Bronchoconstriction In Guinea Pigs Research Articles

Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.

Pharmacological screening of Acalypha indica L.: Possible role in the treatment of asthma

Ethnopharmacological relevanceAcalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica.Aim of the study: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. Materials and methodsEAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. ResultsData received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. ConclusionOur results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.

EVALUATION OF ANTI-ASTHMATIC ACTIVITY OF CAPPARIS DECIDUA

Objective: The present study was conducted to determine the anti-asthmatic activity of Capparis decidua.Methods: The acute oral toxicity study was conducted as per OECD guidelines, and the extract was proved to be safe up to the dose of 2000 mg/kg.The anti-asthmatic activity of C. decidua was evaluated using various experimental models such as histamine-induced bronchoconstriction in guineapigs and milk-induced leukocytosis in mice, histamine-induced bronchospasm in guinea pigs, studies on pre convulsive time and milk-inducedleukocytosis in mice, studies on blood.Results: Antihistaminic drugs Chlorpheniramine maleate and ethanolic extract of C. decidua significantly protected the guinea pigs against histamineinducedbronchospasm. The ethanolic section of C. decidua has dramatically prolonged the latent period of convulsions compared to control. Ethanolicextract of C. decidua suppresses the milk-induced leukocytosis by stabilizing the oxidative stress in the surrounding tissue.Conclusion: The results obtained in the above study suggest the ethanolic extract of C. decidua possesses significant anti-asthmatic activity.

The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs

BackgroundAsthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma.MethodsFirst, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann–Whitney U test or One-way nonparametric Kruskal–Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate.ResultsA dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips.ConclusionsTRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.

Evaluation of Anti-asthmatic Activity of Salvadora oleoids Leaves

Salvadora oleoids (Family: Salvadoraceae) is being used in the traditional medicine for the treatment of severe bronchitis and asthma. So, the study aims to evaluate anti-asthmatic activity of S. oleoids leaves. Leaves are reported to contain flavonoids, saponins, steroids, alkaloids, and tannins, known to possess similar effects. Flavonoids have been shown to smooth muscle relaxant, bronchodilator, antioxidant, and anti-inflammatory activity. The flavonoids are also reported to inhibit mast cell degranulation. Saponins are reported to mast cell stabilizing, anti-allergic, anti-inflammatory and antihistaminic activity. Tannins are reported to inhibit cyclooxygenase (COX) enzyme, decrease vascular permeability and antioxidant activity. Steroids are reported to an extraordinarily strong anti-inflammatory activity by inhibiting cytokine release IL-1, 2 and 6. The present investigation was undertaken to evaluate the anti-asthmatic activity of ethanolic extract of S. oleoids leaves in experimental animals. Asthma is a chronic inflammatory disorder of the airways. Limitations of currently available therapies and associated side effects have created an urge to search new and better treatment options. Thus, present study was designed to evaluate anti-asthmatic activity of S. oleoids leaves. Ethanolic extract of S. oleoides was prepared and used in the dose of 200 mg/kg (p.o.). Various in-vivo models like histamine induced bronchoconstriction in guinea pigs and milk induced leukocytosis in mice were used for evaluating anti-asthmatic activity of the drugs. Ethanolic extract of S. oleoides showed a significant broncho-dilatory, anti-histaminic and anti-inflammatory activity. Thus, ethanolic extract of S. oleoides have significant anti-asthmatic activity. Thus, ethanolic extract of S. oleoides leaves have proved to be an effective drug in prevention of asthma.

Cryptolepine, the major alkaloid of Cryptolepis sanguinolenta (Lindl.) Schlechter (Apocynaceae), attenuates early and late-phase symptoms of asthma

Aqueous root extract of Cryptolepis sanguinolenta has been used traditionally to treat many upper respiratory tract disorders. Besides its well-known broad spectrum antimicrobial activity, we had reasoned that cryptolepine can directly attenuate the symptoms of asthma. Therefore, this study evaluates cryptolepine, the main compound of the aqueous extract of Cryptolepis sanguinolenta, on early and late-phase symptoms of asthma attack. In the early phase study, isolated cryptolepine was evaluated on its ability to reverse histamine-induced bronchoconstriction and reduce histamine release from mast cells and bronchial mucus secretion. In the late phase study, cryptolepine was evaluated on its ability to affect airway inflammation and hypersensitivity as well as its ability to attenuate airway remodeling induced by ovalbumin. In the early asthma phase study, Cryptolepine (10–100 mg/kg) significantly and dose dependently inhibited Histamine-induced bronchoconstriction in guinea pigs. The protection lasted beyond 24 h. It also decreased the volume and optical density of bronchial secretions in mice. Cryptolepine (10–100 µg /mL) stabilized mesentery mast cells in vitro against Compound 48/80 -induced degranulation. In the late phase study, cryptolepine (10–100 mg/kg) prevented ovalbumin-induced airway obstruction and basal membrane smooth muscle hypertrophy. It significantly reduced systemic leukocytosis and inflammatory cell infiltration into airways in antigen-sensitized animals. Using the skin prick test, cryptolepine reduced the hypersensitivity to allergen challenge in antigen-sensitized animals. Cryptolepine's effects in the late phase was similar to dexamethasone (1 mg/kg) used as standard drug. Cryptolepine attenuates both early and late phase symptoms of asthma. It reduces bronchospasms, bronchial secretions, airway remodeling and hypersensitivity. This gives scientific credence to the traditional usage of cryptolepis extracts in upper respiratory tract disorders.

