Isolated Guinea Pig Trachea Research Articles

In Silico and Ex Vivo Studies on the Spasmolytic Activities of Fenchone Using Isolated Guinea Pig Trachea.

Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K+ (25 mM), high K+ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration–response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K+ compared to high K+ with resultant EC50 values of 0.62 mg/mL (0.58–0.72; n = 5) and 6.44 mg/mL (5.86–7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K+ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K+ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K+ [6.28 mg/mL (5.88–6.42, n = 4); CCh] and [6.44 mg/mL (5.86–7.32; n = 5); high K+]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca2+ inhibitor which inhibited both CCh and high K+ at similar concentrations [10.46 µM (9.82–11.22, n = 4); CCh] and [10.28 µM (9.18–11.36; n = 5); high K+]. However, verapamil, a standard Ca2+ channel blocker, showed selectively higher potency against high K+ compared to CCh-mediated contractions with respective EC50 values of 0.84 mg/mL (0.82–0.96; n = 5) 14.46 mg/mL (12.24–16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca2+ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca2+ CRCs with suppression of maximum response, similar to verapamil, a standard Ca2+ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K+ channel activation followed by dual inhibition of PDE and Ca2+ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca2+ channel (−5.3 kcal/mol) and K+ channel (−5.7), which also endorsed the idea of dual inhibition.

Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PurposeIn this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. MethodsA rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. ResultsISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. ConclusionCollectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

Possible Tracheal Relaxant and Antimicrobial Effects of the Essential Oil of Ethiopian Thyme Species (Thymus serrulatus Hochst. ex Benth.): A Multiple Mechanistic Approach.

The genus Thymus is traditionally used for the treatment of hyperactive airways complaints. The purpose of the current study is to investigate the potential tracheal relaxant effect and possible mechanism(s) of the essential oil of Thymus serrulatus (TS Oil) in isolated guinea pig tracheal tissues. The essential oil was obtained from the fresh erial parts of Thymus serrulatus, and its phyto-components were identified by GC-MS analysis. Guinea pig tracheal preparations were used for testing the tracheal relaxant effect of TS Oil with the determination of the mechanism(s) involved in this relaxation. GC-MS findings reveal that terpenes, fragrance constituents, saponins, and higher fatty acids are present in TS Oil. In isolated guinea pig trachea, TS Oil inhibited carbachol (CCh, 1 µM) and K+ (80 mM)-induced contractions in a pattern similar to that of dicyclomine. TS Oil, at 0.3 mg/ml, shifted parallel CCh-curves towards the right, followed by a non-parallel shift at higher concentration (1 mg/ml), thus suppressing maximum response in the same manner as produced by dicyclomine. Pretreatment of tissues with TS Oil (1 and 3 mg/ml) also produced a rightward shift of Ca++ concentration-response curves (CRCs) in the same manner as caused by verapamil. Further, TS Oil at low concentrations (0.3 and 1 mg/ml) shifted isoprenaline-induced inhibitory CRCs towards the left and increased cAMP levels in isolated tracheal homogenates similar to papaverine, a phosphodiesterase (PDE) inhibitor. In the antimicrobial assay performed by the agar well diffusion method, TS Oil was found most active against Candida albicans and Staphylococcus aureus where the zone of inhibition measured was 28 mm. Additionally, there was little difference between standard strains of gram-positive and gram-negative bacteria. However, methicillin-resistant S. aureus (MRSA) showed a small zone of inhibition as compared to standard strains (22 mm). From these results, it can be concluded that the essential oil of T. serrulatus has the potential to produce antimicrobial effects while causing tracheal relaxation mediated possibly by anticholinergic effects, Ca++ channel blockade, and PDE inhibition whereas additional mechanism(s) cannot be ruled out.

Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists

A series of β2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β2-adrenoceptor and β1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β2-adrenoceptor agonistic effect with an EC50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β2-AR agonists.

Antiasthmatic effect of Curcuma aeruginosa extract on isolated organ of the trachea

