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

2021 ◽  
Author(s):  
Mariska van den Berg ◽  
Susan Nijboer - Brinksma ◽  
Sophie Bos ◽  
Maarten van den Berge ◽  
David Lamb ◽  
...  
Keyword(s):  
Pilot Study ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Chronic Respiratory Disease ◽  
The Novel ◽  
Airway Narrowing

Abstract Background: Asthma 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 in against AHR and inflammation guinea-pig models of asthma.Methods: First, 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.Results: A 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.Conclusions: TRPA1 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.

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

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mariska P. M. van den Berg ◽  
Susan Nijboer-Brinksma ◽  
I. Sophie T. Bos ◽  
Maarten van den Berge ◽  
David Lamb ◽  
...  
Keyword(s):  
Pilot Study ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Chronic Respiratory Disease ◽  
The Novel ◽  
Airway Narrowing

Abstract Background Asthma 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. Methods First, 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. Results A 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. Conclusions TRPA1 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.

scholarly journals The Novel TRPA1 Antagonist BI01305834 Inhibits Ovalbumin-Induced Bronchoconstriction in Guinea Pigs

2020 ◽  
Author(s):  
Mariska van den Berg ◽  
Susan Nijboer - Brinksma ◽  
Sophie Bos ◽  
Maarten van den Berge ◽  
David Lamb ◽  
...  
Keyword(s):  
Pilot Study ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Ex Vivo ◽  
Optimal Dose ◽  
Pig Model ◽  
The Novel ◽  
Airway Narrowing ◽  
Guinea Pig Model

Abstract Background: We hypothesized that TRPA1 channels contribute to airway hyperresponsiveness (AHR) and inflammation in asthma. We evaluated the efficacy of the novel TRPA1 antagonist BI01305834 in a guinea pig model of asthma. Methods: First 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 AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), magnitude of EAR and LAR and 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.Results: A 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.Conclusions: TRPA1 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.

TRPA1 in bradykinin-induced mechanical hypersensitivity of vagal C fibers in guinea pig esophagus

2009 ◽  
Vol 296 (2) ◽  
pp. G255-G265 ◽  
Author(s):  
Shaoyong Yu ◽  
Ann Ouyang
Keyword(s):  
Guinea Pig ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Peripheral Sensitization ◽  
Nerve Terminals ◽  
Mechanical Hypersensitivity ◽  
C Fibers

Bradykinin (BK) activates sensory nerves and causes hyperalgesia. Transient receptor potential A1 (TRPA1) is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception. TRPA1 can be activated by BK. TRPA1 knockout mice show impaired responses to BK and mechanical nociception. However, direct evidence from sensory nerve terminals is lacking. This study aims to determine the role of TRPA1 in BK-induced visceral mechanical hypersensitivity. Extracellular recordings of action potentials from vagal nodose and jugular neurons are performed in an ex vivo guinea pig esophageal-vagal preparation. Peak frequencies of action potentials of afferent nerves evoked by esophageal distension and chemical perfusion are recorded and compared. BK activates most nodose and all jugular C fibers. This activation is repeatable and associated with a significant increase in response to esophageal distension, which can be prevented by the B2 receptor antagonist WIN64338. TRPA1 agonist allyl isothiocyanate (AITC) activates most BK-positive nodose and jugular C fibers. This is associated with a transient loss of response to mechanical distensions and desensitization to a second AITC perfusion. Desensitization with AITC and pretreatment with TRPA1 inhibitor HC-030031 both inhibit BK-induced mechanical hypersensitivity but do not affect BK-evoked activation in nodose and jugular C fibers. In contrast, esophageal vagal afferent Aδ fibers do not respond to BK or AITC and fail to show mechanical hypersensitivity after BK perfusion. This provides the first evidence directly from visceral sensory afferent nerve terminals that TRPA1 mediates BK-induced mechanical hypersensitivity. This reveals a novel mechanism of visceral peripheral sensitization.

INHIBITION OF GUINEA-PIG PLATELET FUNCTION IN VIVO AND EX VIVO USING THE THROMBOXANE A2 ANTAGONISTS, AH23848 AND GR32191

1987 ◽  
Author(s):  
P J McCabe ◽  
L E Stratton ◽  
E J Hornby ◽  
M Foster
Keyword(s):  
Platelet Aggregation ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Ex Vivo ◽  
Thromboxane A2 ◽  
In Vivo Studies ◽  
Maximum Inhibition ◽  
Platelet Deposition ◽  
Oral Doses