Transient receptor potential ankyrin-1 causes rapid bronchodilation via nonepithelial PGE2.

Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP2 receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINN-induced airway relaxation required TRPA1, prostaglandins, and PGE2 receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation.

Design, Synthesis, Biological Evaluation, and In Silico ADMET Studies of 1,8-Naphthyridine Derivatives as an H1-receptor Inhibitor

In the present study, 1,8-naphthyridine-3-carboxylic acid derivatives (5a1, 5a2, 5b1, and 5b2) were designed, synthesized, and screened for their in vitro H1-antihistaminic activity. H1R inhibitory activity of the synthesized derivatives was calculated by the modified Van Arman technique, histamine-induced bronchoconstriction in guinea pigs. A good bronchorelaxant effect of compounds was observed in histamine-contracted guinea pig tracheal chain through H1-receptor antagonism. In addition, the hypothetically resulted compounds are checked for their reliability on other in silico drug designing online web services like SwissADME predictor. In silico ADMET analysis results show that all the derivatives had negligible toxicity, good absorption, and solubility profile. These compounds may serve as possible lead for establishing safe and effective antihistaminic agent(s).

In vivo Evaluation of Antiasthmatic Activity of the Essential Oil of Zanthoxylum armatum

Zanthoxylum armatum DC. is used in traditional medicines as a therapy of many diseases including bronchial asthma. The antiasthmatic effect of Zanthoxylum armatum essential oil was studied using histamine aerosol-induced bronchoconstriction in guinea pigs and ovalbumin-sensitized albino mice. Absolute eosinophils count in blood, total immunoglobulin E, eosinophils and neutrophils in bronchoalveolar lavage fluid and histopathology of lung tissue were investigated. Treatment with Zanthoxylum armatum essential oil significantly increased the time of preconvulsive dyspnoea in histamine-induced guinea pigs. Oral treatment of Zanthoxylum armatum oil showed significant decrease in absolute eosinophils count, serum level of immunoglobulin E and the number of eosinophils, neutrophils in bronchoalveolar lavage fluid. Histopathological examination of lungs showed that essential oil rescinded bronchial asthma. Results obtained in the present investigation provided evidence that essential oil of Zanthoxylum armatum caused bronchorelaxation and showed antiasthmatic properties. The traditional use of Zanthoxylum armatum essential oil against asthma could be attributed to the bronchorelaxation and antiasthmatic activity.

P42 Chemical analysis and pharmacodynamic study of Wollea saccata biopolymer effect on respiratory system

Microalgae organisms are of interest for many biotechnology applications due to the production of a wide range of biologically active compounds. This study evaluated effect of Wollea saccata biopolymer on experimentally induced cough reflex and bronchoconstriction in guinea pigs. Incubation of W. saccata in a large scale afforded a mucilaginous, high molecular weight biopolymer composed of carbohydrate, protein and phenolic compounds. The carbohydrate part was rich mainly in hexose (51%) and deoxyhexose (40%) residues. Methylation analysis revealed about 34 types of methylated derivatives, suggesting a very complex structure of Wollea biopolymer. Wollea originated extracellular proteoglycan was then subjected to pharmacodynamic evaluation in 2 different peroral doses, 50 and 75 mg/kg. It suppressed the cough reflex induced by short-term exposure of healthy conscious guinea pigs to citric acid aerosol in dose-dependent manner. However, its effect was lower than that of the control, centrally acting antitussive drug codeine. The bronchodilatory effect, evaluated by the Pennock et al. [1] method using a double-chambered body plethysmograph box, manifested as a decrease in the value of specific airway resistance induced by various inhalatory applied bronchoprovoking agents, i.e. citric acid, histamine and methacholine. The observed bronchodilation was followed on both doses administered and was similar or higher than that of salbutamol, a control bronchodilatory beta adrenoreceptors agonist. Pharmacological studies confirmed antitussive and bronchodilatory effect of cyanobacteria biopolymer as the new pharmacodynamic properties.

