scholarly journals Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea-Pigs

1999 ◽  
Vol 8 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Nöella Germain ◽  
Elisabeth Boichot ◽  
Jean-Michel Planquois ◽  
Vincent Lagente
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Response Curve ◽  
Pde5 Inhibitor ◽  
Pde4 Inhibitor ◽  
Potential Utility ◽  
Phosphodiesterase 3 ◽  
Pde Inhibitors ◽  
Pde3 Inhibitor

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48 h after OA, a significant reduction (p<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (p<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

scholarly journals THE EFFECTS OF DRUGS UPON A GRADED COUGH RESPONSE OBTAINED IN SENSITIZED GUINEA PIGS EXPOSED TO AEROSOL OF SPECIFIC ANTIGEN

1955 ◽  
Vol 101 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Charles A. Winter ◽  
Lars Flataker
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Small Dose ◽  
Response Curve ◽  
Specific Antigen ◽  
Limited Range ◽  
Dose Response Curve ◽  
Cough Response ◽  
Antitussive Drugs ◽  
Antihistaminic Drug

A technique is described for measuring objectively and quantitatively the reaction of sensitized guinea pigs when exposed to an aerosol of specific antigen. The principle involves registration by semi-automatic means of the number of coughs produced in animals passively sensitized with known amounts of antibody. The number of coughs is shown to be linearly related to log dose of antibody within a limited range and a dose-response curve is presented. The cough produced by this procedure is not inhibited by the antitussive drugs, codeine and propadrine, but can be inhibited by anti-allergic agents, such as cortisone and an antihistaminic drug. It is also inhibited by narcotine. The last is the only compound so far tested which suppresses both the cough produced by this procedure and that produced by a simple irritant. The action of cortisone and the antihistaminic drug, pyrilamine, is shown to be synergistic. A small dose of pyrilamine in animals pretreated with cortisone gives a degree of inhibition which cannot be obtained by increasing the dose of pyrilamine in animals not treated with cortisone.

scholarly journals Pro-cognitive effect of upregulating cyclic guanosine monophosphate signalling during memory acquisition or early consolidation is mediated by increased AMPA receptor trafficking

2019 ◽  
Vol 34 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Elentina K Argyrousi ◽  
Pim RA Heckman ◽  
Britt TJ van Hagen ◽  
Hannah Muysers ◽  
Nick P van Goethem ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Molecular Mechanisms ◽  
Memory Function ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Pde4 Inhibitor ◽  
Cognitive Effect ◽  
Pde Inhibitors ◽  
Memory Acquisition

Background: Episodic memory consists of different mnemonic phases, including acquisition and early and late consolidation. Each of these phases is characterised by distinct molecular processes. Although both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are implicated in the acquisition phase, early consolidation only depends on cGMP, whereas late consolidation is mediated by cAMP. Accordingly, the cGMP-selective phosphodiesterase 5 (PDE5) inhibitor vardenafil or the cAMP-selective PDE4 inhibitor rolipram can improve memory acquisition or consolidation when applied during their respective time windows. Aims: Considering the important role of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) during normal memory function, we aimed to investigate whether the differential actions of these PDE inhibitors are mediated through AMPAR dynamics. Methods: For biochemical analysis, mice were treated with either vardenafil or rolipram and sacrificed shortly after injection. For the behavioural studies, mice received either of the inhibitors during the different mnemonic phases, while their spatial memory was tested using the object location task, and they were sacrificed 24 hours later. Results: Administration of either vardenafil or rolipram causes rapid changes in AMPARs. Moreover, treatment with vardenafil during the acquisition or early consolidation of spatial memory resulted in increased surface levels of AMPARs which were still augmented 24 hours after learning. Membrane levels of AMPARs were not affected anymore 24 hours after learning when rolipram was administrated at either the acquisition or late consolidation phase. Conclusions: These results suggest that dissociative molecular mechanisms could mediate the pro-cognitive function of different classes of PDE inhibitors, and in the case of vardenafil, this phenomenon could be explained by changes in AMPAR dynamics.

