aconitine and Disease-Models--Animal

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Glycosides; Chloroform; Disease Models, Animal; Electric Stimulation; Electrophysiology; Heart; Heart Conduction System; Humans; Mice; Myocardial Contraction; Myocardial Infarction; Perfusion; Rats

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents; Caspase 3; Caspase Inhibitors; Central Nervous System Stimulants; Cholinergic Neurons; Colitis, Ulcerative; Colon; Dendritic Cells; Deoxyglucose; Disease Models, Animal; Enzyme Inhibitors; Janus Kinase 2; Mice, Inbred BALB C; Neuroimmunomodulation; Neuropeptides; Nicotine; Oxazolone; rac1 GTP-Binding Protein; STAT3 Transcription Factor; Th2 Cells; Tyrphostins; Vagus Nerve

Pharmacological modulation of parasympathetic activity with donepezil, an acetylcholinesterase inhibitor, improves the long-term survival of rats with chronic heart failure (CHF) after myocardial infarction (MI). However, its mechanism is not well understood. The α7-nicotinic acetylcholine receptor (α7-nAChR) reportedly plays an important role in the cholinergic anti-inflammatory pathway. The purpose of this study was to examine whether blockade of α7-nAChR, either centrally or peripherally, affects cardioprotection by donepezil during CHF.. One-week post-MI, the surviving rats were implanted with an electrocardiogram or blood pressure transmitter to monitor hemodynamics continuously. Seven days after implantation, the MI rats (n = 74) were administered donepezil in drinking water or were untreated (UT). Donepezil-treated MI rats were randomly assigned to the following four groups: peripheral infusion of saline (SPDT) or an α7-nAChR antagonist methyllycaconitine (α7PDT), and brain infusion of saline (SBDT) or the α7-nAChR antagonist (α7BDT).. After the 4-week treatment, the role of α7-nAChR was evaluated using hemodynamic parameters, neurohumoral states, and histological and morphological assessment. Between the peripheral infusion groups, α7PDT (vs. SPDT) showed significantly increased heart weight and cardiac fibrosis, deteriorated hemodynamics, increased plasma neurohumoral and cytokine levels, and significantly decreased microvessel density (as assessed by anti-von Willebrand factor-positive cells). In contrast, between the brain infusion groups, α7BDT (vs. SBDT) showed no changes in either cardiac remodeling or hemodynamics.. Peripheral blockade of α7-nAChR significantly attenuated the cardioprotective effects of donepezil in CHF rats, whereas central blockade did not. This suggests that peripheral activation of α7-nAChR plays an important role in cholinergic pharmacotherapy for CHF.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood Pressure; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Electrocardiography; Heart Failure; Hemodynamics; Male; Myocardial Infarction; Nicotinic Antagonists; Random Allocation; Rats; Rats, Sprague-Dawley

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2-4, α4nAChR, or β2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Depression; Disease Models, Animal; Kynurenic Acid; Kynurenine 3-Monooxygenase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Prefrontal Cortex

Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Central Nervous System Sensitization; Cocaine; Cocaine-Related Disorders; Conditioning, Classical; Disease Models, Animal; Dopamine Uptake Inhibitors; Memory Consolidation; Mental Recall; Nicotinic Antagonists; Prefrontal Cortex; Rats; Rats, Wistar

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.

Topics: Acetic Acid; Aconitine; Analgesics; Animals; Aspirin; Disease Models, Animal; Edema; Female; Formaldehyde; Freund's Adjuvant; Hot Temperature; Mice; Mice, Inbred C57BL; Pain; Pain Threshold

Alzheimer's disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated.. We offer the investigation of the effects of neoline in AD.. In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated.. Neoline improved memory and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice.. Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD.

Topics: Aconitine; Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Disease Models, Animal; Memory; Memory Disorders; Mice, Transgenic; tau Proteins

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Topics: Acetylcholine; Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Case-Control Studies; Disease Models, Animal; Dogs; Heart Atria; Interleukin-6; Neuroimmunomodulation; NF-kappa B; Nicotinic Antagonists; Pulmonary Veins; Refractory Period, Electrophysiological; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha; Vagus Nerve; Vagus Nerve Stimulation

This study aimed to investigate the effects of protopanaxadiol and protopanaxatriol ginsenosides on aconitine-induced cardiomyocyte injury and their regulatory mechanisms. The effects of ginsenosides on aconitine-induced cardiomyocyte damage were initially evaluated using H9c2 cells, and the molecular mechanisms were elucidated using molecular docking and western blotting. The changes in enzyme content, reactive oxygen species (ROS), calcium (Ca2+) concentration, and apoptosis were determined. Furthermore, an aconitine-induced cardiac injury rat model was established, the cardiac injury and serum physiological and biochemical indexes were measured, and the effects of ginsenoside were observed. The results showed that ginsenoside Rb1 significantly increased aconitine-induced cell viability, and its binding conformation with protein kinase B (AKT) protein was the most significant. In vitro and in vivo, Rb1 protects cardiomyocytes from aconitine-induced injury by regulating oxidative stress levels and maintaining Ca2+ concentration homeostasis. Moreover, Rb1 activated the PI3K/AKT pathway, downregulated Cleaved caspase-3 and Bax, and upregulated Bcl-2 expression. In conclusion, Rb1 protected H9c2 cells from aconitine-induced injury by maintaining Ca2+ homeostasis and activating the PI3K/AKT pathway to induce a cascade response of downstream proteins, thereby protecting cardiomyocytes from damage. These results suggested that ginsenoside Rb1 may be a potential cardiac protective drug.

Topics: Aconitine; Animals; Apoptosis; Apoptosis Regulatory Proteins; Calcium; Cardiotoxicity; Cell Line; Disease Models, Animal; Ginsenosides; Heart Diseases; Homeostasis; Male; Molecular Docking Simulation; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sapogenins; Signal Transduction

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Topics: Aconitine; Alzheimer Disease; Amyloid beta-Peptides; Animals; CARD Signaling Adaptor Proteins; Cognition; Diet, Western; Disease Models, Animal; Hippocampus; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-18; Lipopolysaccharides; Microglia; Palonosetron; Peptide Fragments; Pyroptosis; Rats; Receptors, Serotonin, 5-HT3; Risk Factors; Spatial Memory

Remote ischemic postconditioning (RIPost) has been shown to reduce the ischemia-reperfusion injury of the heart and brain. However, the protection mechanisms have not yet been fully elucidated. We have observed that RIPost could alleviate the brain injury after cardiac arrest (CA). The aim of this study was to explore whether α7 nicotinic acetylcholine receptor (α7nAChR) mediates the neuroprotection of RIPost in a rat model of asphyxial CA.. Asphyxial CA model was induced by occlusion of the tracheal tube for 8 min and resuscitated later. RIPost produced by three cycles of 15-min occlusion and 15-min release of the right hind limb by a tourniquet was performed respectively at the moment and the third hour after restoration of spontaneous circulation. The α7nAChR agonist PHA-543613 and the antagonist methyllycaconitine (MLA) were used to investigate the role of α7nAChR in mediating neuroprotective effects.. Results showed that α7nAChR was decreased in hippocampus and cortex after resuscitation, whereas RIPost could attenuate the reduction. The use of PHA-543613 provided neuroprotective effects against cerebral injury after CA. Furthermore, RIPost decreased the levels of neuron-specific enolase, inflammatory mediators, the number of apoptotic cells, and phosphorylation of nuclear factor-κB while increased the phosphorylation of signal transducer and activator of transcription-3. However, the above effects of RIPost were attenuated by α7nAChR antagonist methyllycaconitine.. Neuroprotection of RIPost was related with the activation of α7nAChR, which could suppress nuclear factor-κB and activate signal transducer and activator of transcription-3 in a rat asphyxial CA model.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Asphyxia; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Heart Arrest; Hippocampus; Humans; Hypoxia, Brain; Ischemic Postconditioning; Male; Neuroprotection; NF-kappa B; Quinuclidines; Rats; Signal Transduction; STAT3 Transcription Factor; Treatment Outcome

Nicotine, a potent parasympathomimetic alkaloid, manifests anti-inflammatory properties by activating nicotinic acetylcholine receptors (nAChRs). In this study, we evaluated the effects of nicotine on concanavalin A (ConA)-induced autoimmune hepatitis. Nicotine (0.5 and 1 mg/kg) was intraperitoneally administered to BALB/c mice and mice were intravenously injected with ConA (15 mg/kg) to induce hepatitis. The results showed that nicotine treatment ameliorated pathological lesions in livers and significantly suppressed the expression of pro-inflammatory cytokines in the livers. Such effects were mediated by inhibiting the nuclear factor-kappa B (NF-κB) signaling in livers. Interestingly, nicotine inhibited the ConA-induced inflammatory response in primary cultured Kupffer cells (KCs) but did not alter the proliferation of splenocytes. The protective effects of nicotine against ConA-induced hepatitis were abolished in KC-depleted mice, indicating the requirement of KCs in this process. Additionally, the expression of α7-nAChR on KCs was dramatically increased by nicotine treatment, and the protective effects of nicotine on ConA-induced liver injury were significantly suppressed by treatment with methyllycaconitine (MLA), a specific α7-nAChR antagonist. Consistently, in primary cultured KCs, the activation of NF-κB signaling was also regulated by nicotine treatment. This study suggests that nicotine increases α7-nAChR-mediated cholinergic activity in KCs resulting in decrease of ConA-induced autoimmune hepatitis through inhibiting NF-κB signaling.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Cells, Cultured; Concanavalin A; Disease Models, Animal; Hepatitis, Autoimmune; Humans; Kupffer Cells; Liver; Male; Mice; NF-kappa B; Nicotine; Primary Cell Culture; Protective Agents; Signal Transduction

The current study aimed to study the effects of Bulleyaconitine A (BLA) on asthma. Asthmatic mice model was established by ovalbumin (OVA) stimulation, and the model mice were treated by BLA. After BLA treatment, the changes in lung and airway resistances, total and differential leukocytes in the bronchoalveolar lavage fluid (BALF) were detected, and the changes in lung inflammation and airway remodeling were observed. Moreover, the secretion of IgE, Th1/Th2-type and IL-17A cytokines in BALF and serum of the asthmatic mice were determined. The resuts showed that BLA attenuated OVA-induced lung and airway resistances, inhibited the inflammatory cell recruitment in BALF and the inflammation and airway remodeling of the asthmatic mice. In addition, BLA suppressed the secretion of IgE, Th2-type cytokines, and IL-17A, but enhanced secretions of Th1-type cytokines in BALF and serum. The current study discovered that BLA inhibited the lung inflammation and airway remodeling via restoring the Th1/Th2 balance in asthmatic mice.