Evaluation of Antiasthmatic Activity of Murraya Koenigii L. Leaves

The present investigation was designed to evaluate the anti-asthmatic activity of ethanolic extract of Murraya Koenigii Leaves in experimental animals. Murraya Koenigii Leaves was evaluated for anti-histaminic activity using isolated Guinea pig tracheal chain preparation, histamine induced Bronchoconstriction in Guinea pig and milk induced leucocytosis in mice. Ethanolic extract of Murraya Koenigii Leaves oral dose 400mg/kg body weight significantly inhibited dose dependent contraction of Guinea pig tracheal chain produced by histamine and also showed significant protection by prolonging PreConvulsion Dyspnoea time (PCT) in guinea pigs. Murraya Koenigii Leaves was evaluated by milk induced leucocytosis in mice showed significant decreased of total leukocyte count. Thus, Murraya Koenigii Leaves showed anti-allergic activity against histamine hence possesses potential role in the treatment of asthma.

Mentha arvensis essential oil suppressed airway changes induced by histamine and ovalbumin in experimental animals

The present investigation aimed to evaluate the activity of the essential oil of Mentha arvensis L. on exogenously induced bronchoconstriction in experimental animals. The anti-asthmatic effect of M. arvensis essential oil (MAEO) was studied using histamine aerosol-induced bronchoconstriction in guinea pigs and ovalbumin (OVA) sensitised albino mice. Treatment with M. arvensis oil significantly (p < 0.001) increased the time of preconvulsive dyspnoea in histamine-induced guinea pigs. Oral treatment of MAEO significantly (p < 0.001) decreased absolute eosinophil count, serum level of IgE and the number of eosinophils, neutrophils in BALF. Histopathological examination of lungs showed that essential oil rescinded bronchial asthma. The present investigation provides evidence that MAEO relaxes bronchial smooth muscles and suppressed immunological response to OVA.

Evaluation of anti-histaminic and bronchodilatory Activity of milk of equus africanus Asinus in rodents

The Equus africanus asinus milk commonly known as donkey milk (DM) is often used as a substitute for breast milk, and as medicine for treating the child of delicate health, improving immunity, treatment of respiratory problems like cough, whooping cough and asthma in infants.The present study was therefore designed to evaluate the antihistaminic and bronchodilator activity of milk of Equus africanus asinus in rodents. Equus asinus milk was evaluated using histamine induced contractions on isolated ileum and tracheal chain preparations and histamine induced bronchoconstriction in Guinea pigs. The Equus asinus milk significantly inhibited histamine induced contraction of isolated guinea pig ileum and tracheal chain preparation and significantly protected the guinea pigs against histamine induced Bronchoconstriction as indicated by delay in the pre-convulsive dyspnoea time (PCT) following the exposure of histamine aerosol. The results suggested that Equus asinus milk has antihistaminic and bronchodilator activity and may prove beneficial effect in the management of asthma.

A selective antagonist of histamine H4 receptors prevents antigen‐induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin‐1

Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H₄ receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid. Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

Mast cell mediators cause the early allergic bronchoconstriction in guinea pigs in vivo: a model of relevance to asthma

One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70 % of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.

Modifications of plasma 5-HT concentrations during the allergic bronchoconstriction in guinea pigs

ABSTRACTSeveral contractile mediators involved in the antigen-induced airway obstruction have been identified, but the role of 5-HT (5-hydroxytryptamine or serotonin) has been scantily investigated. In this work, the potential role of 5-HT in the allergic bronchoconstriction was evaluated through a pharmacological approach and plasma 5-HT measurement in blood samples from the right and left ventricles of anesthetized guinea-pigs. Intravenous 5-HT caused a dose-dependent increase of the lung resistance in anesthetized, nonsensitized guinea pigs. Likewise, in sensitized animals the antigenic challenge with ovalbumin also caused a transient bronchoconstriction (356 ± 60% the basal value), which was largely inhibited by the blockade of serotonergic receptors with methiothepin plus tropisetron (134 ± 10%, P = .007). Sensitized animals tended to have plasma 5-HT concentrations higher than nonsensitized controls, and shortly after the peak of the allergic bronchoconstriction the 5-HT levels in the left ventricle (blood flowing out from lungs) tended to be higher than in the right ventricle (blood entering the lungs), although data dispersion precluded the obtaining of statistical significance. Interestingly, the degree of bronchoconstriction highly correlated with the concentrations of 5-HT found in the left ventricle and measured either in platelet-rich plasma (r = 0.97 P = .007) or platelet-poor plasma (r = 0.97, P = .006). After the obstructive response subsided these correlations were lost, but now the degree of bronchoconstriction turned to be correlated with 5-HT concentration in platelet concentrate (r = 0.76, P = .03). In conclusion, our results suggested that 5-HT is actively released from lungs during the antigenic challenge and that this autacoid is involved in the generation of the airway obstruction.

