerve compound action potential.

Aconitine↗
PubMed1991

Studies on the constituents of Aconitum species. IX. The pharmacological properties of pyro-type aconitine alkaloids, components of processed aconite powder 'kako-bushi-matsu': analgesic, antiinflammatory and acute toxic activities.

Eight pyro-type aconitine alkaloids contained in the processed aconite powder 'Kako-bushi-matsu' were studied for their analgesic, antiinflammatory and acute toxic actions. All these compounds showed significant analgesic and antiinflammatory actions. Among the pyro-type alkaloids, 16-epi-pyrojesaconitine and pyrojesaconitine were the most potent analgesics. The analgesic activity of pyro-type aconitine alkaloids was lower than that of each of the parent alkaloids, aconitine, mesaconitine, hypaconitine and jesaconitine. However, pyro-type aconitine alkaloids had very low toxicity, and the decreasing rates of the toxicity in changing from the parent alkaloids to the pyro-type aconitine alkaloids were much larger than those relating to the analgesic activity. Eight pyro-type aconitine alkaloids were found to inhibit the carrageenin-induced hind paw edema at 2 to 6 h after the carrageenin subplantar injection. Consequently, it was demonstrated that the pyro-type aconitine alkaloids produced through the processing of raw aconite roots, 'Bushi', have a role in the medicinal effects of the processed aconite powder 'Kako-bushi-matsu'.

Aconitine↗
PubMed2006

Characterization of metabolites and cytochrome P450 isoforms involved in the microsomal metabolism of aconitine.

Aconitine, a major Aconitum alkaloid, is well known for its high toxicity that induces severe arrhythmias leading to death. The current study investigated the metabolism of aconitine and the effects of selective cytochrome P450 (CYP) inhibitors on the metabolism of aconitine in rat liver microsomes. The metabolites were separated and assayed by liquid chromatography-ion trap mass spectrometry (LC/MS(n)) and further identified by comparison of their mass spectra and chromatographic behaviors with reference substances. Various selective inhibitors of CYP were used to identify the isoforms of CYP, that involved in the metabolism of aconitine. A total of at least six metabolites were found and characterized in rat liver microsomal incubations. Result showed that the inhibitor of CYP 3A had an inhibitory effect on aconitine metabolism in a concentration-dependant manner, the inhibitor of CYP1A1/2 had a modest inhibitory effect, whereas inhibitors of CYP2B1/2, 2D and 2E1 had no obvious inhibitory effects on aconitine metabolism. Aconitine might be metabolized by CYP 3A and CYP1A1/2 isoforms in rat liver microsome.

Aconitine↗
PubMed1999

Antagonism of the aconitine-induced inexcitability by the structurally related Aconitum alkaloids, lappaconitine and ajacine.

Aconitine, lappaconitine and ajacine are structurally related alkaloids occurring in several species of the Aconitum genus. While aconitine is known to activate the voltage-dependent sodium channel, lappaconitine has been reported to block this channel. To investigate a possible antagonism of the aconitine action on neuronal activity by lappaconitine and the closely related alkaloid ajacine, we have performed extracellular recordings of stimulus evoked population spikes and field excitatory postsynaptic potential (EPSP) in rat hippocampal slices. Aconitine (10-100 nM) diminished the amplitude of the orthodromic population spike in a concentration-dependent manner. When aconitine was applied in presence of 10 microM lappaconitine, the concentration-response curve was shifted to the right. Furthermore, the complete suppression of the population spike evoked by 100 nM aconitine was reversed by 10 microM lappaconitine. The action of lappaconitine was mimicked by ajacine, however, the latter alkaloid was less potent. Both lappaconitine and ajacine shifted the input-output relationship of the presynaptic fiber spike as function of the stimulation intensity and of the field EPSP as function of the presynaptic fiber spike to the right. After pharmacological isolation, the presynaptic fiber spike was decreased by both compounds in a frequency-dependent manner indicative for a use-dependent action. Thus, electrophysiologically these alkaloids seem to inhibit predominantly the excitability of the afferent fibres and, in consequence, neurotransmission between Schaffer collaterals and the CA1 neurons, thereby suppressing the firing of the latter. Ajacine and lappaconitine inhibited stimulus-triggered epileptiform population bursts in area CA1 elicited by omission of Mg(2+) as well as spontaneously occurring epileptiform discharges in area CA3 elicited by omission of Mg(2+) and elevation of K(+). It is concluded that the inhibitory and antiepileptiform effect of ajacine and lappaconitine is mediated by a frequency-dependent inhibition of the voltage-dependent sodium channel, thereby decreasing the excitability which might be important for filtering high frequency bursts of action potentials characteristic for epileptiform activity in the hippocampus. Moreover, these alkaloids are naturally occurring antagonists of the sodium channel activator aconitine.