Background:Asthma is a major health problem worldwide. Antiasthma drugs have side effects and can be expensive. It is important to develop antiasthma drugs from medicinal plants that have fewer side effects and are cheaper. One of the medicinal plants used for antiasthma treatment comes fromCurcuma aeruginosa(Zingiberaceaefamily). The aim of the research is to examine spasmolytic activity of ethanol extract ofC. aeruginosaon isolated guinea pig tracheas to determine the antiasthma effects.Methods:The spasmolytic activity ofC. aeruginosaextracts was tested in separated organs of guinea pig trachea. Guinea pig was sacrificed and its trachea rings were suspended in L-shaped wire loops in organ baths containing the Krebs solution aerated with carbogen. Isometric contractions of tracheal rings were measured by the transducer coupled to the amplifier. The trachea rings were exposed to DMSO as negative control, aminophylline as positive control andC. aeruginosaextracts. The single concentration-relaxation curve was obtained in every preparation.Results:The result showed that the decrease of the spasmolytic activity in the guinea pig tracheal tone due toC. aeruginosaextract was significantly better (p=0.022) when compared to the negative control. Meanwhile, the EC50value of aminophylline (0.019 ± 0.05) was not significantly different (p=0.454) withC. aeruginosa(0.024 ± 0.05).Conclusion:It could be concluded thatC. aeruginosaextracts have the potency to be further developed as a new natural source of the antiasthma agents.

Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists.

A series of novel β2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β2-adrenoceptor agonistic effects and high β2/β1-selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.

Anti-histaminic and bronchodilatory activities of aqueous and methanol extracts of <i>Calotropis procera</i> (Ait) R.Br. root bark on allergic asthma in rodents

The root bark of Calotropis procera (C. procera) (Asclepiadaceae) has been reported to be a part of herbal remedies for the management of allergic conditions including asthma. However, there is paucity of data on its anti-histaminic and bronhodilatory activity in asthma. This study therefore aimed to provide some pharmacological rationale for the ethnomedical use of C. procera as an anti-histamine and bronchodilator in asthma. The aqueous and methanol extracts of C. procera were investigated for anti-histaminic and bronchodilatory activities using histamine induced contraction of isolated guinea pig tracheal chain (at 0.5 ml, 1 ml and 2 ml, and stock concentration of 0.5 mg/ml), histamine induced contraction of isolated guinea pig ileum strip test (at 0.1, 0.2, 0.4, 0.8 and 1 ml, and stock concentration of 10 mg/ml), and haloperidol induced catalepsy test in rats (at 200 mg/kg and 300 mg/kg doses). Both extracts of C. procera significantly relaxed (p˂0.01) histamine induced contraction of isolated guinea pig trachea. The extracts also significantly inhibited (p˂0.001) histamine induced contraction of isolated guinea pig ileum. The aqueous extract did not significantly inhibit haloperidol-induced catalepsy. However, methanol extract significantly inhibited (p˂0.05) haloperidol-induced catalepsy at 300 mg/kg. The aqueous and methanol root bark extract of C. procera was found to poses anti-histaminic and bronchodilatory activities in in vivo and in vitro antiasthmatic test on animal models, with the methanol extract having greater activity than the aqueous extract, thus support the folkloric use of the plant in inflammatory and allergic conditions including asthma.Keywords: Calotropis procera, Anti-histaminic, Bronchorelaxant, Anti-asthmatic, Histamine

RELAXATION ACTIVITY OF TETANUS (LEEA AEQUATA L.) LEAF ETHANOLIC EXTRACT ON GUINEA PIG ISOLATED TRACHEA

Objective: The aim of this study is to determine the relaxation activity of the ethanolic extract of tetanus leaf (EETL) against contracting isolated guinea pig trachea induced by acetylcholine.Methods: Isolated trachea was equilibrated for 45 min until a stable condition in the Creb’s solution with a temperature of 37°C aerated with carbogen gas (O2:CO2=95%:5%). Test of the relaxation effect conducted after guinea pig trachea contracted with maximum acetylcholine concentration (EC80: 2.0449×10–3 mol) and then a cumulative with concentration of EETL (0.5 mg/mL–4 mg/mL) and concentration of atropine sulfate (6.95×10-6 mg/mL–2.08×10–2 mg/mL).Results: The results showed that EETL could lower the contraction smooth muscle of guinea pig trachea induced by acetylcholine. EETL at a concentration of 3.5 mg/mL had the ability to relax the muscle. It was not significantly different compared to that of atropine sulfate 6.95×10-3 mg/ mL (p>0.005).Conclusion: EETL has a relaxation effect on smooth muscle of guinea pig isolated trachea.