Topics: Aconitine; Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Immunoglobulin E; Interleukin-17; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Signal Transduction; Th1 Cells; Th1-Th2 Balance; Th2 Cells; Treatment Outcome

Diffuse axonal injury (DAI) is the predominant effect of severe traumatic brain injury and significantly contributes to cognitive deficits. The mechanisms that underlie these cognitive deficits are often associated with complex molecular alterations. α7nAChR, one of the abundant and widespread nicotinic acetylcholine receptors (nAChRs) in the brain, plays important physiological functions in the central nervous system. However, the relationship between temporospatial alterations in the α7nAChR and DAI-related learning and memory dysfunction are not completely understood. Our study detected temporospatial alterations of α7nAChR in vulnerable areas (hippocampus, internal capsule, corpus callosum and brain stem) of DAI rats and evaluated the development and progression of learning and memory dysfunction via the Morris water maze (MWM). We determined that α7nAChR expression in vulnerable areas was mainly reduced at the recovery of DAI in rats. Moreover, the escape latency of the injured group increased significantly and the percentages of the distance travelled and time spent in the target quadrant were significantly decreased after DAI. Furthermore, α7nAChR expression in the vulnerable area was significantly positively correlated with MWM performance after DAI according to regression analysis. In addition, we determined that a selective α7nAChR agonist significantly improved learning and memory dysfunction. Rats in the α7nAChR agonist group showed better learning and memory performance than those in the antagonist group. These results demonstrate that microstructural injury-induced alterations of α7nAChR in the vulnerable area are significantly correlated with learning and memory dysfunctions after DAI and that augmentation of the α7nAChR level by its agonist contributes to the improvement of learning and memory function.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzamides; Bridged Bicyclo Compounds; Cognitive Dysfunction; Diffuse Axonal Injury; Disease Models, Animal; Learning; Male; Maze Learning; Memory; Rats; Rats, Sprague-Dawley

Monoester-diterpenoid alkaloids are the main bioactive components of Sini decoction, which is a well-known traditional Chinese medicine formula for the treatment of myocardial infarction (MI) and heart failure in China. In this work, an ultra-high-performance liquid chromatography-mass spectrometry combined with microdialysis method was successfully established and applied for investigating for the first time comparative plasma pharmacokinetics of three monoester-diterpenoid alkaloids (benzoylmesaconitine, benzoylaconitine and benzoylhypacoitine) in normal and MI rats after oral administration of Sini decoction. The statistical results of pharmacokinetic parameters demonstrated that benzoylmesaconitine, benzoylaconitine and benzoylhypacoitine showed lower peak concentration, longer half-life, smaller area under the concentration-time curve, slower clearance, time to peak concentration and mean residence time in MI rats than in normal rats (p < 0.05), which indicated that monoester-diterpenoid alkaloids exhibited lower systemic exposure and slower elimination in the MI rats. The results provided the experimental basis for understanding the metabolic fate and therapeutic effects of Sini decoction.

Topics: Aconitine; Administration, Oral; Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Limit of Detection; Linear Models; Male; Microdialysis; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry

BACKGROUND Bulleyaconitine A (BLA) has been widely used as analgesic against chronic inflammatory pain in China. However, its potential therapeutic role in asthma remains unclear. The purpose of this study was to investigate the effect of BLA on airway inflammation in mice with allergic asthma. MATERIAL AND METHODS Specific-pathogen-free (SPF) female Balb/c mice were randomly divided into the following 6 groups: (1) Control group (NC), (2) Asthma group (AS), (3) BLA-L group, (4) BLA-M group, (5) BLA-H group, and (6) Dexamethasone group. An asthma mouse model was established by administration of ovalbumin (OVA) and mice were sacrificed within 24 h after the last challenge. Enzyme-linked immunosorbent assay (ELISA) method was used to determine the relative expression levels of IgE and IgG in mouse serum. In addition, bronchoalveolar lavage fluid (BALF) was collected and IL-4, TNF-α, and MCP-1 levels were determined by ELISA. Furthermore, eosinophils, lymphocytes, and macrophages in BALF were classified and analyzed, and inflammatory cell infiltration in the airways of mice was determined by hematoxylin-eosin (HE) staining. The expression of NF-κB1 and PKC-δ in mouse lung tissue was determined by Western blot analysis. RESULTS The levels of serum IgE and IgG in BLA- or Dex- treated mice were significantly reduced compared to those in the asthma (AS) group (P<0.01), whereas the levels of cytokines IL-4, TNF-α, and MCP-1 were significantly decreased (P<0.01). HE-staining showed that BLA significantly reduced inflammatory cell infiltration and mucus secretion in lung tissue. Moreover, BLA inhibited the expression of NF-κB1 and PKC-d via the NF-κB signaling pathway in the lung. CONCLUSIONS Our data show that BLA activates PKC-δ/NF-κB to reduce airway inflammation in allergic asthma mice.

Topics: Aconitine; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Chemokine CCL2; China; Cytokines; Disease Models, Animal; Eosinophils; Female; Inflammation; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Protein Kinase C-delta; Tumor Necrosis Factor-alpha

α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neurological and psychiatric disorders. Nevertheless, no α7nAChR activating ligand has been clinically approved. Here, we investigated the effects of antagonizing α7nAChRs using the selective antagonist methyllycaconitine (MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA significantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation. Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glutamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA concentrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippocampal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes in rats. While the focus to enhance cognition by modulating α7nAChRs lies on agonists and positive modulators, antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatric disorders.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Cognition; Disease Models, Animal; Glutamic Acid; Hippocampus; Humans; Long-Term Potentiation; Memory; Nicotinic Antagonists; Rats; Receptors, Nicotinic

Evidence suggests that α7 nicotinic acetylcholine receptor (α7 nAChR) in the central nervous system has a critical role in the regulation of microglial function and neuroinflammation associated with the pathophysiology of major depressive disorder. The objectives of the present study were to determine the effects of PNU 120596, an α7 nAChR positive allosteric modulator (PAM), on depressive-like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba-1), a microglial marker, in male C57BL/6J mice following lipopolysaccharide (LPS) administration, an animal model for depressive-like behavior. Forced swim test (FST), tail suspension test (TST), and sucrose preference test were used to determine the effects of PNU 120596 on depressive-like behavior, measured by increased immobility time or decreased sucrose preference. We also examined the effects of PNU 120596 on Iba-1 expression by using Western blot analysis and immunofluorescence staining in the hippocampus and prefrontal cortex, the brain regions implicated in major depressive disorder. Administration of LPS (1 mg/kg, i.p.) significantly increased immobility time during FST and TST and decreased sucrose preference. The PNU 120596 (1 or 4 mg/kg, i.p.) dose-dependently prevented LPS-induced depressive-like behavior during FST, TST, and sucrose preference test. The PNU 120596 (1 or 4 mg/kg) alone did not show any significant alteration on immobility time and sucrose preference. Pretreatment of methyllycaconitine (3 mg/kg, i.p.), an α7 nAChR antagonist, significantly prevented the antidepressant-like effects of PNU (4 mg/kg). Similarly, the PNU 120596 (4 mg/kg, i.p.) significantly reduced LPS-induced increased expression of Iba-1 in the hippocampus or prefrontal cortex. Overall, these results suggest that PNU 120596 reduces LPS-induced depressive-like behavior and microglial activation in the hippocampus and prefrontal cortex in mice. Therefore, α7 nAChR PAMs could be developed as potential therapeutic utility for the treatment of major depressive disorder in humans.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antidepressive Agents; Calcium-Binding Proteins; Cholinergic Agents; Depressive Disorder; Disease Models, Animal; Hippocampus; Inflammation; Isoxazoles; Lipopolysaccharides; Male; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Motor Activity; Phenylurea Compounds; Prefrontal Cortex

Smoking cessation is the most effective treatment in patients with emphysema and lung inflammation. The aim of the present study was to examine the effect of varenicline, a smoking cessation drug, on emphysema in porcine pancreatic elastase (PPE)-inhaled mice. PPE-inhaled mice were treated with varenicline and an α7 nicotinic acetylcholine receptor (nAChR) antagonist, methyllycaconitine (MLA) for 5 and 21 days. Varenicline markedly ameliorated alveolar expansion and inflammatory response in bronchoalveolar lavage fluid in PPE-inhaled mice. These blocking effects were inhibited by MLA. Our findings demonstrate that varenicline likely has an anti-inflammatory property including reduced inflammatory cell recruitment in lung tissue to protect PPE-induced alveolar expansion via α7 nAChR.

Topics: Aconitine; Administration, Inhalation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Emphysema; Mice, Inbred C57BL; Nicotinic Agonists; Pancreatic Elastase; Pulmonary Alveoli; Smoking Cessation; Varenicline

Activation of transient receptor potential vanilloid type 1 (TRPV1) decreases lung ischemia-reperfusion injury (LIRI) in rabbits and rats. Stimulation of α7 nicotinic acetylcholine receptors (α7nAChRs) protects against lung injury. Here we examined whether α7nAChRs contribute to TRPV1-mediated protection against LIRI.. Wild-type (WT) and TRPV1-knockout (KO) mice were subjected to 1-h lung ischemia by clamping left hilum, followed by 2-h reperfusion. WT or KO mice were pretreated with vehicle, TRPV1 agonist capsaicin, TRPV1 antagonist capsazepine, α7nAChR antagonist methyllycaconitine, or α7nAChR agonist PNU-282987. Arterial blood and lung tissues were obtained for blood gas, lung wet-to-dry weight ratio, interleukin (IL)1β, IL6, tumor necrosis factor-α (TNF-α), apoptosis-related proteins (caspases, Bax, Fas), and pathologic scoring.. TRPV1 activation alleviates LIRI, partially dependent on α7nAChR activity. The α7nAChR stimulation with or without existence of TRPV1 alleviates LIRI. Thus, α7nAChR is involved in the pathway of TRPV1-mediated protection against LIRI and the specific mechanism remains to be revealed.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Apoptosis; Benzamides; Bridged Bicyclo Compounds; Capsaicin; Disease Models, Animal; Down-Regulation; Humans; Lung; Lung Injury; Male; Mice; Mice, Knockout; Reperfusion Injury; Treatment Outcome; TRPV Cation Channels

Screening active constituents of traditional Chinese medicines (TCMs) is vital for lead compound discovery. Sini decoction (SND) is a well-known TCM formula for relieving myocardial ischemia (MI) in clinic. Due to complex nature, the effective compounds of SND are still unknown. In this study, a novel "system to system" strategy based on the correlation of drug-related and drug-induced ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOFMS) serum metabolomic profiles was developed to discover bioactive compounds of SND against isoproterenol-induced MI. Thirteen SND-induced metabolites and 19 SND-related metabolites were identified by UHPLC-Q-TOFMS coupled with S-plot and SUS-plot of orthogonal projection to latent structure-discriminant analysis (OPLS-DA) models, respectively. Canonical correlation analysis between the SND-induced and SND-related metabolites revealed that 12 compounds had strongly correlated relationship with the protective effect of SND on MI, and these compounds include isotalatizidine, songorine, fuziline, neoline, talatizamine, 14-acetyltalatizamine, liquiritigenin, benzoylmesaconitine, isoliquiritin, benzoylaconitne, benzoylhypaconitine and 6-gingerol. Combination functional enrichment analysis and network topology analysis revealed that the targeted metabolic pathways of these correlated compounds were involved in valine, leucine and isoleucine biosyntheses, tryptophan metabolism, glycerophospholipid metabolism and sphingolipid metabolism. The results demonstrated that the "system to system" strategy may be a high-throughput method to discover potentially effective compounds from TCMs.

Topics: Aconitine; Alkaloids; Animals; Aspartate Aminotransferases; Catechols; Chalcone; Chromatography, High Pressure Liquid; Creatine Kinase; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Alcohols; Flavanones; Glucosides; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Malondialdehyde; Mass Spectrometry; Metabolome; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Oral Bulleyaconitine A (BLA) is effective for treating neuropathic pain in human patients, but the underlying mechanism is poorly understood. Here, we tested whether BLA blocked voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons. Compelling evidence shows that voltage-gated sodium channels are upregulated in uninjured DRG neurons but downregulated in injured ones following peripheral nerve injury. We found that BLA preferably inhibited Na currents in uninjured DRG neurons in neuropathic rats. Compared to sham rats, IC50 values for resting and inactivated Na currents were 113 and 74 times lower in injured and uninjured neurons of L4-6 DRGs in spared nerve injury (SNI) rats (4.55 and 0.56 nM) and were 688 and 518 times lower in the uninjured L4 and L6 DRG neurons of L5 spinal nerve ligation (L5-SNL) rats. The use-dependent blockage of BLA on Na currents was more potent in neuropathic rats compared to sham rats. Bulleyaconitine A facilitated the inactivation of Na channels in each group. IC50 values for resting and inactivated tetrodotoxin-sensitive (TTX-S) channels were 1855 and 1843 times lower than those for TTX-resistant channels in the uninjured neurons of L5 spinal nerve ligation rats. The upregulation of protein kinase C was associated with the preferable effect of BLA on TTX-S Na channels in the uninjured DRG neurons. Local application of BLA onto L4-6 DRGs at 0.1 to 10 nM dose-dependently alleviated the mechanical allodynia and thermal hyperalgesia in L5 spinal nerve ligation model. Thus, preferable blockage of TTX-S Na channels in uninjured DRG neurons may contribute to BLA's antineuropathic pain effect.