Aconitine↗
PubMedDate not supplied

Hemodynamic and arrhythmogenic effects of aconitine applied to the left atria of anesthetized cats. Effects of amiodarone and atropine.

The arrhythmogenic and hemodynamic effects of 0.04% aconitine solution applied locally to the left atria of cats and the effects of amiodarone (10 mg/kg) and atropine (0.2 mg/kg) on the responses to aconitine were investigated. Cats were anesthetized with sodium pentobarbital. The left atrial and limb lead electrocardiograms and the arterial pressure were recorded. Cardiac output was determined with the thermo dilution technique. Aconitine nitrate induced dysrhythmias lasting for a mean of 111 min. Atrial fibrillation occurred in 47% of the animals. A long-lasting (at least 3 hr) cardiodepressant action was seen in response to aconitine. Pretreatment with atropine largely prevented the hemodynamic effects of aconitine and prevented fibrillation. However, mean maximum atrial rates recorded during successive 5 min intervals were similar in control and atropine-treated animals. Amiodarone suppressed dysrhythmias in both atropine-treated and nontreated animals at a dose which exerted only minimal cardiodepression. The method described for evaluating potential activity against supraventricular dysrhythmias in the cat is relatively simple, reproducible, and suitable for statistical analyses. Aconitine appears to exert a long-lasting cholinergic action which may be involved in the genesis of aconitine-induced atrial fibrillation.

Aconitine↗
PubMed1994

Effects of magnesium on polymorphic ventricular tachycardias induced by aconitine.

We examined the effects of Mg2+ on aconitine-induced polymorphic ventricular tachycardias (PVT) in excised rabbit hearts under Langendorff perfusion and in Purkinje-muscle preparations. Local electrograms using bipolar electrodes and transmembrane potentials with the microelectrode technique were recorded from Langendorff hearts and Purkinje-muscle preparations, respectively. In Langendorff preparations, intracoronary application of 0.1 microM aconitine induced PVT 28.8 +/- 3.4 min after development of regular monomorphic ventricular tachycardias (MVT) in all 18 preparations. Application of 5 and 10 mM Mg2+ restored aconitine-induced PVT to sinus rhythm after 26.8 +/- 3.4 min (n = 9), but < 3 mM Mg2+ was not effective in restoring of sinus rhythm. Increased Mg2+ concentrations < or = 5 mM in the coronary perfusate prevented development of PVT by aconitine. Intracoronary application of 10 microM tetrodotoxin (TTX) also restored aconitine-induced PVT to sinus rhythm after 3.2 +/- 0.8 min (n = 4). Although applications of 50 microM lidocaine, 10 microM flecainide, or 1 microM verapamil could change PVT to MVT, they were not effective in restoring sinus rhythm. In Purkinje-muscle preparations, spontaneous action potentials (AP) from slow diastolic depolarization appeared after aconitine at the maximum diastolic potential of -75.0 +/- 3.7 mV in Purkinje fibers and were conducted to ventricular muscles (n = 5). Spontaneous activity gradually increased in rate and then developed triggered activity arising from early after depolarization (EAD). EAD induced by aconitine always appeared first in Purkinje fibers and later in muscle fibers. Once triggered activities started from EAD, rate, rhythm and amplitudes of APs became fast and variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitine↗
PubMed1996

Aconitine, a main component of aconite, increases spontaneous acetylcholine release from the frontal cerebral cortex of freely moving rats.