Pharmacological evaluation of Musa paradisiaca (Linn.) on bronchial asthma

Objective The present study was conducted to investigate the antiasthmatic potential from the flowers of Musa paradisiaca Linn. to validate its traditional claims. Materials and methods The antiasthmatic activity of the hydroalcoholic extract of M. paradisiaca flower (HMPF) was evaluated by studying histamine or acetylcholine-induced bronchospasm in guinea pigs, compound 48/80-induced mast cell degranulation in albino rats, and histamine-induced constriction in isolated guinea pig trachea. The preconvulsion dyspnea time at the 0th and seventh day at a dose of 200 and 400 mg/kg in guinea pigs, the percentage of granulated and degranulated mast cells at doses of 500, 750, and 1000 μg/ml in rats, and muscular contraction at doses of 500, 750, and 1000 μg/ml in isolated guinea pig trachea were evaluated and compared with their respective control groups. Results Phytochemical studies revealed the presence of flavonoids, steroids, saponin, terpenoids, lignins, and phenolic compounds in the extract. In addition, treatment with HMPF significantly ( P Conclusion The present study concluded that the antiasthmatic activity of the HMPF may be due to the presence of the above-mentioned phytoconstituents causing membrane stabilization, suppression of antibody production, and inhibition of antigen-induced histamine and acetylcholine.

Isoforskolin from Native Plant <i>Coleus forskohlii</i> of Yunnan, China Plays Multiple Biological Roles

Isoforskolin (ISOF) was isolated from Coleus forskohlii native to Yunnan in China. It is identified as one analog of diterpene forskolin (FSK) which comes from the Indian plant Coleus forskohlii. Researches found that the Yunnan native plant Coleus forskohlii contained rich ISOF but not FSK. ISOF was reported to activate adenylyl cyclase (AC) isoforms. The ophthalmologic and cardiovascular effects of ISOF were firstly reported in the 1990s. The researchers in Kunming, China, found ISOF could lower blood pressure and intraocular pressure. Recent researches found the respiratory tract effects of ISOF, and showed that ISOF significantly elevated cyclic adenosine monophosphate (cAMP) levels in rat lung homogenate, and relaxed the histamine-induced contraction of isolated guinea pig trachea and lung smooth muscle, isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (LPS) in several models, lowered LPS-induced secretion of the inflammatory cytokine in human monocytes.

The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough.

Cannabis has been demonstrated to have bronchodilator, anti-inflammatory, and antitussive activity in the airways, but information on the active cannabinoids, their receptors, and the mechanisms for these effects is limited. We compared the effects of Δ(9)-tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, cannabidiolic acid, and tetrahydrocannabivarin on contractions of the guinea pig-isolated trachea and bronchoconstriction induced by nerve stimulation or methacholine in anesthetized guinea pigs following exposure to saline or the proinflammatory cytokine, tumor necrosis factor α (TNF-α). CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), a synthetic cannabinoid agonist, was also investigated in vitro. The cannabinoids were also evaluated on TNF-α- and lipopolysaccharide-induced leukocyte infiltration into the lungs and citric acid-induced cough responses in guinea pigs. TNF-α, but not saline, augmented tracheal contractility and bronchoconstriction induced by nerve stimulation, but not methacholine. Δ(9)-Tetrahydrocannabinol and CP55940 reduced TNF-α-enhanced nerve-evoked contractions in vitro to the magnitude of saline-incubated trachea. This effect was antagonized by the cannabinoid 1 (CB(1)) and CB(2) receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-caroxamide] and JTE907 [N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide], respectively. Tetrahydrocannabivarin partially inhibited the TNF-α-enhanced nerve-evoked contractions, whereas the other cannabinoids were without effect. The effect of cannabidiol and Δ(9)-tetrahydrocannabinol together did not differ from that of the latter alone. Only Δ(9)-tetrahydrocannabinol inhibited TNF-α-enhanced vagal-induced bronchoconstriction, neutrophil recruitment to the airways, and citric acid-induced cough responses. TNF-α potentiated contractions of airway smooth muscle in response to nerve stimulation by enhancing postganglionic acetylcholine release. Δ(9)-Tetrahydrocannabinol and CP55940 inhibited the TNF-α-enhanced acetylcholine release, and hence contraction and bronchoconstriction, through activation of presynaptic CB(1) and CB(2) receptors. The other cannabinoids did not influence cholinergic transmission, and only Δ(9)-THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways.

Pharmacological evaluation of calendula officinalis L. on bronchial asthma in various experimental animals