Topics: Aconitine; Animals; Cadmium Chloride; Disease Models, Animal; Electric Stimulation; Enzyme Inhibitors; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Male; Neuralgia; Patch-Clamp Techniques; Protein Kinase C; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Sodium Channel Blockers; Tetrodotoxin; Time Factors; Voltage-Gated Sodium Channels

The high prevalence of chronic pain in posttraumatic stress disorder (PTSD) individuals has been widely reported by clinical studies, which emphasized an urgent need to uncover the underlying mechanisms and identify potential therapeutic targets. Recent studies suggested that targeting activated glia and their pro-inflammatory products may provide a novel and effective therapy for the stress-related pain. In this study, we investigated whether activation of alpha-7 nicotinic acetylcholine receptor (α7 nAChR), a novel anti-inflammatory target, could attenuate PTSD-related chronic pain. The experiments were conducted in a rat model of single prolonged stress (SPS), an established model of PTSD-pain comorbidity. We found that SPS exposure produced persistent mechanical allodynia. Immunohistochemical and enzyme-linked immuno sorbent assay analysis showed that SPS also induced elevated activation of glia cells (including microglia and astrocytes) and accumulation of pro-inflammatory cytokines in spinal cord. In another experiment, we found that intrathecal injection of PHA-543613, a selective α7 nAchR agonist, attenuated the SPS-evoked allodynia in a dose dependent manner. However, this anti-hyperalgesic effect was blocked by pretreatment with methyllycaconitine (MLA), a selective α7 nAchR antagonist. Further analyses showed that PHA-543613 suppressed SPS-induced spinal glial activation and SPS-elevated spinal pro-inflammatory cytokines, and these were abolished by MLA. Taken together, the present study showed that spinal activation of α7 nAChR by PHA-543613 attenuated mechanical allodynia induced by PTSD-like stress, and the suppression of spinal glial activation may underlie this anti-hyperalgesic effect. Our study demonstrated the therapeutic potential of targeting α7 nAChR in the treatment of PTSD-related chronic pain.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agents; Chronic Pain; Comorbidity; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Neuroglia; Quinuclidines; Random Allocation; Rats, Sprague-Dawley; Spinal Cord; Stress Disorders, Post-Traumatic; Touch

Aconitum plants have been widely used in China for thousands of years. Recent evidences indicate that aconitine, the main active ingredient of Aconitum, has immunomodulatory properties that might be useful for treating autoimmune diseases, such as rheumatoid arthritis. In this study, we conducted a pilot study to explore the effect and mechanisms of aconitine on the treatment of systemic lupus erythematosus.. A pristane-induced murine model was used. The pristane-induced mice were treated with aconitine (25, 75 μg kg. We found that aconitine significantly improved the mouse health, decreased the elevated blood leukocyte counts, reduced the serum level of anti-double-stranded DNA (anti-dsDNA) antibody, greatly ameliorated renal histopathologic damage and reduced IgG deposit in glomerular. Furtherly, the levels of PGE2, IL-17a and IL-6, were found to have decreased in aconitine treated mice.. We have demonstrated that aconitine can inhibit the progression of disease and ameliorate the pathologic lesion of systemic lupus erythematosus.

Topics: Aconitine; Animals; Antibodies, Antinuclear; Cytokines; Dinoprostone; Disease Models, Animal; Female; Immunoglobulin G; Immunologic Factors; Kidney; Leukocyte Count; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Pilot Projects; Proliferating Cell Nuclear Antigen; Proteinuria; Spleen; Terpenes

Activation of antiinflammatory cholinergic (vagal) pathways can reduce inflammation, and in vitro studies support a pivotal role of α7 nicotinic acetylcholine receptors (α7-nAChR), macrophages, and T cells in these events. The aim of this study was to assess α7-nAChR agonists as an antiinflammatory treatment for Freund's complete adjuvant (CFA)-induced monoarthritis.. Arthritis was induced by intraarticular injection of CFA unilaterally into the knee joints of mice. Animals were treated with α7-nAChR agonists (AR-R17779 or A844606), with or without antagonists (COG133 or methyllycaconitine), and joint inflammation and pain were assessed. Experiments were repeated in c-Kit(W-sh) mast cell-deficient mice, and the effects of an α7-nAChR agonist on mast cell proliferation, migration, and activation by lipopolysaccharide (LPS) were tested.. Treatment with α7-nAChR agonists significantly exacerbated CFA-induced arthritis and pain, as gauged by all indices of assessment, the specificity of which was confirmed by coadministration of an nAChR antagonist that attenuated the increase in disease severity. Toluidine blue-positive mast cells were increased in the joint capsule of CFA plus AR-R17779-treated mice, and AR-R17779 enhanced LPS-induced TNF proliferation and migration of a human mast cell line. The AR-R17779-driven increase in severity of CFA-induced arthritis was significantly reduced in mast cell-deficient mice.. Using CFA to elicit a local inflammatory response, we found that pharmacologic activation of α7-nAChR exacerbated joint inflammation and pain, in part via mast cells, which illustrates the organ- and disease-specific nature of regulatory neuroimmune mechanisms. Thus, α7-nAChR activation may not be uniformly antiinflammatory in all types of inflammatory joint disease.

Topics: Aconitine; Adjuvants, Immunologic; alpha7 Nicotinic Acetylcholine Receptor; Animals; Apolipoproteins E; Arthritis, Experimental; Bridged-Ring Compounds; Cell Movement; Cell Proliferation; Disease Models, Animal; Disease Progression; Freund's Adjuvant; Inflammation; Injections, Intra-Articular; Lipopolysaccharides; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nicotinic Antagonists; Peptide Fragments; Pyrroles; Spiro Compounds; Xanthones

The relationship between atrial fibrillation (AF) and flap survival has not been fully characterized. Therefore, the goal of this study was to investigate the effect of AF on survival areas of pedicled flap and survival rates of free flap in an experimental rat AF model. An aconitine-induced rat AF model was established without intubation anesthesia. Survival areas of the pedicled rectangular epigastric flap were compared between AF rats (n = 7) and control rats (n = 7), and survival rates of the free epigastric flap were compared between AF rats (n = 10) and control rats (n = 10). Animals that died during the study or in which AF was not induced were excluded from study. A total of 64 rats were assessed in this study. Atrial fibrillation was induced with a success rate of 77.8% (21/27) throughout the study. Pedicled flap survival area was significantly higher in controls (75.1 ± 9.0%; n = 7) than that in AF animals (55.7 ± 13.0%; n = 7) (P < 0.01, nonpaired Student t test). Free flap survival rates were 80% in controls and 40% in AF animals (P = 0.07, χ² test). This is the first study to develop an aconitine-induced model of AF in rats. Atrial fibrillation has a detrimental effect on survival areas of the pedicled flap and survival rates of the free flap.

Topics: Aconitine; Animals; Atrial Fibrillation; Disease Models, Animal; Plastic Surgery Procedures; Rats; Rats, Sprague-Dawley; Surgical Flaps

Aconitine and its structurally-related diterpenoid alkaloids have been shown to interact differentially with neuronal voltage-dependent sodium channels, which was suggested to be responsible for their analgesia and toxicity. Bulleyaconitine A (BAA) is an aconitine analogue and has been prescribed for the management of pain. The present study aimed to evaluate the inhibitory effects of BAA on pain hypersensitivity and morphine antinociceptive tolerance, and explore whether the expression of dynorphin A in spinal microglia was responsible for its actions. Single intrathecal or subcutaneous (but not intraventricular or local) injection of BAA blocked spinal nerve ligation-induced painful neuropathy, bone cancer-induced pain, and formalin-induced tonic pain by 60 to 100% with the median effective dose values of 94 to 126 ng per rat (intrathecal) and 42 to 59 μg/kg (subcutaneous), respectively. After chronic treatment, BAA did not induce either self-tolerance to antinociception or cross-tolerance to morphine antinociception, and completely inhibited morphine tolerance. The microglial inhibitor minocycline entirely blocked spinal BAA (but not exogenous dynorphin A) antinociception, but failed to attenuate spinal BAA neurotoxicity. In a minocycline-sensitive and lidocaine- or ropivacaine-insensitive manner, BAA stimulated the expression of dynorphin A in the spinal cord, and primary cultures of microglia but not of neurons or astrocytes. The blockade effects of BAA on nociception and morphine tolerance were totally eliminated by the specific dynorphin A antiserum and/or κ-opioid receptor antagonist. Our results suggest that BAA eliminates pain hypersensitivity and morphine tolerance through directly stimulating dynorphin A expression in spinal microglia, which is not dependent on the interactions with sodium channels.. The newly illustrated mechanisms underlying BAA antinociception help us to better understand and develop novel dynorphin A expression-based painkillers to treat chronic pain.

Topics: Aconitine; Aconitum; Analgesics; Analysis of Variance; Animals; Animals, Newborn; Bone Neoplasms; CD11b Antigen; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Dynorphins; Female; Functional Laterality; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Microglia; Microscopy, Confocal; Morphine; Neurons; Pain; Pain Measurement; Phosphopyruvate Hydratase; Rats; Receptors, Opioid, kappa; RNA, Messenger; Spinal Cord; Time Factors

Sustained neuroinflammation contributes to the pathogenesis of postoperative cognitive dysfunction. Dexmedetomidine, a selective α-2 adrenergic receptor agonist, exhibits a protective role in the brain. This study investigated whether dexmedetomidine pretreatment attenuates neuroinflammation induced by tibial fracture in rats, as well as the mechanism by which dexmedetomidine provides its neuroprotection. In our study, we observed that tibial fracture significantly increased the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and the expression of nuclear factor-kappa B (NF-κB) in the hippocampus. Overexpression of microglial (CD11b) and astrocytic (GFAP) responses to injury were observed in the hippocampus. Dexmedetomidine pretreatment significantly suppressed the inflammatory responses, as evidenced by lower TNF-α and IL-1β levels, significantly inhibited NF-κB activity, and alleviated overexpression of microglia and astrocytes in the hippocampus. However, pretreatment with dexmedetomidine failed to attenuate cytokine responses and activity of NF-κB, CD11b and GFAP after vagotomy or treatment with methyllycaconitine, an α-7 nicotinic acetylcholine receptor (α7nAChR) antagonist. These results suggest that pretreatment with dexmedetomidine may attenuate neuroinflammation caused by tibial fracture in rats through vagal-dependent and α7nAChR-dependent mechanisms.

Topics: Aconitine; Adrenergic alpha-2 Receptor Agonists; alpha7 Nicotinic Acetylcholine Receptor; Animals; Astrocytes; Dexmedetomidine; Disease Models, Animal; Encephalitis; Hippocampus; Interleukin-1beta; Male; Microglia; Neuroprotective Agents; NF-kappa B; Rats; Rats, Sprague-Dawley; Tibial Fractures; Tumor Necrosis Factor-alpha

Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock.. Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine.. Both levels of tumor necrosis factor α, interleukin 1β, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA.. Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

Topics: Acetylcholine; Aconitine; Animals; Circadian Rhythm; Corticosterone; Cytokines; Disease Models, Animal; Hormone Antagonists; Inflammation; Kidney; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; Mifepristone; Nicotinic Antagonists; Vesicular Acetylcholine Transport Proteins

We investigated α-7 nAchR expression in human peritoneal macrophages and examined whether activation of nAchR might be a new therapy for endometriosis.. Human peritoneal fluid mononuclear cells (PFMC) were stimulated with lipopolysaccharide (LPS) in the presence of α-7 nAChR agonists. In a murine endometriosis model, α-7 nAChR modulators were administered.. Human PFMC expressed α-7 nAChR at the mRNA and protein levels. Activation of α-7 nAChR with its agonists led to significant (P<.01) suppression of LPS-induced interleukin (IL) -1β expression. In a murine endometriosis model, one week after inoculation of endometrium to the peritoneal cavity, α-7 nAChR agonist significantly suppressed the expression of IL-1β mRNA (P<.01), which was negated when α-7 nAChR antagonist was administered simultaneously. α-7 nAChR agonist significantly suppressed the formation of endometriotic lesions, which was reversed with α-7 nAChR antagonist.. Activation of nAChR might be a new candidate for treatment of endometriosis.