We investigated whether peripherally administered aconitine increases spontaneous acetylcholine (ACh) release from the frontal cerebral cortex in freely moving rats using in vivo microdialysis, as it relates to aconitine-induced bradycardia estimated by a tail-artery cuff technique in unilateral anterior hypothalamus (AH)-lesion mice. Intraperitoneally administered aconitine significantly increased cortical ACh release within 15 min at 10 and 30 micrograms/kg. The increasing effect disappeared 30 min after the administration of aconitine. Aconitine-induced ACh release was not inhibited by intracerebroventricularly preadministered atropine (1 and 3 micrograms/rat). Atropine (1 micrograms/mouse) preadministered into the contralateral intact AH in mice did not affect aconitine (30 micrograms/kg, i.p.)-induced bradycardia. These results indicate that the cortical ACh release caused by peripherally administered aconitine does not occur through activation of the central muscarine receptor, and thus its ACh release may not be concerned with the occurrence of bradycardia.

Acetylcholine↗
PubMed1992

The influence of tetrodotoxin on the toxic effects of aconitine in vivo.

Both aconite toxins (aconitine, mesaconitine, and hypaconitine) and a pufferfish toxin (tetrodotoxin, TTX) were detected in the blood of a legal autopsy case. In order to elucidate the in vivo influence of TTX on the toxic effects of aconitine, a mixture of aconitine and TTX was administered to male ICR mice orally or intraperitoneally. The animal experiments revealed that the time of death due to aconitine was significantly delayed in proportion to the dose of TTX compared with the case for aconitine alone, and that the mortality of aconitine was lowered by TTX when the dose ratio of the two toxins was in a particular range. Accordingly, it is thought that the toxic effects of aconitine are attenuated by TTX in vivo.

Aconitine↗
PubMed2005

[Comparing the actions of the three flavone ingredients in choerospondias axillaris on arrhythmias induced by aconitine].

OBJECTIVE: To compare the actions of the three flavone ingredients in choerospondias axillaris on arrhythmias Induced by aconitine. METHOD: Langendorff perfuse was applied in the experiment, the antiarrhythmic action was to study by using aconitine on the the isolated heart; The antiarrhythmic action of the three flavone ingredients in choerospondias axillaris was to study by using i.v. aconitine in rat to induce arrhythmias. RESULT: Compared with the NS group, sample 1 and sample 2 both significantly prolonged the beginning time of VF of isolated heart and increased the dosage of aconitine, sample 3 reduced the beginning time of VF of isolated heart and decreased the dosage of aconitine, sample 1 and sample 2 both greatly prolonged the beginning time of VE, VT, VF, HA; sample 3 greatly reduced the beginning time of VT,VF. The actions of the three samples were in a concentration-dependent way. CONCLUSION: Sample 1 and sample 2 both resisted the occurrence of arrhythmias induced by aconitine, sample 3 markedly promoted the occurrence of arrhythmias induced by aconitine.

Aconitine↗
PubMed2003

Characterization of aconitine-type alkaloids in the flowers of Aconitum kusnezoffii by electrospray ionization tandem mass spectrometry.

The fragmentation mechanism of aconitine-type alkaloids in the flowers of Aconitum kusnezoffii (FAK) was investigated using electrospray ionization tandem mass spectrometry (ESI-MS(n)) firstly. The analysis of the collision-induced dissociation (CID) spectra of three purified aconitine standards and six previously reported aconitines indicated that the fragmentation of the protonated aconitines at low-energy CID follows a similar pathway. The elimination of a C(8)-substituent such as an acetic acid or a fatty acid is the dominant fragmentation mode in MS2. Successive losses of CH(3)COOH, CH(3)OH, H(2)O, BzOH, and CO are the main fragmentation pathways of aconitine-type alkaloids in MS(3) spectra. Based on these features, a rapid method for the direct detection and characterization of alkaloids from an ethanolic extract of FAK is described. All the known aconitum alkaloids are detected and a series of lipo-aconitines has been found for the first time in this plant.

Aconitine↗
PubMed1988

Effects of aconitine and batrachotoxin on Na currents and gating currents in the frog node of Ranvier.