Background: Calendula officinalis Linn. (Asteraceae) is an aromatic herb growing in the forests of India, China, Central Europe, and some tropical areas. The study was designed to investigate the scientific basis for the traditional claim of C. Officinalis on asthma. In the present study, methanol extract of whole plants was evaluated for preliminary phytochemical screening and antiasthmatic activity on different animals. Subjects and Methods: The asthmatic activity was evaluated by histamine- or acetylcholine-induced bronchospasm in guinea pigs, compound 48/80-induced mast cell degranulation in wistar rats, histamine-induced constriction on isolated guinea pig trachea, and ovalbumin-induced sensitization in mice at different dose levels of C. Officinalis. The preconvulsion dyspnoea time at 0 th and 7 th days at the dose of 250 and 500 mg/kg in guinea pig, the percentage of granulated and degranulated mast cell of at the dose of 600, 800, 1000 μg/mL in rats, muscular contraction at the dose of 600, 800, and 1000 μg/mL on isolated guinea pig trachea and the inflammatory cell count, that is, eosinophils, neutrophills, lymphocytes, macrophages, interleukin (IL)-4, IL-5, and immunoglobulin-E (IgE) from bronchoalveolar lavage fluid at the dose levels of 50, 100, and 250 mg/kg in mice were evaluated and compared with respective control groups. Results: Phytochemical studies revealed the presence of flavonoids, steroids, saponin, terpenoids, lignins, and phenolic compounds in the extract. In addition, the treatment of methanolic extract of C. officinalis (MECO) significantly (P < 0.001) decreased the bronchospasm induced by histamine or acetylcholine in guinea pigs, degranulation mast cell in rats, histamine-induced constriction on isolated guinea pig trachea, and the level of inflammatory cells as compared with inducer groups. The antiasthmatic activity was potentiated in all the doses in dose-dependent manner. Conclusion: The present study concludes that the antiasthmatic activity may be due to the presence of above phytoconstituents by antihistaminic, anticholinergic, antispasmodic, and mast cell stabilizing property.

General pharmacological studies on pepleomycin sulfate (NK 631) (author's transl)

Pharmacological actions of pepleomycin sulfate (NK 631) which is a new antitumor agent derived from bleomycin were studied and the following results were obtained. NK 631 had no significant influences on the central, motor and sensory nervous systems at relatively higher doses (5 approximately 10 mg/kg, i.v., i.p., s.c.). NK 631 (5 approximately 10 mg/kg, i.v.) caused a slight decrease in blood pressure in anesthetized rats and slight increases in blood pressure, heart rate and peripheral blood flow in anesthetized dogs. NK 631 (1 approximately 3 mg) given close-arterially caused a slight increase in the developing tension in the isolated blood-perfused papillary muscle. NK 631 slightly contracted the isolated guinea pig ileum and rat uterus but did not affect the contraction of isolated guinea pig trachea. NK 631 caused significant increases in urine output and Cl excretion in saline loaded rats at 20 mg/kg, i.p. By the local injection of NK 631, a slight edema of rat paw and an increase in rabbit cutaneous permeability were observed. The intraperitoneal injection of NK 631 caused a significant increase in leakage of dye injected intravenously into the peritoneal cavity of mice. NK 631 did not affect hemolysis and prothrombin time at 10(-4) g/ml. In pharmacological actions, significant differences between NK 631 and pepleomycin were not observed.

Spasmolytic effect of novel antagonists of the adenosine A2 receptor in isolated guinea pig tracheal smooth muscle

We have investigated the relaxation effect of nine novel adenosine A2B antagonists on precontracted guinea pig tracheas by carbachol (10μM). Isometric contractions of isolated guinea pig tracheas were recorded at 2g resting tension; and carbachol dose-response curves were performed. EC50 and IC50 values were identified by plotting cumulative concentration-response curve and pD2 values were calculated. Theophylline was able to relax carbachol precontracted tracheas on 10−3 M conc. The relaxant effect of 1×10−4M compound 5 (ARR-1) was found highly significant as compared to theophylline (P<0.001), whereas compound 6 (ARR-2) showed equipotent effect in a concentration dependent manner. However, other compounds were not able to attenuate contractions induced by carbachol significantly as compared to theophylline. Compound 5 (ARR-1) may be an important new compound in testing the current hypotheses proposing a therapeutic role for an adenosine antagonist in asthma. This effect might be attributed to inhibition of cAMP through adenyl cyclase enzyme. The results exclude an important contribution of adenosine A2B receptors.

Evaluation of antiasthmatic activity of ethanolic extract of Elephantopus scaber L. leaves.

Aims:The aim of study was to evaluate the scientific basis for the traditional use of Elephantopus scaber leaves.Materials and Methods:In the present study, ethanol extract of Elephantopus scaber leaves was evaluated for preliminary phytochemical screening and antiasthmatic activity using histamine and acetylcholine-induced bronchospasm, mast cell degranulation and histamine induced constriction on isolated guinea pig tracheal chain at different dose levels. Student's t-Test and Dunett's test were used for statistical analysis.Results:The result of present investigation showed that the ethanolic extract of E. scaber significantly (P<0.001) decreased the bronchospasm induced by histamine, acetylcholine and protected mast cell degranulation as compared to control groups. It also decreased the histamine induce constriction on isolated guinea pig trachea in dose-dependent manner. Phytochemical studies revealed the presence of steroids, saponin, flavonoids, and phenolic compounds in the extract.Conclusions:The present study concludes that the antiasthmatic activity of ethanolic extract of E. scaber leaves may be due to the presence of flavonoids or steroids. Antiasthmatic action of the E. scaber could be due to its antihistaminic, anticholinergic and mast-cell-stabilizing property.