The thromboxane A2 antagonist, GR32191 (Lumley et al., this meeting) was tested as an inhibitor of platelet aggregation in the guinea-pig and compared with another Tx-antagonist, AH23848 (Brittain et al, 1985). Guinea-pigs were dosed with AH23848 or GR32191 at 0.01-1.0mg/kg. At intervals, blood was taken and PRP was prepared for ex vivo aggregation studies. Collagen concentrations causing half maximal aggregation (IC50) were calculated for test and vehicle-dosed groups. Inhibition was expressed as a concentration ratio (IC50 test/IC50 vehicle). For in vivo studies, 111In-labelled platelets (12μCi, 200μl) were injected into anaesthetised guinea-pigs and 24 hrs later oral doses of AH23848 or GR32191 (0.01-1.0mg/kg) or indomethacin (5mg/kg) were given. After one hour, blood was taken for platelet and radioactivity counting. The carotid artery was exposed under anaesthesia and a current of 2mA was applied for 60 sec. After 90 min, 1cm of the damaged and contralateral carotid vessels were removed for gamma-counting. Inhibition of accumulation of platelets on the injured artery was measured by comparison with the undamaged contralateral artery. Numbers of platelets deposited were calculated from the radioactivity of each section of artery and the radioactivity and platelet count in the blood. Oral doses of AH23848 or GR32191 inhibited ex vivo platelet aggregation induced by collagen. Maximum inhibition occurred one hour after dosing, and was still present at 6 hours for AH23848 (l.Omg/kg) and GR32191 (0.3mg/kg). GR32191 and AH23848 were active in vivo causing inhibition of platelet deposition at doses of 0.01-lmg/kg. The maximum inhibition of deposition was 58% for AH23848 (0.1mg/kg) and 63% for GR32191 (0.1mg/kg), with 50% inhibition at 0.02mg/kg for both. Indomethacin (5mg/kg p.o.) caused maximum inhibition of 58% at 5mg/kg p.o. suggesting that this represents the total thromboxane involvement in platelet deposition. GR32191 and AH23848 are thromboxane A2 antagonists with antithrombotic activity after oral dosing to guinea-pigs.Brittain R.T. et al Circulation, 72, 1208-1218, 1985.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

scholarly journals EVIDENCE THAT THE L-ASPARAGINASE OF GUINEA PIG SERUM IS RESPONSIBLE FOR ITS ANTILYMPHOMA EFFECTS

1963 ◽  
Vol 118 (1) ◽  
pp. 99-120 ◽  
Author(s):  
J. D. Broome
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Serum Proteins ◽  
Deae Cellulose ◽  
Salt Precipitation ◽  
Asparaginase Activity ◽  
Pig Serum

A number of the properties of the L-asparaginase present in guinea pig serum have been examined and shown to be indistinguishable from those of the agent responsible for inhibiting cells of lymphoma 6C3HED in vivo. The patterns of instability of the enzyme to changes in temperature and pH were found to parallel closely those of the antilymphoma agent. L-Asparaginase activity was essentially absent from the serum of newborn guinea pigs and this failed to inhibit 6C3HED cells. On separating guinea pig serum proteins by salt precipitation, electrophoresis, and chromatography on DEAE cellulose, antilymphoma activity was found only in fractions which contained L-asparaginase.

scholarly journals Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways

2008 ◽  
Vol 155 (4) ◽  
pp. 547-557 ◽  
Author(s):  
M G Belvisi ◽  
H J Patel ◽  
V Freund-Michel ◽  
D J Hele ◽  
N Crispino ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Inhibitory Activity ◽  
Receptor Agonist ◽  
Sensory Nerve ◽  
The Novel ◽  
Nerve Function ◽  
Cb2 Receptor

scholarly journals Encapsulated cyclosporine does not change the composition of the human microbiota when assessed ex vivo and in vivo

2020 ◽  
Vol 69 (6) ◽  
pp. 854-863
Author(s):  
Catherine O'Reilly ◽  
Órla O’Sullivan ◽  
Paul D. Cotter ◽  
Paula M. O’Connor ◽  
Fergus Shanahan ◽  
...  
Keyword(s):  
Pilot Study ◽  
Gut Microbiota ◽  
Targeted Delivery ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Microbiota Composition ◽  
Faecal Samples

Introduction. Management of steroid-refractory ulcerative colitis has predominantly involved treatment with systemic cyclosporine A (CyA) and infliximab. Aim. The purpose of this study was to assess the effect of using a colon-targeted delivery system CyA formulation on the composition and functionality of the gut microbiota. Methodology. Ex vivo faecal fermentations from six healthy control subjects were treated with coated minispheres (SmPill) with (+) or without (−) CyA and compared with a non-treated control in a model colon system. In addition, the in vivo effect of the SmPill+CyA formulation was investigated by analysing the gut microbiota in faecal samples collected before the administration of SmPill+CyA and after 7 consecutive days of administration from eight healthy subjects who participated in a pilot study. Results. Analysis of faecal samples by 16S rRNA gene sequencing indicated little variation in the diversity or relative abundance of the microbiota composition before or after treatment with SmPill minispheres with or without CyA ex vivo or with CyA in vivo. Short-chain fatty acid profiles were evaluated using gas chromatography, showing an increase in the concentration of n-butyrate (P=0.02) and acetate (P=0.32) in the faecal fermented samples incubated in the presence of SmPill minispheres with or without CyA. This indicated that increased acetate and butyrate production was attributed to a component of the coated minispheres rather than an effect of CyA on the microbiota. Butyrate and acetate levels also increased significantly (P=0.05 for both) in the faecal samples of healthy individuals following 7 days’ treatment with SmPill+CyA in the pilot study. Conclusion. SmPill minispheres with or without CyA at the clinically relevant doses tested here have negligible direct effects on the gut microbiota composition. Butyrate and acetate production increased, however, in the presence of the beads in an ex vivo model system as well as in vivo in healthy subjects. Importantly, this study also demonstrates the relevance and value of using ex vivo colon models to predict the in vivo impact of colon-targeted drugs directly on the gut microbiota.