Pharmacological evaluation of Cissus quadrangularis fractionated extracts for bronchodilatory activity using Guinea pigs

BACKGROUND AND PURPOSEThe bronchospasm in bronchial smooth muscle was the most studied feature of asthma and COPD. In the present study, we characterized the pharmacological activity of successively extracted CQME and CQEAE.MATERIALS AND METHODSThe Bronchodilatory activity of CQME and CQEAE were investigated in a guinea pig bronchoconstriction model using restrained double chamber plethysmograph respectively.RESULTSHistamine induced bronchoconstriction in guinea pigs, exhibited marked inhibitory activity against histamine challenge with specific airway resistance (RxV) 3.07, and 4.12 in comparison to RxV of salbutamol 1.87 and histamine control group 6.48 on CQME and CQEAE administration.CONCLUSIONThese results demonstrate that CQME induced remarkable bronchodilator activity, so CQME may be beneficial in treating airway obstructive pulmonary diseases.

The In-vivo Study of Anti-asthmatic Effect of Partially Purified Extracts From The Leaves of Labisia Pumila

Labisia pumila popularly known as Kacip Fatimah is a sub herbaceous plant which belonging to the Myrsinaceae family. It has been used in folk medicine to treat dysenteries and inflammatory disorders, such as rheumatism. Our previous study showed that crude dichloromethane extract exhibited a very strong anti-asthmatic and mast-cell stabilizing activity. In this present study, partially purified fractions A-E, of dichloromethane (DELP) crude extract obtained by column chromatography techniques were studied for their anti-asthmatic effect. 1% histamine, serotonin and bradykinin (0.1ml/rat) was dissolved with 0.9% (w/v) saline and subcutaneously injected to induce edema formation. 2mg of arachidonic acid was dissolved in 20μl of acetone and topically applied to mouse ear to induce ear edema. Also, 1% histamine and acetylcholine was dissolved in saline and was used to induce bronchoconstriction in guinea pigs. Oral treatment of partially purified fractions A-E (100mg/kg), and indomethacin (10mg/kg) inhibited significantly (p<0.001) the formation of the histamine, serotonin and bradykinin-induced paw edema measured in the fifth hour. The highest inhibition was observed in fraction E which was 5.07% 5.63% for histamine, 5.65% for serotonin, 9.59% for bradykinin and 43% for arachidonic acid ear edema. Fraction A showed 55% and 48.17% respectively for inhibition of histamine and acetylcholine-induced bronchoconstriction after 24 hrs treatment and 68% and 51.21% protection after 14 days treatment. Phytochemical screening revealed the presence of flavonoids, steroids, saponins, alkaloids and tannins. The present study confirmed that the extracts exhibited anti-asthmatic activity by its antiinflammatory and bronchodilatory action.

Low Voltage Vagal Nerve Stimulation Reduces Bronchoconstriction in Guinea Pigs Through Catecholamine Release

Electrical stimulation of the vagus nerve at relatively high voltages (e.g., >10 V) can induce bronchoconstriction. However, low voltage (≤2 V) vagus nerve stimulation (VNS) can attenuate histamine-invoked bronchoconstriction. Here, we identify the mechanism for this inhibition. In urethanea-nesthetized guinea pigs, bipolar electrodes were attached to both vagus nerves and changes in pulmonary inflation pressure were recorded in response to i.v. histamine and during VNS. The attenuation of the histamine response by low-voltage VNS was then examined in the presence of pharmacologic inhibitors or nerve ligation. Low-voltage VNS attenuated histamine-induced bronchoconstriction (4.4 ± 0.3 vs. 3.2 ± 0.2 cm H(2) O, p < 0.01) and remained effective following administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, and after sympathetic nerve depletion with guanethidine, but not after the β-adrenoceptor antagonist propranolol. Nerve ligation caudal to the electrodes did not block the inhibition but cephalic nerve ligation did. Low-voltage VNS increased circulating epinephrine and norepinephrine without but not with cephalic nerve ligation. These results indicate that low-voltage VNS attenuates histamine-induced bronchoconstriction via activation of afferent nerves, resulting in a systemic increase in catecholamines likely arising from the adrenal medulla.

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β(2)-adrenoceptor and a functional selectivity over β(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.