Synthesis and Biological Activities of Some Thiazolidin-4-ones

In this study, fifteen 2,3-disubstituted-4-thiazolidinone derivatives were synthesized by the reaction of Schiff bases and alpha-mercaptoacetic acid. The structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR, mass spectral data and elementary analysis. The antihistaminic and anticholinergic activities of the compounds were determined by tests performed on isolated guinea pig trachea in comparison with aminophylline (CAS 317-34-0). Compound 15 (3-[3-(2-methyl-piperidine-1-yl)propyl]-2-(4-methyl-phenyl)thiazolidin-4-one hydrochloride) showed the highest inhibition (53 %).

Alterations of in-vitro 5-HT receptor pharmacology as a function of multiple treatment with 5-hydroxytryptamine or 8-hydroxy-2-(di-N-propylamino) tetralin in rat isolated aorta, uterus and fundus, and guinea-pig isolated trachea.

The effects of single and multiple (5, 10, or 15 days) administration of the 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (3 mg kg-1, i.p.) or 5-HT (3 mg kg-1, i.p.) in-vivo on the response of selected isolated smooth muscles to 5-HT in-vitro were investigated. Single dosing with 8-OH-DPAT did not alter the responses of the isolated tissues (rat aorta, uterus or fundus, or guinea-pig trachea) to 5-HT, while multiple dosing with 8-OH-DPAT produced rightward shifts and a suppression of the maximum response of all these tissues to 5-HT, with the exception of the rat stomach fundus. Multiple administration of 5-HT had no effect on the in-vitro response of the tissues to 5-HT. These data indicate that multiple administration of 8-OH-DPAT desensitizes or down-regulates the peripheral 5-HT2 receptors found on the rat aorta and uterus, and guinea-pig trachea.

Targeting the toll-like receptor 7 pathway in asthma: a potential immunomodulatory approach?

In allergic airways, as in asthma, inflammation and impaired functioning of toll-like receptor 7 (TLR7) has been found. The augmentation of this receptor with agonist compounds resulted in bronchodilation and a switch of the TH2 inflammatory pattern, specific for allergic conditions, to TH1 inflammation, characterised by an increased production of interferon-γ. This was a preclinical study evaluating the effects of two TLR7 agonists, imiquimod and resiquimod, on the isolated guinea pig trachea. The TLR7-related downstream signalling pathways were also assessed. Both TLR7 agonists were shown to reduce serotonin-induced bronchoconstriction, which is possibly exerted via the p38MAPK and NF-κB pathways. Therapeutic targeting of TLR7 with specific agonists might represent a promising immunomodulatory approach in asthma, especially if systemic exposure is minimised with inhaled formulations.

Relaxant Effect of Quinoline Derivatives on Histamine-induced Contraction of the Isolated Guinea Pig Trachea

Separation of active component derived from the methanol extract of Ruta chalepensis leaves was performed base on anti-asthma activities. Quinoline was isolated from the extract of R. chalepensis leaves through bioassay-guided fractionation. Quinoline had a strong relaxant effect (IC50=0.42 mM) on the contractile activity of the isolated guinea pig trachea, and this relaxant effect was compared to that of five commercially available compounds. The structure-activity relationship revealed that quinoxaline (IC50=0.46 mM) and quinazoline (IC50=0.48 mM) have strong relaxant effects. The results indicated that R. chalepensis extract and quinoline derivatives have anti-asthma activity.

Biphasic Tracheal Relaxation Induced by Higenamine and Nantenine From Nandina domestica THUNBERG

We compared the effects of the extract from fruits of Nandina domestica THUNBERG (NDE) and its constituents, higenamine and nantenine, on contractile responses in isolated guineapig trachea. NDE (1 mg/ml) caused biphasic relaxation of the trachea precontracted with high-K+ stimulation: the fast component was blocked by propranolol and mimicked by higenamine; and the slow was resistant to propranolol and mimicked by nantenine. Ca2+-induced contraction under high-K+ stimulation was antagonized by nantenine or NDE + propranolol. These results suggest that NDE relaxes the trachea quickly through β-adrenoceptor stimulation by higenamine and slowly through Ca2+ antagonism by nantenine.