scholarly journals No Relationship Between Perceived Health Anomalies and Perceived Experimental Success in Retired Breeder Male Hartley Albino Guinea Pigs

2020 ◽  
Author(s):  
Chandra B. Bain ◽  
Julie M. Settlage ◽  
Grace A. Blair ◽  
Steven Poelzing
Keyword(s):  
Guinea Pig ◽  
Hair Loss ◽  
Guinea Pigs ◽  
Ex Vivo ◽  
Perceived Health ◽  
Electrophysiological Recordings ◽  
Electrophysiological Studies ◽  
Monthly Pattern ◽  
Time Of Year ◽  
Whole Heart

ABSTRACTGuinea pigs used in our laboratory for cardiac research sometimes exhibit physical abnormalities. These issues may abate or intensify during the time they are housed in our facility. After using a guinea pig for research, experimentalists note the apparent health of an animal based on visible features and/or abnormal electrophysiology of the heart. There was an existing anecdotal observation that the health of the Guinea Pigs, and subsequently the experimental success rate, had a seasonal variation; therefore we sought to determine if there is a time of year in which our guinea pigs are more likely to be perceived as unhealthy, and whether any determined monthly pattern correlates with an experimentalist’s ability to complete an experimental protocol. An electronic log was created to record the perceived health of the animal and the ability to complete the experiment successfully. Irregular symptoms included, but were not limited to, severe weight or hair loss and irregularities with the heart found post thoracotomy or during baseline electrophysiological recordings of whole-heart preparations. Animals that did not exhibit significant weight or hair loss, or other ailments were considered “healthy”. Overall, our results indicate that there are no monthly variations in perceived Hartley Albino guinea pig health or correlations with experimental completion rates, suggesting mild hair or weight loss that is common when shipping animals may not significantly affect the ability to conduct ex vivo whole-heart electrophysiological studies.

scholarly journals Effects of an antiplatelet glycoprotein Ib antibody on hemostatic function in the guinea pig

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 690-694 ◽  
Author(s):  
BH Becker ◽  
JL Miller
Keyword(s):  
Animal Model ◽  
Platelet Count ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Bleeding Time ◽  
Model System ◽  
Platelet Counts ◽  
Equal Dose ◽  
Guinea Pig Model

Abstract Previous studies in the guinea pig model system have established a close structural homology between human and guinea pig glycoproteins Ib (GPIb) and IIb/IIIa (GPIIb/IIIa). Moreover, the murine monoclonal antibody (MoAb) PG-1, which recognizes GPIb in guinea pig platelets and megakaryocytes, exerted full inhibition on von Willebrand factor (vWF)- dependent platelet agglutination without inhibiting aggregation induced by ADP, collagen, or thrombin. The present research extends this animal model system to study of the effects on hemostatic function following the in vivo injection of MoAb PG-1 or its F(ab')2 fragments. A hind limb template bleeding time methodology was developed for use in guinea pigs. Normal bleeding time was determined to be 2.7 +/- 0.5 minutes (mean +/- SD), with an observed range of two to four minutes. Platelet counts in these same animals were 501 +/- 82 x 10(3)/microL. After intraperitoneal (IP) injection of busulfan, guinea pigs became increasingly thrombocytopenic. As long as the platelet count remained above approximately 150 x 10(3)/microL, the bleeding time was not more than five minutes; however, further decrease in the platelet count was accompanied by more marked prolongations of the bleeding time. For 14 to 72 hours after IP injection of 1.3 mg/kg intact PG-1 MoAb, a hemorrhagic state was produced with a bleeding time greater than 20 minutes. The platelet count concurrently decreased to approximately 50% of its baseline value but could not be further decreased either by raising the initial PG-1 dosage tenfold or by administering a second, equal dose 24 hours after the initial injection. This finding may reflect a heterogeneity of circulating platelets with respect to GPIb, to Fc receptors, or to an interaction between them. After IP injection of 0.63 to 2.5 mg/kg PG-1 F(ab')2 fragment, platelet counts did not decrease more than 21% below baseline levels in a 72-hour period, and bleeding times never increased by more than one minute over baseline values. Nevertheless, platelets obtained from animals 24 hours after injection of 2.5 mg/kg PG-1 F(ab')2 showed full inhibition of agglutination induced by ristocetin. The response of these platelets to aggregation by asialo-vWF was also severely inhibited as compared with control platelets. PG-1 F(ab')2 produced no effect on aggregation induced by ADP. These studies show that virtually complete functional block of the vWF receptor by F(ab')2 fragments of the anti-GPIb MoAb PG- 1 is not sufficient to produce a hemorrhagic state in the guinea pig animal model system.

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