The effects of aconitine and batrachotoxin (BTX) on Na currents and gating currents were studied on voltage clamped frog nodes of Ranvier. The relation between steady-state values of charge movement and test pulse potential (Q-E) was compared with the fraction of open channels at a given potential (F-E). In aconitine-treated nodes the half potential, Emid, of the F-E curve was -87 mV and the slope factor, k, was 6.6 mV. Compared to normal nodes aconitine shifted the F-E curve by -53 mV along the voltage axis without significantly altering the slope. The parameters of the Qon-E curve of aconitine-treated nodes were Emid = -63 mV and k = 18.8 mV compared with Emid = -30 mV and k = 17 mV in a normal node. For the Qoff-E curve Emid was -76 mV, fairly close to Emid of the F-E curve, but the slope remained much smaller than that of the F-E curve. Thus, in aconitine-treated nodes, the normalized Qon-E and Qoff-E curves stay below the F-E curve over almost the whole potential range, a situation different from that in untreated or chloramine-T-treated nodes (Drews 1987). Similar results were obtained with BTX. The F-E curve of BTX-treated fibres had a half potential Emid = -85.1 mV and a slope factor k = 4.7 mV. In contrast to aconitine-treated nodes, the F-E curve showed a secondary rise at E greater than -50 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitine↗
PubMed1996

Age-dependent differences in sensitivity to aconitine of rat hippocampal slices.

The effect of aconitine, a plant alkaloid known to bind at site 2 of the sodium channel, was investigated on neuronal excitability in hippocampal slices of adult and juvenile rats. Aconitine (0.01-1 microM) diminished the extracellularly recorded population spike in a concentration-dependent manner. At each concentration, the inhibitory action of aconitine was significantly stronger and was obtained after a shorter latency in slices of juvenile rats (20-25 days) as compared with slices of adult rats (45-50 days). When maximal inhibition was achieved, a prolonged application of aconitine evoked an increase in spike amplitude of up to 15% in slices of juvenile but not of adult rats. The latency of recovery from the aconitine-induced inhibition was also significantly shorter in slices of juvenile rats. This effect was concentration-dependent and significantly stronger in slices of juvenile rats. These observations indicate that juvenile hippocampi have a higher susceptibility to the effect of aconitine, but also provide a partial protective mechanism.

Aconitine↗
PubMed1990

Different actions of aconitine and veratrum alkaloids on frog skeletal muscle.

1. The electrophysiological effects of veratridine, cevadine and aconitine (10(-8)-2 x 10(-4), 2 x 10(-7)-2 x 10(-6) and 2 x 10(-6)-10(-4) mol/l, respectively) were compared on frog muscle membrane using conventional microelectrodes. 2. Veratridine and aconitine were equally effective in depolarizing the resting membrane with the threshold concentration of 5 x 10(-5) mol/l. 3. Volleys of repetitive discharges and slow transient depolarizations were observed when single electrical stimuli were applied in the presence of veratridine (5 x 10(-8)-2 x 10(-5) mol/l), but not aconitine. Volleys with aconitine could be evoked only by repetitive stimulation; however no tendency of repolarization was observed following these volleys. Two orders of magnitude more aconitine than veratridine was required to induce volleys with similar parameters. 4. The effects of cevadine were similar to those of the corresponding concentrations of veratridine. 5. The observed differences between the electrophysiological actions of aconitine and veratrum alkaloids may be explained in part with differences in Na+ channel inactivation produced by these toxins, in addition to differences in their use-dependent behavior.

Aconitine↗
PubMed1994

Fatal accidental aconitine poisoning following ingestion of Chinese herbal medicine: a report of two cases.

Two Hong Kong Chinese adults were prescribed aconitine-containing herbal preparations by Chinese herbal practitioners for relief of minor musculoskeletal pain. After ingestion both quickly developed ventricular tachycardia followed by ventricular fibrillation and cardiac arrest refractory to resuscitation; death in both cases occurred within 12 h of ingestion. Neither had a history of cardiac disease. Coroners' autopsies showed no significant macroscopic or microscopic findings, with no evidence of ischaemic heart disease or other cardiac disease. Toxicological examination of stomach contents showed a trace of hydrolysed aconitine in one case but was negative in the other. Analysis of the herbal preparations consumed, however, confirmed the presence of the aconitine-containing herbs in quantities greatly in excess of the maximum recommended in the P.R. China pharmacopoeia. Both patients therefore consumed an accidental overdose of aconitine, which has a narrow safety margin between therapeutic analgesic effect and its known cardiotoxic effect. These particular herbal medicines are controlled substances in mainland China and Taiwan, but no controls on their dispensing exist in Hong Kong. Together with reported non-fatal cases of aconitine poisoning, these cases emphasise that legal controls of the dispensing and use of aconitine-containing herbal preparations are necessary in Hong Kong.