Topics: Aconitine; Adult; alpha7 Nicotinic Acetylcholine Receptor; Animals; Ascitic Fluid; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Endometriosis; Endometrium; Female; Gene Expression Regulation; Humans; Interleukin-1beta; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; Mice; Nicotine; Primary Cell Culture; Quinuclidines; RNA, Messenger; Severity of Illness Index; Signal Transduction

Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Indoles; Inflammation Mediators; Male; Mice, Inbred ICR; Peroxidase; Tropisetron

Agonists of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as therapeutic approaches for managing cognitive deficits in Alzheimer's disease (AD). Present study was designed to evaluate the effect of α7 nAChR selective activation by PHA-543613 (PHA) on beta-amyloid (Aβ)25-35-mediated cognitive deficits in mice. For this purpose, PHA (1mg/kg, i.p.), a selective α7 nAChR agonist, and galantamine (Gal) (3mg/kg, s.c.), an acetylcholine-esterase inhibitor (AChEI) effects on α7 nAChR were tested in Aβ25-35-received (intracerebroventricular, 10 nmol) mice model of AD. Methyllycaconitine (MLA) (1mg/kg, i.p.), a α7 nAChR antagonist, was used for receptor blockage effects evaluation. Working and reference memory in animals was assessed by the Morris water maze (MWM) task. The mRNA and protein levels of α7 subunit were analyzed by real-time PCR and Western blotting, respectively. PHA and Gal, ameliorate Aβ-impaired working and reference memory. However, Gal had less effect than PHA in this regard. Pretreatment with MLA reverses both Gal and PHA effects in MWM. PHA and Gal treatment prevent Aβ-induced α7 subunit protein reduction, but Gal has lesser effect than PHA. This effect blocked by pretreatment with MLA. In neither the pretreatment nor treatment group, the mRNA levels of nAChR α7 subunit were significantly changed. Therefore, α7 nAChR activation, reduces Aβ-induced cognitive deficits and increases the α7 protein level and subsequent neuron survival. However, blockage of receptor, increases Aβ toxicity and cognitive impairment and reduces the α7 nAChR protein level and flowing neuroprotection.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Amyloid beta-Peptides; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Galantamine; Gene Expression Regulation; Male; Maze Learning; Mice; Mice, Inbred BALB C; Nicotinic Agonists; Nicotinic Antagonists; Peptide Fragments; Psychomotor Performance; Quinuclidines; RNA, Messenger; Time Factors

Aconitum laciniatum is used in Bhutanese traditional medicine for treating various chronic infections and inflammatory conditions. We carried out in-depth isolation and characterization of the phytochemicals from the root component and determined the anti-inflammatory effects of the isolated compounds against chemically-induced colitis in mice. Five diterpenoid alkaloids - pseudaconitine, 14-veratroylpseudaconine, 14-O-acetylneoline, neoline, and senbusine A - were isolated from A. laciniatum for the first time. Two of the alkaloids were tested for anti-inflammatory properties in the TNBS-induced colitis model in mice. Various parameters were measured to assess pathology including weight loss, clinical and macroscopic scores, histological structure and IFN-γ production in the gut. Of the two alkaloids tested, 14-O-acetylneoline showed significant protection against different parameters of colitic inflammation. Compared to control mice that received TNBS alone, mice treated with 14-O-acetylneoline experienced significantly less weight loss and had significantly lower clinical scores, macroscopic pathology and grades of histological inflammation. Moreover, colonic IFN-γ mRNA levels were significantly reduced in mice that received 14-O-acetylneoline compared to control mice that received TNBS alone. This alkaloid is now considered a novel anti-colitis drug lead compound.

Topics: Aconitine; Aconitum; Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Colon; Disease Models, Animal; Diterpenes; Epithelial Cells; Interferon-gamma; Male; Mice; Mice, Inbred C57BL; Plant Extracts; RNA, Messenger; Trinitrobenzenesulfonic Acid; Weight Loss

Paclitaxel, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and at present no effective drug is available for treatment of the serious side effect. Here, we tested if intragastrical application of bulleyaconitine A (BLA), which has been approved for clinical treatment of chronic pain in China since 1985, could relieve the paclitaxel-induced neuropathic pain. A single dose of BLA attenuated the mechanical allodynia, thermal hyperalgesia induced by paclitaxel dose-dependently. Repetitive administration of the drug (0.4 and 0.8 mg/kg, t.i.d. for 7 d) during or after paclitaxel treatment produced a long-lasting inhibitory effect on thermal hyperalgesia, but not on mechanical allodynia. In consistency with the behavioral results, in vivo electrophysiological experiments revealed that spinal synaptic transmission mediated by C-fiber but not A fiber was potentiated, and the magnitude of long-term potentiation (LTP) at C-fiber synapses induced by the same high frequency stimulation was ~50% higher in paclitaxel-treated rats, compared to the naïve rats. Spinal or intravenous application of BLA depressed the spinal LTP, dose-dependently. Furthermore, patch clamp recordings in spinal cord slices revealed that the frequency but not amplitude of both spontaneous excitatory postsynaptic current (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in lamina II neurons was increased in paclitaxel-treated rats, and the superfusion of BLA reduced the frequency of sEPSCs and mEPSCs in paclitaxel-treated rats but not in naïve ones. Taken together, we provide novel evidence that BLA attenuates paclitaxel-induced neuropathic pain and that depression of spinal LTP at C-fiber synapses via inhibiting presynaptic transmitter release may contribute to the effect.

Topics: Aconitine; Analysis of Variance; Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Evoked Potentials; Hyperalgesia; In Vitro Techniques; Male; Nerve Fibers, Unmyelinated; Neuralgia; Paclitaxel; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn; Synaptic Potentials; Time Factors

Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action. Therefore, the aim of this work is the study of capability of aconitine-containing antiangiogenic agent BC1 to enhance anticancer activity of DCA against Ehrlich carcinoma.. DCA (total dose was 1.3 g/kg of b.w.) and BC1 (total dose was 0.9 mg/kg of b.w.) were administered per os starting from the 2(nd) and 3(rd) days, respectively (8 admini-strations for each agent). Antitumor efficacy of agents was estimated. Lactate level, LDH activity and the state of mitochondrial electron transport chain in tumor cells as well as phagocytic activity and reactive oxygen species (ROS) production of tumor-associated macrophages (TAM) were studied.. Combined administration of DCA and ВС1 resulted in 89.8% tumor growth inhibition (p < 0.001), what is by 22.5% (p < 0.05) higher that that of DCA alone. This combined treatment was accompanied with a decrease of lactate level in tumor tissue by 30% (p < 0.05) and significant elevation of LDH activity by 70% (p < 0.01). Increased level of NO-Fe-S clusters and 2-fold reduction of Fe-S cluster content were revealed in tumor tissue of mice after DCA and BC1 administration. It was shown that combined therapy did not effect TAM quantity and their phagocytic activity but stimulated ROS production by TAMs by 78% (p < 0.05) compared to this index in control animals.. Antiangiogenic agent ВС1 in combination with DCA considerably enhances antitumor activity of DCA via significant decrease of Fe-S-containing protein level resulted from substantial elevation of nitrosylation of these proteins.

Topics: Aconitine; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Dichloroacetic Acid; Disease Models, Animal; Drug Synergism; Humans; Lactate Dehydrogenases; Lactic Acid; Mice; Nitric Oxide; Reactive Oxygen Species; Tumor Burden; Xenograft Model Antitumor Assays

Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity.. The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 μM) blocker of INa-L.. VT/VF were induced either by local aconitine injection (50 μg) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined.. Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02).. The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Male; Pyridines; Rats; Rats, Inbred F344; Tachycardia, Ventricular; Triazoles; Ventricular Fibrillation

Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7(+/+) wild-type and nAChRα7(-/-) knockout mice with muscular injury induced with 60µL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3mg/kg and 1.0mg/kg) and the antagonist methyllycaconitine (MLA at 1.0mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by increasing muscular regeneration. These effects were not accompanied with fibrosis and/or deposition of non-functional collagen. The nAChRα7 activation may be considered as a potential target for pharmacological strategies to reduce inflammation and activate mechanisms of muscular regeneration.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzamides; Bridged Bicyclo Compounds; Bupivacaine; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Necrosis; Nicotinic Agonists; Nicotinic Antagonists; Regeneration

The acetylcholine receptor-operated K(+) (KACh) channel may be a novel target for atrial-specific antiarrhythmic therapy. Recently it has been demonstrated that tertiapin, a selective blocker of KACh channel, suppressed aconitine-induced atrial fibrillation (AF) in dogs. However, the precise mechanism by which the KACh-channel blocker inhibits the aconitine-induced AF remains unknown. This study was undertaken to determine the role of KACh channel in aconitine-induced AF in guinea pigs. Tertiapin terminated the aconitine-induced AF in anesthetized guinea pigs. The results of an in vitro electrophysiological experiment using atrial cells and atrial preparations suggest that aconitine might activate KACh channels in atrial cells, probably by intracellular Na(+) accumulation, and inhibition of KACh channels by tertiapin might suppress AF by producing conduction block, probably due to further decrease in the resting membrane potential. Since it has been reported that constitutively active KACh channels can be observed in atrial cells of patients with chronic AF, aconitine-induced AF may be used as an experimental model for evaluation of drug effect on chronic AF.

Topics: Aconitine; Animals; Atrial Fibrillation; Bee Venoms; Cells, Cultured; Chronic Disease; Disease Models, Animal; Dogs; Electrocardiography; Electrophysiological Phenomena; Guinea Pigs; Heart Atria; In Vitro Techniques; Membrane Potentials; Molecular Targeted Therapy; Potassium Channel Blockers; Potassium Channels; Sodium

Recent studies have shown that vagus nerve activation inhibits cytokine production in a variety of non-neural cells though activation of α7 nicotinic acetylcholine receptor (α7nAChR). Since chronic inflammation plays a pivotal role in liver fibrosis, this study was designed to investigate the role of hepatic vagus nerve in the progression of hepatic fibrosis in rats. Cirrhosis was induced by chronic ligation of the bile duct. Hepatic hydroxyproline level, portal pressure, serum transaminase level, hepatic TIMP-1 (tissue inhibitor of metalloproteinase-1) and MCP-1 (monocyte chemoattractant peptide-1) expression were measured in order to assess the progression of liver cirrhosis. α7nAChR expression was assessed using RT-PCR as well as immunostaining. RT-PCR analysis of the liver showed that α7nAChR mRNA is expressed in rat liver. Immunostaining study demonstrated that hepatic α7nAChR is mainly expressed in the hepatocytes of cirrhotic liver with minimum α7nAChR expression in biliary epithelium or myofibroblasts. Bile duct ligation was associated with portal hypertension, increased hepatic hydroxyproline level as well as TIMP-1 and MCP-1 expression in the liver. However neither selective hepatic vagotomy nor methyllycaconitine (an α7nAChR antagonist) could significantly affect development of portal hypertension or hepatic fibrosis in rats. Selective hepatic vagotomy could only attenuate serum aspartate aminotransferase level in bile duct ligated rats but did not have a significant effect on hepatic inflammation as assessed by MCP-1 mRNA expression. Our study provides evidence against a crucial role for the hepatic vagus nerve as an intrinsic protective mechanism in modulation of hepatic fibrosis in a rat model of biliary cirrhosis.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Aspartate Aminotransferases; Chemokine CCL2; Disease Models, Animal; Disease Progression; Epithelium; Hepatocytes; Liver; Liver Cirrhosis, Biliary; Male; Myofibroblasts; Nicotinic Antagonists; Rats, Sprague-Dawley; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Vagotomy; Vagus Nerve

