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1.
Lung ; 196(2): 219-229, 2018 04.
Article in English | MEDLINE | ID: mdl-29380034

ABSTRACT

Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.


Subject(s)
Airway Resistance/drug effects , Bethanechol/toxicity , Bronchial Hyperreactivity/chemically induced , Bronchoconstriction/drug effects , Cytokines/metabolism , Lung/drug effects , Muscarinic Agonists/toxicity , Transcriptional Activation/drug effects , Administration, Inhalation , Animals , Animals, Newborn , Bethanechol/administration & dosage , Bronchial Hyperreactivity/metabolism , Bronchial Hyperreactivity/physiopathology , Cytokines/genetics , Inflammation Mediators/metabolism , Lung/metabolism , Lung/physiopathology , Muscarinic Agonists/administration & dosage , Sus scrofa , Up-Regulation
2.
Chem Biol Interact ; 180(2): 312-7, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19497430

ABSTRACT

As part of our continuing search for bioactive natural products from plants, the present study was carried out in order to evaluate the gastroprotective properties of alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora (Rutaceae). Anti-ulcer assays were performed using the following protocols in mice: nonsteroidal anti-inflammatory drug (NSAID)/bethanecol-induced ulcer, ethanol/HCl-induced ulcer, and stress-induced ulcer. The effects of the extract on gastric content volume, pH and total acidity were also evaluated, using the pylorus ligated model. Treatment using doses of 50, 125 and 250 mg/kg of G. longiflora alkaloid extract and positive controls (omeprazol or cimetidine) significantly diminished the lesion index, total lesion area, and percentage of lesion, in comparison with the negative control groups in all the models evaluated. Regarding the model of gastric secretion, a reduction in volume of gastric juice and total acidity was observed, as well as an increase in gastric pH. The main alkaloid of the plant, 2-phenylquinoline, was also evaluated in the ethanol-induced ulcer model. The results showed that at a dose of 50 mg/kg, it significantly inhibited ulcerative lesions. However, this effect was less than that of the alkaloid extract. All these results taken together show that G. longiflora displays gastroprotective activity, as evidenced by its significant inhibition of the formation of ulcers induced by different models. There are indications that mechanisms involved in anti-ulcer activity are related to a decrease in gastric secretion and an increase in gastric mucus content. Also, there is evidence of involvement of NO in the gastroprotector mechanisms. These effects may be attributed, at least in part, to the presence of some alkaloids, particularly 2-phenylquinoline.


Subject(s)
Alkaloids/pharmacology , Plant Extracts/pharmacology , Quinolines/pharmacology , Rutaceae/chemistry , Stomach Ulcer/prevention & control , Alkaloids/chemistry , Animals , Anti-Ulcer Agents/chemistry , Anti-Ulcer Agents/pharmacology , Bethanechol/toxicity , Dose-Response Relationship, Drug , Ethanol/toxicity , Hydrochloric Acid/toxicity , Indomethacin/toxicity , Mice , Molecular Structure , Plant Bark/chemistry , Plant Extracts/chemistry , Quinolines/chemistry , Rats , Rats, Wistar , Stomach Ulcer/chemically induced
3.
J Pharmacol Toxicol Methods ; 52(1): 83-9, 2005.
Article in English | MEDLINE | ID: mdl-15914033

ABSTRACT

INTRODUCTION: The ICH guideline S7A recommends that the effects of drugs on the respiratory system are evaluated in laboratory mammals prior to administration in man. Previously, animals have been placed in plethysmography chambers for short durations. This study investigates the possibility of restraining animals in chambers for a longer duration to assess respiratory function over extended periods. METHODS: Respiratory function in conscious rats was assessed using plethysmography chambers where the rat body was enclosed in a sealed chamber while the head was free. Thoracic movements were measured by pressure transducers linked to a Buxco amplifier system and respiratory parameters were captured and analyzed by the Notocord HEM data acquisition system. Each animal was subjected to 5 acclimatization sessions of escalating duration (1, 2, 4, 5, and 6 hours (h)) over 5 days prior to testing, with a baseline recording session conducted the day prior to dosing. Animals (8 males/group) were dosed subcutaneously with saline or bethanecol (3, 10, or 30 mg/kg) and placed in the chambers for 6 h of continuous recording. Additionally, a recording session was conducted at 24 h post-dose. RESULTS: Subcutaneous administration of 30 mg/kg bethanecol decreased respiration rate by up to 33% during the first 1.5 h post-dose and increased tidal volume by up to 46% from 0.25 to 1.25 h post-dose when compared to vehicle group data. A decrease in minute volume of up to 33% was observed 0.25 h following administration of the 10 and 30 mg/kg doses. DISCUSSION: These data show a respiratory depression caused by the cholinergic agonist bethanecol, an effect partially compensated for by an increase in tidal volume. This also demonstrates the ability to continuously restrain and record respiratory parameters in conscious rats for up to 6 h without any negative impact on the quality of the data.


Subject(s)
Bethanechol/toxicity , Drug Evaluation, Preclinical/methods , Drug-Related Side Effects and Adverse Reactions , Muscarinic Agonists/toxicity , Respiratory Physiological Phenomena/drug effects , Animals , Injections, Subcutaneous , Male , Plethysmography, Whole Body/methods , Rats , Rats, Sprague-Dawley , Restraint, Physical , Tidal Volume/drug effects
4.
Eur J Pharmacol ; 292(1): 47-55, 1994 Nov 01.
Article in English | MEDLINE | ID: mdl-7532588

ABSTRACT

Mechanisms for the hypertrophy of rat pancreas induced by long-term administration of bethanechol were investigated. The administration of bethanechol, an acetylcholine receptor agonist, to male Wistar rats for 14 days induced significant increases in the pancreatic weight and contents of protein, amylase and RNA in the pancreas without altering the content of DNA and the incorporation of [3H]thymidine into DNA. Simultaneous administration of atropine with bethanechol suppressed the bethanechol-induced pancreatic hypertrophy. Long-term administration of other acetylcholine receptor agonists also showed similar effects as produced by bethanechol. CR1505 (loxiglumide; D,L-4-(3,4-dichlorobenzoyl-amino)-5-(N-3-methoxypropyl-pentylam ino)-5- oxopentanoic acid), an antagonist of cholecystokinin receptors, inhibited pancreatic growth induced by long-term administation of pentagastrin, whereas pancreatic hypertrophy induced by bethanechol was not inhibited by CR1505. These results suggest that long-term administration of bethanechol induces pancreatic hypertrophy through direct activation of muscarinic receptors in the pancreas.


Subject(s)
Bethanechol/toxicity , Pancreas/drug effects , Pancreas/pathology , Amylases/blood , Amylases/metabolism , Animals , Atropine/therapeutic use , Cholinergic Agonists , Cholinergic Antagonists , Drug Administration Schedule , Drug Interactions , Gastrins/pharmacology , Hypertrophy/chemically induced , Hypertrophy/prevention & control , Male , Organ Size/drug effects , Pentagastrin/pharmacology , Proglumide/analogs & derivatives , Proglumide/toxicity , Rats , Rats, Wistar , Receptors, Cholecystokinin/antagonists & inhibitors , Receptors, Cholecystokinin/metabolism , Sincalide/pharmacology
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