Aconitine↗
PubMed2004

Effects of sodium-calcium exchange inhibitors, KB-R7943 and SEA0400, on aconitine-induced arrhythmias in guinea pigs in vivo, in vitro, and in computer simulation studies.

The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 microM) suppressed abnormal electrical activity induced by aconitine, but SEA (100 microM) did not show such effects. KBR (10 microM) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 microM) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na+ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

Aconitine↗
PubMed1997

Aconitine induces bradycardia through a transmission pathway including the anterior hypothalamus in conscious mice.

Aconitine administered intraperitoneally (i.p.) produces bradycardia mainly by a central muscarinic action. The involvement of hypothalamic regions in the occurrence of aconitine-induced bradycardia was investigated in hypothalamus-lesioned mice. The lesions were made by passing a direct current (1.5 mA, 13 s) through a monopolar electrode. The aconitine (30 micrograms/kg, i.p.)-induced bradycardia was prevented by bilateral lesions of either the whole hypothalamus, except for the lateral hypothalamus area, or the anterior hypothalamus (AH). The bradycardia was not prevented by bilateral lesions of the ventromedial, the paraventricular, the posterior or the lateral hypothalamus regions. Bupivacaine, but not atropine (1 microgram, administered into the intact AH) prevented aconitine-induced bradycardia in mice with a contralaterally lesioned AH. Aconitine (0.8 microgram) directly administered into the unilateral AH in intact mice caused a late phase and lesser extent of bradycardia. These results suggest that a transmission pathway including the AH contributes to the aconitine-induced bradycardia but does not involve the activation of muscarinic receptors in the AH.

Aconitine↗
PubMed1994

Positive chronotropic and inotropic effects of higenamine and its enhancing action on the aconitine-induced tachyarrhythmia in isolated murine atria.

Aconitine and higenamine are the components of aconite root. We investigated the cardiac effects of these compounds on murine right and left atria and the interaction of higenamine with aconitine on the rate of spontaneously beating right atria. Higenamine increased the rate (EC50 = 38 nM) and the force of contraction (EC50 = 97 nM), the maximal responses being comparable with those of isoproterenol. The positive chronotropic effect of higenamine was antagonized by propranolol (30-300 nM) and practolol (10 nM-3 microM), but not by butoxamine (1 microM), indicating that it was a beta 1-adrenoceptor-mediated action. The positive chronotropic effect of higenamine was not changed by pretreatment with reserpine (4 mg/kg, i.p., 4 hr). Aconitine (0.16-0.25 microM) induced tachyarrhythmia in right atria was attenuated by quinidine (1 microM), atropine (8.6 microM) and AF-DX 116 (8.6 microM), suggesting that aconitine activates sodium channels and muscarinic receptors. Higenamine (2.5 nM) and dobutamine (1 nM) did not cause chronotropic effects by themselves, but enhanced the aconitine-induced tachyarrhythmia. These results indicate that higenamine is a beta 1-adrenoceptor full agonist in murine atria and that the aconitine-induced tachyarrhythmia is augmented by the beta 1-adrenergic action of higenamine.

Aconitine↗
PubMed1996

Effects of antiarrhythmic agents and Mg2+ on aconitine-induced arrhythmias.

The effects of antiarrhythmic agents, including Classes I and IV and 3-10 mM Mg2+ on aconitine-induced arrhythmias were examined using a conventional microelectrode and patch clamp method in Langendorff-perfused rabbit hearts and isolated guinea-pig ventricular myocytes. Intracoronary application of 0.1 microM aconitine induced polymorphic ventricular tachycardia (PVT) which continued for more than 60 minutes. Application of aconitine to ventricular myocytes caused a prolonged action potential duration (APD) and the appearance of early afterdepolarization (EAD) together with the occurrence of an inward hump of the I-V curve around -60 to -40 mV and increased outward current at positive voltages. Application of 10 microM TTX and 5 mM or higher Mg2+ restored aconitine-induced PVT to sinus rhythm in Langendorff-perfused preparations and also shortened the prolonged APD, demonstrating the abolishment of EAD by aconitine in ventricular myocytes. However, antiarrhythmic agents did not exert such effects. In conclusion, the antiarrhythmic actions of Mg2+ and TTX in aconitine-induced arrhythmia are to abolish EAD and shorten the prolonged APD by suppression of the inward Na+ current around -60 to -40 mV.

Aconitine↗