Varenicline is one of the most widely used drugs for smoking cessation. However, whether an adverse effect of varenicline is associated with the risk of serious cardiovascular events remains controversial. In this study, we determined if varenicline increases the risk of cardiovascular events using apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice (8 weeks old) were injected with varenicline 0.5 mg kg(-1)day(-1) for 3 weeks. Varenicline aggravated atherosclerotic plaque formation in whole aorta from ApoE KO mice compared with vehicle. Methyllycaconitine, an α7 nicotinic acetylcholine receptor (nAChR) antagonist, inhibited varenicline-induced aggravated plaque formation. Our findings show that varenicline progresses atherosclerotic plaque formation through α7 nAChR, and thereby increases the risk of cardiovascular events.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Apolipoproteins E; Benzazepines; Body Weight; Cardiovascular Diseases; Cholesterol; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotinic Agonists; Plaque, Atherosclerotic; Quinoxalines; Varenicline

Blood-brain barrier disruption and consequent vasogenic edema formation codetermine the clinical course of intracerebral hemorrhage (ICH). This study examined the effect of PHA-543613, a novel α7 nicotinic acetylcholine receptor agonist, on blood-brain barrier preservation after ICH.. Male CD-1 mice, subjected to intrastriatal blood infusion, received PHA-543613 alone or in combination with α7 nicotinic acetylcholine receptor antagonist methyllycaconitine or phosphatidylinositol 3-kinase inhibitor wortmannin.. PHA-543613 alone, but not in combination with methyllycaconitine or wortmannin, inhibited glycogen synthase kinase-3β, thus, stabilizing β-catenin and tight junction proteins, which was paralleled by improved blood-brain barrier stability and ameliorated neurofunctional deficits in ICH animals.. PHA-543613 preserved blood-brain barrier integrity after ICH, possibly through phosphatidylinositol 3-kinase-Akt-induced inhibition of glycogen synthase kinase-3β and β-catenin stabilization.

Topics: Aconitine; Androstadienes; Animals; beta Catenin; Blood-Brain Barrier; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Hemorrhage; Claudin-3; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred Strains; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quinuclidines; Receptors, Nicotinic; Signal Transduction; Wortmannin

The current paper presents research results related to antiarrhythmic activity of halogen-containing derivatives of lappaconitine. Lappaconitine derivatives with iodine, chlorine or bromine substituting the anthranilate moiety at C-5` position were shown in vivo and in vitro to exhibit a more (Br, I) or less (Cl) pronounced antiarrhythmic activity in the models of calcium chloride- and adrenaline-induced arrhythmias as compared with the reference compound lappaconitine. The intensity of antiarrhythmic action depending on halogen substituent was found to be expressed by the following order: Cl < I < Br.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Halogens; Heart Rate; Humans; Molecular Structure; Rats

According to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat.. The animal groups included the control group; the sham 48 and sham 72 groups (without sleep deprivation); and the test 48 and test 72 groups, who experienced REM sleep deprivation for 48h and 72h, respectively. For induction of cardiac arrhythmia, aconitine was infused via the tail vein of the animals.. After 72h of REM sleep deprivation, the blood pressure (BP) levels and the QTc interval of the electrocardiogram (ECG) were significantly increased (P<.05 and P<.01, respectively). However, the sleep deprivation had no significant effect on the heart rate (HR), myocardial oxygen consumption index, and plasma corticosterone level. Furthermore, sleep deprivation increased the latency times of premature ventricular contraction (PVC), ventricular tachycardia (VT), and also the PVC number; however, it did not increase the number, duration, and severity of VT and ventricular fibrillation (VF).. Our findings suggest that 72h of REM sleep deprivation is associated with increased risk for hypertension and QT interval prolongation under nonstressful conditions; however, it does not increase the susceptibility to lethal ventricular arrhythmia in rat.

Topics: Aconitine; Animals; Blood Pressure; Corticosterone; Disease Models, Animal; Electrocardiography; Heart Rate; Humans; Male; Oxygen Consumption; Rats; Rats, Wistar; Risk Factors; Sleep Deprivation; Sleep, REM; Tachycardia, Ventricular; Ventricular Fibrillation; Voltage-Gated Sodium Channel Agonists

Aconitine, well-known for its high cardiotoxicity, causes severe arrhythmias, such as ventricular tachycardia and ventricular fibrillation, by opening membrane sodium channels. Tetrodotoxin, a membrane sodium-channel blocker, is thought to antagonize aconitine activity. Tetrodotoxin is a potent blocker of the skeletal muscle sodium-channel isoform Na(v)1.4 (IC50 10 nM), but micromolar concentrations of tetrodotoxin are required to inhibit the primary cardiac isoform Na(v)1.5. This suggests that substantial concentrations of tetrodotoxin are required to alleviate the cardiac toxicity caused by aconitine. To elucidate the interaction between aconitine and tetrodotoxin in the cardiovascular and respiratory systems, mixtures of aconitine and tetrodotoxin were simultaneously administered to mice, and the effects on electrocardiograms, breathing rates, and arterial oxygen saturation were examined. Compared with mice treated with aconitine alone, some mice treated with aconitine-tetrodotoxin mixtures showed lower mortality rates and delayed appearance of arrhythmia. The decreased breathing rates and arterial oxygen saturation observed in mice receiving aconitine alone were alleviated in mice that survived after receiving the aconitine-tetrodotoxin mixture; this result suggests that tetrodotoxin is antagonistic to aconitine. When the tetrodotoxin dose is greater than the dose that can block tetrodotoxin-sensitive sodium channels, which are excessively activated by aconitine, tetrodotoxin toxicity becomes prominent, and the mortality rate increases because of the respiratory effects of tetrodotoxin. In terms of cardiotoxicity, mice receiving the aconitine-tetrodotoxin mixture showed minor and shorter periods of change on electrocardiography. This finding can be explained by the recent discovery of tetrodotoxin-sensitive sodium-channel cardiac isoforms (Na(v)1.1, 1.2, 1.3, 1.4 and 1.6).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biomarkers; Disease Models, Animal; Electrocardiography; Heart Rate; Male; Mice; Mice, Inbred ICR; Myocardium; Oxygen; Respiratory Rate; Sodium Channel Blockers; Tetrodotoxin; Time Factors; Voltage-Gated Sodium Channels

Arctigenin possesses biological activities, but its underlying mechanisms at the cellular and ion channel levels are not completely understood. Therefore, the present study was designed to identify the anti-arrhythmia effect of arctigenin in vivo, as well as its cellular targets and mechanisms.. A rat arrhythmia model was established via continuous aconitine infusion, and the onset times of ventricular premature contraction, ventricular tachycardia and death were recorded. The Action Potential Duration (APD), sodium current (I(Na)), L-type calcium current (I(Ca, L)) and transient outward potassium current (I(to)) were measured and analysed using a patch-clamp recording technique in normal rat cardiomyocytes and myocytes of arrhythmia aconitine-induced by.. Arctigenin significantly delayed the arrhythmia onset in the aconitine-induced rat model. The 50% and 90% repolarisations (APD50 and APD90) were shortened by 100 µM arctigenin; the arctigenin dose also inhibited the prolongation of APD50 and APD90 caused by 1 µM aconitine. Arctigenin inhibited I(Na) and I(Ca,L) and attenuated the aconitine-increased I(Na) and I(Ca,L) by accelerating the activation process and delaying the inactivation process. Arctigenin enhanced Ito by facilitating the activation process and delaying the inactivation process, and recoverd the decreased Ito induced by aconitine.. Arctigenin has displayed anti-arrhythmia effects, both in vivo and in vitro. In the context of electrophysiology, I(Na), I(Ca, L), and I(to) may be multiple targets of arctigenin, leading to its antiarrhythmic effect.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Furans; Ion Channels; Lignans; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channels; Rats; Rats, Wistar; Sodium Channels

We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 μg/side.d and 41 μg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Dihydro-beta-Erythroidine; Disease Models, Animal; Drug Delivery Systems; Hippocampus; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Nicotine; Nicotinic Antagonists; Rats; Rats, Wistar; Receptors, Nicotinic; Stress, Psychological; Time Factors

To investigate the ability of the pericardium meridian (PM) to mitigate or enhance the cardiotoxic effects of aconitine injected at specific acupoint and non-acupoint sites in rabbits.. This study consisted of 3 experiments that were designed to test the effects of injection of 30 μg/kg of aconitine at acupoints on the PM (Test 1), at non-acupoint sites on the PM (Test 2), and at acupoints on other meridians and non-meridian sites (Test 3). In Test 1, 24 rabbits were randomly assigned to receive injections at Quze (PC3), Tianquan (PC2), or intramuscularly. In Test 2, 24 rabbits were randomly assigned to receive injections of aconitine at non-acupoint I, non-acupoint II, or intramuscularly. In Test 3, 48 rabbits were randomly assigned to receive injections at Neiguan (PC6), Sanyinjiao (SP6), Yangjiao (GB35), a non-meridian and non-acupoint site (NMNA), intravenously, and intramuscularly. Electrocardiographs of the rabbits were performed before, during and after injection to determine the incidence of arrhythmia, latency of ventricular rhythm, and recovery rate after aconitine injection. The recovery time index and extent of arrhythmia scores were calculated.. In all groups the incidence of arrhythmia was 100%, and the latency of ventricular rhythm was less than 30 min. In Tests 1 and 2, the recovery rates of the Quze and non-acupoint II groups were significantly higher than those of the muscular group (P < 0.05). In Test 3, the recovery time index and extent of arrhythmia scores of the Neiguan group were low. There were no significant differences between the other acupoint groups, or the NMNA group, when compared with the group receiving aconitine intramuscularly.. Acupoints or non-acupoints along the PM could reduce the severity of the arrhythmia induced by aconitine in healthy rabbits. Meridians play an important role in protecting body functions.

Topics: Aconitine; Acupuncture Points; Acupuncture Therapy; Analysis of Variance; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Electrocardiography; Male; Meridians; Pericardium; Rabbits; Random Allocation

Modulation of the inward rectifier K current (IK1) has profound effect on cardiac excitability and underlies new antiarrhythmic strategies. However, IK1-specific pharmacological tools, especially the selective IK1 agonists, are still lacking in the market. Zacopride, a gastrointestinal prokinetic drug, was found to be a selective IK1 channel agonist. By using the whole-cell patch clamp technique, it was found that zacopride (0.1-10 μmole/L) dose dependently enhanced the IK1 current in isolated rat cardiomyocytes, had no effects on other ion channels, transporters, or pumps. At the same dosage range, zacopride hyperpolarized the resting potential and shortened the action potential duration. When applied at the optimal dose of 1.0 μmole/L, zacopride could prevent or eliminate aconitine induced after depolarization and triggered activity in isolated cardiomyocytes. In a rat model of aconitine-induced arrhythmias both ex vivo and in vivo, zacopride (1.0 μmole/L or 25 μg/kg, respectively) treatment apparently protected the heart from ventricular tachyarrhythmias, which compares favorably with 7.5 mg/kg of lidocaine, a classical aconitine antidote. In conclusion, zacopride was found to be a selective IK1 agonist, and agonizing IK1 could prevent or eliminate aconitine-induced arrhythmias in the rat.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Guinea Pigs; Male; Membrane Potentials; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular

The analysis of behavioural hyperactivity can provide insights into how perturbations in normal activity may be linked to the altered function of the nervous system and possibly the symptoms of disease. As a small vertebrate zebrafish have numerous experimental advantages that are making them a powerful model for these types of studies. While the majority of behavioural studies have focused on adult zebrafish, it has become apparent that larvae can also display complex stereotypical patterns of behaviour. Here we have used three compounds (pentylenetetrazole (PTZ), aconitine and 4-aminopyridine) that have different neuronal targets (GABA, sodium and potassium channels), to induce distinct patterns of hyperactivity in larvae. Our studies have revealed that each compound produces a number of distinct concentration-dependent activity patterns. This work has shown for the first time that at sub-convulsive concentrations, PTZ can reverse the normal behavioural response to alternating periods of light and dark in zebrafish larvae. It also appears that both PTZ and 4-aminopyridine produce distinct changes in the normal startle response patterns immediately following light/dark transitions that may be the result of an elevation in stress/anxiety. Aconitine produces a general elevation in activity that eliminates the normal response to light and dark. In addition to differences in the patterns of behaviour each compound also produces a unique pattern of c-fos (an immediate early gene) expression in the brain. While more work is required to make direct links between region specific neuronal activity and individual behaviours, these models provide a framework with which to study and compare mechanistically different types of inducible behaviours.

Topics: 4-Aminopyridine; Aconitine; Animals; Anxiety; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperkinesis; Neurons; Pentylenetetrazole; Zebrafish

Infectious complications, predominantly pneumonia, are the most common cause of death in the postacute phase of stroke, although the mechanisms underlying the corresponding immunosuppression are not fully understood. We tested the hypothesis that activation of the α7 nicotinic acetylcholine receptor (α7nAChR) pathway is important in the stroke-induced increase in lung injury caused by Pseudomonas aeruginosa pneumonia in mice. Prior stroke increased lung vascular permeability caused by P. aeruginosa pneumonia and was associated with decreased lung neutrophil recruitment and bacterial clearance in mice. Pharmacologic inhibition (methyllycaconitine IC(50): 0.2-0.6 nM) or genetic deletion of the α7nAChR significantly (P<0.05) attenuates the effect of prior stroke on lung injury and mortality caused by P. aeruginosa pneumonia in mice. Finally, pretreatment with PNU-282987, a pharmacologic activator of the α7nAChR (EC(50): 0.2 μM), significantly (P<0.05) increased lung injury caused by P. aeruginosa pneumonia, significantly (P<0.05) decreased the release of KC, a major neutrophil chemokine, and significantly (P<0.05) decreased intracellular bacterial killing by a mouse alveolar macrophage cell line and primary mouse neutrophils. In summary, the α7 nicotinic cholinergic pathway plays an important role in mediating the systemic immunosuppression observed after stroke and directly contributes to more severe lung damage induced by P. aeruginosa.

Topics: Aconitine; Adrenergic beta-Antagonists; alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzamides; Bridged Bicyclo Compounds; Cell Line; Disease Models, Animal; Immune Tolerance; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Nicotinic Agonists; Nicotinic Antagonists; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Edema; Receptors, Nicotinic; Signal Transduction

Clinical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease (CKD). We have shown that nicotine promotes mesangial cell proliferation and hypertrophy via nonneuronal nicotinic acetylcholine receptors (nAChRs). The α7-nAChR is one of the most important subunits of the nAChRs. These studies were designed to test the hypothesis that nicotine worsens renal injury in rats with 5/6 nephrectomy (5/6Nx) and that the α7-nAChR subunit is required for these effects. We studied five different groups: Sham, 5/6Nx, 5/6Nx + nicotine (Nic; 100 μg/ml dry wt), 5/6Nx + Nic + α7-nAChR blocker methyllicaconitine (MLA; 3 mg·kg(-1)·day(-1) sq), and Sham + Nic. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. After 12 wk, the rats were euthanized and kidneys were collected. We observed expression of the α7-nAChR in the proximal and distal tubules. The administration of nicotine induced a small increase in blood pressure and resulted in cotinine levels similar to those found in the plasma of smokers. In 5/6Nx rats, the administration of nicotine significantly increased urinary protein excretion (onefold), worsened the glomerular injury score and increased fibronectin (∼ 50%), NADPH oxidase 4 (NOX4; ∼100%), and transforming growth factor-β expression (∼200%). The administration of nicotine to sham rats increased total proteinuria but not albuminuria, suggesting direct effects on tubular protein reabsorption. These effects were prevented by MLA, demonstrating a critical role for the α7-nAChR as a mediator of the effects of nicotine in the progression of CKD.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood Pressure; Chronic Disease; Disease Models, Animal; Disease Progression; Kidney Diseases; Male; NADPH Oxidase 4; NADPH Oxidases; Nephrectomy; Nicotine; Nicotinic Antagonists; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Transforming Growth Factor beta

To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.. The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.. In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED₅₀ value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and V(max), prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V(max) in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I(Na) (IC₅₀=26.9 μmol/L) and I(Ca,L)(IC₅₀=69.2 μmol/L), whereas the inward rectifier (I(K1)) and the delayed rectifier potassium currents (I(K)) were unaffected.. As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Potassium Channels; Rabbits; Rats; Rats, Sprague-Dawley; Sodium Channels; Sulfuric Acid Esters

Many studies have shown that the relationship between alcohol consumption and most cardiovascular diseases is U-shaped, with nondrinkers and heavier drinkers having higher risks than moderate drinkers. However, the association between cardiac arrhythmias and acute alcohol consumption is not well understood. We set up several experimental arrhythmia animal models to examine the effects of acute administration of ethanol on arrhythmia. The results showed 0.4, 0.8 and 1.6 g/kg ethanol consumption obviously delayed the onset time of atrial fibrillation (AF) (P < 0.05 or P < 0.01) and increased the survival rates on acetylcholine-CaCl₂-induced AF in mice. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption significantly delayed the onset time of ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) (P < 0.01), and 0.4 and 0.8 g/kg ethanol consumption increased the survival rates on CaCl₂-induced arrhythmia in rats. Ethanol (0.4 g/kg) essentially increased the cumulative dosage of aconitine required to CA (P < 0.05), and 0.8 g/kg, 1.6 g/kg ethanol reduced the cumulative aconitine dosage to induce VT, VF and CA (P < 0.05 or P < 0.01) on aconitine-induced arrhythmia in rats. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption remarkably increased the cumulative dosage of deslanoside to induce ventricualr premature contraction (P < 0.01) on deslanoside-induced arrhythmia in guinea pigs. Collectively, our results indicate that low concentrations of ethanol had anti-arrhythmic effect on experimental arrhythmia, and high concentrations of ethanol may aggravated the occurrence of experimental arrhythmia.

Topics: Acetylcholine; Aconitine; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium Chloride; Cardiotonic Agents; Central Nervous System Depressants; Cholinergic Agonists; Deslanoside; Disease Models, Animal; Drug Interactions; Ethanol; Guinea Pigs; Heart Arrest; Male; Mice; Mice, Inbred ICR; Rats; Rats, Sprague-Dawley; Risk Factors; Tachycardia, Ventricular; Ventricular Fibrillation; Voltage-Gated Sodium Channel Agonists

Oxymatrine is one of the main alkaloid components extracted from SOPHORA roots and has been shown to play various protective roles in the cardiovascular system. The present study was designed to study the protective effect of oxymatrine on arrhythmias and their ionic channel mechanism. Rat arrhythmic models were established by aconitine injection and coronary artery ligation. Rat cardiomyocytes were acutely isolated, and the whole-cell patch clamp technique was employed to investigate the effects of oxymatrine on sodium channels. Pretreatment with oxymatrine markedly increased the dose of aconitine required to induce arrhythmias in rats. Additionally, oxymatrine significantly delayed the initial time and shortened the duration time of rat arrhythmias induced by coronary artery ligation. Cardiac mortality rate in coronary artery ligation-induced arrhythmias was also effectively decreased by oxymatrine in rats. The electrophysiological study showed that oxymatrine could significantly inhibit sodium and calcium currents in isolated rat cardiomyocytes in a concentration-dependent manner. In summary, oxymatrine plays a remarkably preventive role in rat arrhythmias through the inhibition of sodium and calcium currents.

Topics: Aconitine; Alkaloids; Animals; Arrhythmias, Cardiac; Calcium; Cardiovascular Agents; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Myocytes, Cardiac; Phytotherapy; Plant Extracts; Plant Roots; Quinolizines; Rats; Rats, Wistar; Sodium; Sodium Channels; Sophora

The effect of histone deacetylase inhibitors on dystrophic heart function is not established. To investigate this aspect, dystrophic mdx mice and wild-type (WT) animals were treated 90 days either with suberoylanilide hydroxamic acid (SAHA, 5 mg/kg/day) or with an equivalent amount of vehicle.. The following parameters were evaluated: (i) number of ventricular arrhythmias in resting and stress conditions (restraint test) or after aconitine administration; (ii) cardiac excitability, conduction velocity, and refractoriness; (iii) expression and distribution of connexins (Cxs) and Na(v)1.5 sodium channel. Ventricular arrhythmias were negligible in all resting animals. During restraint, however, an increase in the number of arrhythmias was detected in vehicle-treated mdx mice (mdx-V) when compared with SAHA-treated mdx (mdx-SAHA) mice or normal control (WT-V). Interestingly, aconitine, a sodium channel pharmacologic opener, induced ventricular arrhythmias in 83% of WT-V mice, 11% of mdx-V, and in 57% of mdx-SAHA. Epicardial multiple lead recording revealed a prolongation of the QRS complex in mdx-V mice in comparison to WT-V and WT-SAHA mice, paralleled by a significant reduction in impulse propagation velocity. These alterations were efficiently counteracted by SAHA. Molecular analyses revealed that in mdx mice, SAHA determined Cx remodelling of Cx40, Cx37 and Cx32, whereas expression levels of Cx43 and Cx45 were unaltered. Remarkably, Cx43 lateralization observed in mdx control animals was reversed by SAHA treatment which also re-induced Na(v)1.5 expression.. SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Connexins; Disease Models, Animal; Electrocardiography, Ambulatory; Heart Conduction System; Heart Rate; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; NAV1.5 Voltage-Gated Sodium Channel; Restraint, Physical; Sodium Channels; Telemetry; Time Factors; Vorinostat

CDP-choline (citicholine; cytidine-5'-diphosphate choline) is an endogenously produced nucleotide which, when injected intracerebroventricularly, exerts an antinociceptive effect in acute pain models mediated by central cholinergic mechanisms and alpha7 nicotinic acetylcholine receptors (alpha7nAChR). Previous reports also suggest that the peripheral cholinergic system has an antiinflammatory role mediated by alpha7nAChRs on macrophages.. We used male Sprague-Dawley rats to assess the antihypersensitivity and antiinflammatory effect of CDP-choline after intraplantar injection of carrageenan (100 microL, 2%). Mechanical paw withdrawal thresholds and paw thickness were measured by Randall-Selitto testing and microcallipers, respectively. All drugs were administered intraplantarly in a volume 50 microL.. CDP-choline (1, 2.5, 5 micromol; intraplantar) increased the mechanical paw withdrawal threshold and decreased paw edema in a dose- and time-dependent manner in the carrageenan-injected hindpaw. CDP-choline administration to the noninflamed contralateral hindpaw did not alter ipsilateral inflammation. Methyllycaconitine (100 nmol), a selective alpha7nAChR antagonist, completely blocked the effects of CDP-choline when administered to the inflamed hindpaw. However, the administration of methyllycaconitine to the contralateral hindpaw did not block the effects of CDP-choline in the ipsilateral paw. The administration of CDP-choline (5 micromol) 10 min after carrageenan administration to the ipsilateral hindpaw did not reduce swelling and edema but did significantly reduce hypersensitivity. Treatment with CDP-choline decreased tumor necrosis factor-alpha production in the rat paw tissue after carrageenan.. The results of this study suggest that intraplantar CDP-choline has antihypersensitivity and antiinflammatory effects mediated via alpha7nAChRs in the carrageenan-induced inflammatory pain model.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cytidine Diphosphate Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Injections; Male; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Time Factors; Tumor Necrosis Factor-alpha

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca(2+)](i)) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca(2+)](i) overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M(3)-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M(3)-mAChR. The mechanism may be related to the improvement of Ca(2+) handling.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Disease Models, Animal; Female; Guinea Pigs; Male; Microscopy, Confocal; Muscarinic Agonists; Muscarinic Antagonists; Myocytes, Cardiac; Ouabain; Pilocarpine; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3; Time Factors

Status epilepticus (SE) is a seizure or series of seizures that persist for >30 min and often results in mortality. Death rarely occurs during or immediately following seizure activity, but usually within 30 days. Although ventricular arrhythmias have been implicated in SE-related mortality, the effects of this prolonged seizure activity on the cardiac function and susceptibility to arrhythmias have not been directly investigated. We evaluated myocardial damage, alterations in cardiac electrical activity, and susceptibility to experimentally induced arrhythmias produced by SE in rats. SE resulted in seizure-related increases in blood pressure, heart rate, and the first derivative of pressure, as well as modest, diffuse myocyte damage assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. Ten to twelve days following seizures, electrocardiographic recordings showed arrhythmogenic alterations in cardiac electrical activity, denoted by prolonged QT interval corrected for heart rate and QT dispersion. Finally, SE increased susceptibility to experimentally induced (intravenous aconitine) cardiac arrhythmias. These data suggest that SE produces tachycardic ischemia following the activation of the sympathetic nervous system, resulting in cardiac myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias.

Topics: Aconitine; Actin Cytoskeleton; Action Potentials; Animals; Arrhythmias, Cardiac; Biomarkers; Blood Pressure; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Heart Rate; In Situ Nick-End Labeling; Lithium Chloride; Male; Myocardium; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Sympathetic Nervous System; Time Factors; Troponin I

1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. 2. After oral administration of diammonium glycyrrhizinate (50 mg kg(-1)), the peak plasma concentration (C(max)), area under the plasma concentration-time curve from zero to time tau (AUC(0-tau)), and absolute bioavailability of aconitine (0.2 mg kg(-1)) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t(1/2)) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15 mg kg(-1)) did not affect any of the pharmacokinetic parameters of aconitine (0.02 mg kg(-1)). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination. 3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.

Topics: Aconitine; Administration, Oral; Animals; Biological Transport; Cyclosporine; Disease Models, Animal; Enzyme Inhibitors; Glycyrrhizic Acid; Intestinal Absorption; Male; Membrane Transport Proteins; Nitrophenols; Rats; Rats, Sprague-Dawley; Time Factors; Verapamil

Zebrafish (Danio rerio) have been widely used to study the molecular mechanisms of development including neurodevelopment. More recently, they have begun to be used to study neuropharmacology and neurotoxicology. Critical for this line of research are methods to study behavioral function in zebrafish. Previous studies have compared zebrafish with mammalian models to determine similarities and differences in locomotor behavior, learning and memory. Relatively little research has been conducted on stress response and anxiety behavior as well as the pharmacologic response in zebrafish. We have developed a test for zebrafish to assess stress response and anxiety: the novel tank diving test. In this short test normally zebrafish dive to the bottom of a novel tank and then gradually over the 5-min test begin exploring higher levels of the tank. Nicotine, which has anxiolytic effects in rodents and humans was found to diminish this novel tank diving response in zebrafish. The current study examined the nicotinic receptor subtype selectivity involved in the actions of nicotine. Two nicotinic receptor subtype selective antagonists were used: MLA (an alpha7 antagonist) and DHbetaE (an alpha4beta2 antagonist). We replicated our previous finding of the anxiolytic effect of nicotine with significantly less bottom dwelling by the fish after nicotine treatment. This nicotine-induced anxiolytic effect was reversed by both MLA and DHbetaE, indicating that both nicotinic alpha7 and alpha4beta2 receptors are involved in the nicotinic effect on anxiety in zebrafish.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Dihydro-beta-Erythroidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Female; Immobility Response, Tonic; Male; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic; Swimming; Zebrafish; Zebrafish Proteins

It is well known that choline has protective effects on ischemic arrhythmias. We designed the present study to evaluate the antiarrhythmic effects of choline and to detect its related mechanisms in aconitine-induced rat and ouabain-induced guinea pig models of arrhythmia. Laser scanning confocal microscopy and patch-clamp technique were utilized to study the action of choline on intracellular calcium concentration and L-type calcium current (ICa-L) of cardiac myocytes. M3 receptor antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) was applied preliminarily to evaluate the role of the M3 receptor. Choline significantly increased the survival time of arrhythmic rats and guinea pigs, delayed the onset of arrhythmias and ventricular tachycardia, and decreased the arrhythmia score. The overload of intracellular Ca2+ induced by aconitine or ouabain was reduced in isolated myocytes pretreated with choline. Choline reduced the increased density of ICa-L induced by aconitine or ouabain. Moreover, the beneficial effects of choline were reversed by 4-DAMP. Choline produced antiarrhythmic actions on arrhythmia models by stimulating the cardiac M3 receptor. The mechanism may be related to the improvement of Ca2+ handling.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Choline; Disease Models, Animal; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3

Atrial fibrillation (AF) is thought to be sustained by multiple reentrant wavelets or firing foci.. The aim of this study was to compare the spectral domain characteristics in the left atrium (LA) and right atrium (RA) in two different models of AF.. Rectangular 8 x 14 electrode arrays were placed on the LA and RA of 14 anesthetized dogs. AF episodes were induced with burst pacing and aconitine in each dog. For each model, AF was induced from the RA in six dogs and from the LA in six dogs. Dominant frequencies (DFs) were obtained using the fast Fourier transform of the unipolar recordings obtained from each electrode of the array. Standard deviation (SD) was used to compute the frequency dispersion within an atrium. Regularity of the signal was quantified using an organization index (OI).. DFs were largest in the atrium where aconitine was applied. Aconitine AF had larger gradients than burst-pacing AF (5.0 +/- 4.5 vs. 0.9 +/- 1.0 Hz: P <.006). Aconitine AF when compared with burst-pacing AF had greater absolute LA-RA differences in the SD of DFs (2.3 +/- 1.9 vs. 0.2 +/- 0.2 Hz; P <.001) and in OI (0.11 +/- 0.07 vs. 0.06 +/- 0.07; P <.07).. Differences in frequency gradients and organization were observed during AF induced by burst pacing and aconitine. This suggests that different mechanisms of AF are possible and may be identified with frequency domain analysis.

Topics: Aconitine; Animals; Atrial Fibrillation; Atrial Function, Left; Atrial Function, Right; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Electrocardiography; Fourier Analysis; Heart Atria; Heart Rate; Signal Processing, Computer-Assisted; Tachycardia, Atrioventricular Nodal Reentry

Withdrawal symptoms are a major deterrent when people try to quit smoking. The alpha7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, and has been suspected to play a major role in nicotine addiction. We studied the influence of alpha7-containing nAChRs on nicotine withdrawal and tolerance, in wild type mice and mice null for the alpha7 nAChR subunit (alpha7 -/-). For withdrawal experiments, animals were implanted with osmotic minipumps delivering nicotine for 13 days. A single intraperitoneal injection of the nAChR antagonists mecamylamine (MEC) or methyllycaconitine (MLA) was used to precipitate withdrawal. In wild type mice, both MEC- and MLA-precipitated somatic signs of withdrawal such as increased grooming, scratching and shaking. In alpha7 -/- mice, the somatic effects of MEC-precipitated nicotine withdrawal were significantly reduced. Interestingly, the presumed alpha7-specific antagonist MLA also precipitated withdrawal. Tolerance, which was measured as a decrease in nicotine-induced hypolocomotion after subchronic nicotine treatment, was normal in alpha7 -/- mice. Finally, because anxiety and withdrawal symptoms are highly correlated in humans, we studied anxiety-like behaviors in alpha7 -/- mice using a battery of anxiety-related tests. The behavior of alpha7 -/- mice was indistinguishable from that of control mice. Our results point to the alpha7 subunit as one of the players in nicotine withdrawal, but not in nicotine tolerance or basal anxiety-like behavior.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Anesthetics, Local; Animals; Behavior, Animal; Cocaine; Disease Models, Animal; Drug Tolerance; Exploratory Behavior; Female; Male; Maze Learning; Mecamylamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotinic Antagonists; Receptors, Nicotinic; Substance Withdrawal Syndrome

Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. Previous studies demonstrated the participation of alpha-7 nicotinic receptors (nAChR) in the neurotoxic effect of methamphetamine. The aim of this paper was to study the role of this receptor type in the acute effects and neurotoxicity of MDMA in mice. In vivo, methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist, significantly prevented MDMA-induced neurotoxicity at dopaminergic but not at serotonergic level, without affecting MDMA-induced hyperthermia. Glial activation was also fully prevented by MLA. In vitro, MDMA induced intrasynaptosomal reactive oxygen species (ROS) generation, which was calcium-, nitric-oxide synthase-, and protein kinase C-dependent. Also, the increase in ROS was prevented by MLA and alpha-bungarotoxin. Experiments with reserpine point to endogenous dopamine (DA) as the main source of MDMA-induced ROS. MLA also brought the MDMA-induced inhibition of [3H]DA uptake down, from 73% to 11%. We demonstrate that a coordinated activation of alpha-7 nAChR, blockade of DA transporter function and displacement of DA from intracellular stores induced by MDMA produces a neurotoxic effect that can be prevented by MLA, suggesting that alpha-7 nAChR have a key role in the MDMA neurotoxicity in mice; however, the involvement of nicotinic receptors containing the beta2 subunit cannot be conclusively ruled out.

Topics: Aconitine; Analysis of Variance; Animals; Cocaine; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Flow Cytometry; Male; Mice; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Neuroprotective Agents; Neurotoxicity Syndromes; Nicotinic Agonists; Nicotinic Antagonists; Radioligand Assay; Reactive Oxygen Species; Receptors, Nicotinic; Synaptosomes; Tritium

We used the hot plate test and the formalin test to evaluate the antinociception of choline after i.c.v. or i.v. administration. The analgesic mechanism of choline was also studied. The response latency of mice was significantly prolonged in the hot plate test after choline (90-120 mug/animals) i.c.v. administration in a dose-dependent manner. Pretreatment with methyllycaconitine citrate (MLA), alpha-bungarotoxin, or atropine blocked the antinociception of choline in the hot plate test. In contrast, mecamylamine and naloxone had no effect. No antinociceptive action of choline was found in the hot plate test, but it did have an effect in the late phase of the formalin test after i.v. administration. The effect of choline on anti-inflammatory pain was blocked by MLA, but not by mecamylamine, naloxone and atropine, which is indicative of the involvement of alpha7 receptors in peripheral sites. When choline (2 mg/kg) was coadministered with aspirin (9.4 mg/kg), the licking/biting times in the late phase significantly decreased, although no effects were shown when these doses of drugs were used alone. Similarly, coadministration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the antinociception of morphine in the late phase, but had no effect in the early phase. These results demonstrate that activation of alpha7 nicotinic receptors by choline elicits antinociceptive effects both in an acute thermal pain model and in an inflammatory pain model. Choline holds promise for development as a non-addictive analgesic drug and in reducing the regular dose of aspirin or morphine in inflammatory pain.

Topics: Aconitine; Acute Disease; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Aspirin; Atropine; Bungarotoxins; Central Nervous System; Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Inflammation; Mice; Morphine; Muscarinic Antagonists; Nicotinic Antagonists; Nociceptors; Pain; Pain Measurement; Reaction Time; Receptors, Nicotinic

Deficient inhibitory processing of the P50 auditory evoked potential is a pathophysiological feature of schizophrenia. Several lines of evidence suggest that alpha 7 nicotinic receptors play a critical role in this phenomenon. Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 auditory evoked potential, which is thought to be a rodent analog of the human P50 auditory evoked potential.. The present study was undertaken to examine whether tropisetron, a partial agonist at alpha 7 nicotinic receptors and an antagonist at 5-hydroxytryptamine-3 receptors, improves this deficit in DBA/2 mice.. Administration of tropisetron (1 mg/kg i.p.) significantly improved the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. Coadministration of methyllycaconitine (MLA; 3 mg/kg i.p.), a partially selective antagonist at alpha 7 nicotinic receptors, significantly blocked the normalizing effect of tropisetron. Furthermore, MLA alone did not alter the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice.. The data suggest that tropisetron improves the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice by effects on alpha 7 and perhaps alpha 4 beta 2 nicotinic receptors. Tropisetron may be useful for the treatment of deficient inhibitory processing in schizophrenia.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Auditory Perceptual Disorders; Disease Models, Animal; Drug Interactions; Evoked Potentials, Auditory; Indoles; Male; Mice; Mice, Inbred DBA; Nicotinic Antagonists; Receptors, Nicotinic; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Time Factors; Tropisetron

Antiarrhythmic properties of taurhythman were demonstrated on experimental models of ventricular (early occlusion and calcium chloride-induced) and atrioventricular (aconitine-induced) arrhythmias. The preparation reduced or prevented episodes of paroxysmal tachycardia and ventricular fibrillation, decreased the incidence of arrhythmias, and increased the lethal dose (LD) of arrhythmogenic agents. By its efficiency, taurhythman was superior to procainamide and comparable to lidocaine.

Topics: Aconitine; Alkanesulfonic Acids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Heart Arrest; Lidocaine; Male; Procainamide; Rats; Tachycardia, Paroxysmal; Ventricular Fibrillation

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.

Topics: Aconitine; Action Potentials; Aniline Compounds; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Computer Simulation; Disease Models, Animal; Electrophysiology; Guinea Pigs; Heart Ventricles; Kinetics; Muscle Cells; Phenyl Ethers; Sodium Channels; Sodium-Calcium Exchanger; Thiourea

Hypercortisolemia, long-term exposure of the brain to high concentrations of stress hormones (i.e. cortisol), may occur in patients suffering from depression, alcoholism, and other disorders. This has been suggested to produce neuropathological effects, in part, via increased function or sensitivity of N-methyl-d-aspartate (NMDA)-type glutamate receptors. Given that cigarette smoking is highly prevalent in some of these patient groups and nicotine has been shown to reduce toxic consequences of NMDA receptor function, it may be suggested that nicotine intake may attenuate the neurotoxic effects of hypercortisolemia. To investigate this possibility, organotypic hippocampal slice cultures derived from rat were pre-treated with corticosterone (0.001-1 microM) alone or in combination with selective glucocorticoid receptor antagonists for 72-h prior to a brief (1-h) NMDA exposure (5 microM). Pre-treatment with corticosterone (0.001-1 microM) alone did not cause hippocampal damage, while NMDA exposure produced significant cellular damage in the cornu ammonis (CA)1 subregion. No significant damage was observed in the dentate gyrus or CA3 regions following NMDA exposure. Pre-treatment of cultures with corticosterone (0.1-1 microM) markedly exacerbated NMDA-induced CA1 and dentate gyrus region damage. This effect in the CA1 region was prevented by co-administration of the glucocorticoid receptor antagonist RU486 (>or=1 microM), but not spironolactone (1-10 microM), a mineralocorticoid receptor antagonist. In a second series of studies, both acute and pre-exposure of cultures to (-)-nicotine (1-10 microM) significantly reduced NMDA toxicity in the CA1 region. Co-administration of cultures to (-)-nicotine (1-10 microM) with 100 nM corticosterone prevented corticosterone's exacerbation of subsequent CA1 insult. This protective effect of (-)-nicotine was not altered by co-exposure of cultures to 10 microM dihydro-beta-erythroidine but was blocked by co-exposure to 100 nM methyllycaconitine, suggesting the involvement of nicotinic acetylcholine receptors possessing the alpha7* subunit. The present studies suggest a role for hypercortisolemia in sensitizing the hippocampal NMDA receptor system to pathological activation and indicate that prolonged nicotine exposure attenuates this sensitization. Thus, it is possible that one consequence of heavy smoking in those suffering from hypercortisolemia may be a reduction of neuronal injury and sparing of cellular function.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Cell Survival; Corticosterone; Disease Models, Animal; Drug Interactions; Hippocampus; In Vitro Techniques; Male; Mifepristone; N-Methylaspartate; Neurons; Neuroprotective Agents; Neurotoxins; Nicotine; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

It has been found that intravenous administration of nociceptin (0.4 mg/kg) prevents development of aconitine-induced arrhythmias but has no effect on the incidence of occlusion, reperfusion, CaCl2-induced arrhythmias, and exacerbates epinephrine-evoked dysrhythmias. Pretreatment with hexamethonium, atropine, guanethidine and naloxone did not abolish the arrhythmic effect of nociceptin. Intracerebroventricular infusion of orphanin FQ was shown to increase cardiac tolerance of arrhythmogenic influence of aconitine, but this effect is completely abolished by hexamethonium administration. It has been suggested that stimulation of both central and peripheral ORL1 receptors increases cardiac resistance against arrhythmogenic effect of aconitine via different mechanisms.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Electrocardiography; Epinephrine; Heart; Heart Rate; Injections, Intravenous; Injections, Intraventricular; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Rats; Rats, Wistar; Receptors, Opioid

The aim of study was to modify the structure of indoline-2,3-diones and 1,2-benzenedicarboximides using the pharmacophores of new generation antiarrhythmics and to assess the impact of their structure upon the acute toxicity and antiarrhythmic action. The quaternary derivatives of N-aminoalkylindoline-2,3-diones and N-aminoalkyl-1,2-benzenedicarboximides were synthesized. The acute toxicity of compounds for white mice was tested. Using the calcium chloride- and aconitine-induced arrhythmia models in rats the antiarrhythmic action of derivatives was assessed. It was shown, that the antiarrhythmic action of N-aminoalkyl-1,2-benzenedicarboximides increases by lengthening of alkylene chain from one methylene group to two or by the presence of methanesulfonamide group in benzene ring. These structural changes, especially the presence of methanesulfonamido group, cause the decrease of acute toxicity. Among the N-aminoalkylindoline-2,3-diones the most antiarrhythmic action and minimal toxicity demonstrates the compound containing the bromo-substituted benzene ring.

Topics: Aconitine; Alkenes; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Chloride; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Indoles; Lethal Dose 50; Male; Mice; Quaternary Ammonium Compounds; Rats

Nicotinic acetylcholine receptor (nAChR) antagonists have been shown previously to decrease nicotine self-administration and precipitate elevations in brain reward thresholds and somatic signs of withdrawal in animals chronically exposed to nicotine. Both the positive-reinforcing effects of acute nicotine and the negative effects of nicotine withdrawal have been hypothesized to contribute to the development and maintenance of nicotine dependence. The aim of the present study was to use methyllycaconitine (MLA), an alpha 7 nAChR antagonist, to investigate the role of alpha 7 receptors in the reinforcing effects of nicotine and nicotine withdrawal. MLA was administered to animals allowed to self-administer nicotine intravenously, and also to animals that had been prepared with nicotine-containing osmotic mini-pumps and trained on a brain stimulation reward procedure. The results indicated that pretreatment with the highest doses of MLA used (3.9 and 7.8 mg/kg) significantly reduced nicotine self-administration at two doses of self-administered nicotine (0.03 and 0.06 mg/kg/infusion). Nevertheless, MLA administration, at all doses tested, had no effect on brain reward thresholds or the number of somatic signs of withdrawal observed in rats chronically exposed to either nicotine or saline. In conclusion, the alpha 7 nAChR subtype appears to play a significant role in the reinforcing effects of acute nicotine administered intravenously, but not in nicotine dependence, as reflected in the lack of precipitation of the nicotine withdrawal syndrome in nicotine-treated animals.

Topics: Aconitine; Animals; Behavior, Animal; Brain; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Male; Nicotine; Nicotinic Antagonists; Rats; Rats, Wistar; Reward; Self Administration; Substance Withdrawal Syndrome; Tobacco Use Disorder

The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro derivative of TY-12533) and cariporide on the platelet Na(+)/H(+) exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533, TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before ischemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Guanidines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Sulfones

Blockade of the mu and delta receptors exerted no effect upon the heart resistance against arrhythmogenic influences. Stimulation of the delta receptors increased the myocardial resistance against arrhythmogenic influences. Autonomic nervous system seems to take no part in this effect.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium Chloride; Disease Models, Animal; Disease Susceptibility; Epinephrine; Heart Rate; Male; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Vasoconstrictor Agents

The effects of garlic (Allium sativum L., Liliaceae) dialysate were studied on arrhythmias induced in anaesthetized dogs and on isolated left rat atria. Garlic dialysate suppressed premature ventricular contractions (PVC) and ventricular tachycardia (VT) in ouabain-intoxicated dogs as well as the ectopic rhythms induced by isoprenaline (10(-6) M) and aconitine (10(-8) M) on electrically driven left rat atria. The effective refractory period (ERP) and the sinus node recovery time (SNRT) of isolated rat atria were prolonged in a dose-dependent manner by the administration of this extract. Garlic dialysate decreased the positive inotropic and chronotropic effects of isoprenaline in a concentration-dependent manner. These last effects were increased by propranolol. The results suggest that garlic dialysate has a significant antiarrhythmic effect in both ventricular and supraventricular arrhythmias.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Dialysis; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrocardiography; Female; Garlic; Heart Atria; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Ouabain; Plant Extracts; Plants, Medicinal; Propranolol; Rats; Refractory Period, Electrophysiological; Tachycardia

The anti-nociceptive effect of processed aconiti tuber (TJ-3021), one of the traditional oriental herbal medicines (Kampo), was investigated by utilizing various methods including repeated cold stress and adjuvant articular inflammation in rats and mice. Analgesic potency was compared with that of mesaconitine, a potent component of aconitine alkaloids, and other analgesic agents. It was found that mesaconitine was more potent than morphine, and a processed aconiti tuber [(TJ-3021), Tsumura-shuchi-bushi-matsu] showed some analgesic effect, although it was weaker than those of dichlofenac, aminopyrine and indomethacine.

Topics: Acetates; Acetic Acid; Aconitine; Analgesics; Animals; Arthritis, Experimental; Cold Temperature; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Male; Mice; Mice, Inbred ICR; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley

The antiarrhythmic activity of IST was studied on some experimental models of cardiac arrhythmia--caused by adrenaline in rats, caused by barium in non-narcotized rabbits, caused by strophanthin in guinea pigs, caused by aconitine and calcium in rats. Rhythmic disturbances were recorded by a 12-channel polyphysiograph "Galileo" or a single-channel electrocardiograph "Cardiomat". The obtained results showed that IST manifested antiarrhythmic activity in respect to adrenaline, barium and strophanthin arrhythmias without affecting substantially aconitine and calcium arrhythmias. It is thought that antiarrhythmic activity of IST, found in the indicated experimental models of cardiac arrhythmias, is most probably connected with a lowering of the peripheral sympathetic activity, realized by a central way.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Aporphines; Arrhythmias, Cardiac; Barium; Barium Compounds; Calcium; Chlorides; Disease Models, Animal; Drug Evaluation, Preclinical; Epinephrine; Guinea Pigs; Male; Mice; Rabbits; Rats; Strophanthins

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.

Topics: Aconitine; Aconitum; Animals; Disease Models, Animal; Dogs; Electrocardiography; Electrodes, Implanted; Heart; Quinidine; Tachycardia

Topics: Aconitine; Amides; Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Electric Stimulation; Guinea Pigs; Heart Rate; In Vitro Techniques; Myocardial Contraction; Rats; Structure-Activity Relationship

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Guinea Pigs; Humans; Ion Channels

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Disease Models, Animal; Female; Male; Manganese; Metals; Mice; Verapamil

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Anura; Disease Models, Animal; Epinephrine; Phenyl Ethers; Propanolamines; Rabbits; Rats; Tachycardia

Topics: Aconitine; Aconitum; Animals; Arrhythmias, Cardiac; Calcium Chloride; Cats; Disease Models, Animal; Dogs; Female; Male; Prostaglandins; Prostaglandins A; Prostaglandins E; Prostaglandins F; Rabbits; Rats