Enhanced airway responses to substance P after repeated challenge in guinea pigs

1989 ◽  
Vol 66 (2) ◽  
pp. 955-961 ◽  
Author(s):  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Enzyme Inhibitor ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Dose Response Curves ◽  
Airway Responses

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.

Repeated antigen challenge induces airway hyperresponsiveness with tissue eosinophilia in guinea pigs

1989 ◽  
Vol 67 (3) ◽  
pp. 1133-1139 ◽  
Author(s):  
K. Ishida ◽  
L. J. Kelly ◽  
R. J. Thomson ◽  
L. L. Beattie ◽  
R. R. Schellenberg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Blood Gas Analysis ◽  
Neutrophil Infiltration ◽  
Gas Analysis ◽  
Antigen Challenge ◽  
Response Curves ◽  
Tissue Eosinophilia ◽  
Antigenic Exposure

To test the hypothesis that the development of airway hyperresponsiveness (AHR) lasting greater than or equal to 3 days after the last antigenic exposure required repeated mediator release, we compared dose-response changes in lung resistance (RL) to acetylcholine (ACh) in animals sensitized with 1% ovalbumin (OA), 4% Bordatella pertussis aerosol and subsequently challenged with 0.5% OA aerosol twice weekly for 4–6 wk vs. animals receiving saline aerosol instead of OA. Despite antihistamine pretreatment, each OA challenge produced cyanosis and inspiratory indrawing. Blood gas analysis in six guinea pigs revealed an immediate fall in arterial PO2 (PaO2) from 104.3 +/- 4.9 to 35.4 +/- 2.2 Torr after a 1-min exposure to aerosolized OA. ACh dose-response measurements of RL 3 days after the last OA challenge demonstrated a leftward shift and an increased magnitude of response. These differences were less marked at 7 days, and by 14 days after the last OA challenge, ACh dose-response curves were not different from those of control guinea pigs. Sensitization without repeated antigen challenge did not cause hyperresponsiveness. Morphometric analysis showed significantly increased numbers of eosinophils in the epithelium of airways in hyperresponsive guinea pigs, without neutrophil infiltration or alterations in epithelium and airway wall areas. We conclude that repeated antigenic challenge, but not sensitization alone, causes prolonged AHR in guinea pigs, which is associated with tissue eosinophilia.

Dose‐response relationship of ozone‐induced airway hyperresponsiveness in unanesthetized guinea pigs

1990 ◽  
Vol 30 (2) ◽  
pp. 123-134 ◽  
Author(s):  
Masanori Nishikawa ◽  
Shunsuke Suzuki ◽  
Hirotada Ikeda ◽  
Tsutomu Fukuda ◽  
Junnichi Suzuki ◽  
...  
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Relationship Of

Factor VII Clotting Assay: Influence of Different Thromboplastins and Factor VII-Deficient Plasmas

1991 ◽  
Vol 65 (02) ◽  
pp. 160-164 ◽  
Author(s):  
Marina Poggio ◽  
Armando Tripodi ◽  
Guglielmo Mariani ◽  
Pier Mannuccio Mannucci ◽  
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Dose Response ◽  
Response Curve ◽  
Ischemic Heart ◽  
Factor Vii ◽  
Response Curves ◽  
Assay Sensitivity ◽  
Clinical Laboratories ◽  
Coagulant Activity

SummaryBeing a putative predictor of ischemic heart disease, the measurement of factor VII (FVTI) coagulant activity will be presumably requested to clinical laboratories with increasing frequency. To assess the influence on FVII assays of different thromboplastins and FVII-deficient plasmas we compared performances of all possible combinations of 5 thromboplastins and 6 deficient plasmas. The reproducibility of the clotting times of the dose-response curves for human and rabbit thromboplastins were acceptable (CV lower than 7%), whereas bovine thromboplastin had a higher CV. Reproducibility was very similar for all deficient plasmas when they were used in combination with a given thromboplastin. Responsiveness of the dose-response curve did not depend on the deficient plasma but rather on the thromboplastin: one rabbit thromboplastin was the least responsive, the bovine thromboplastin the most responsive, the human and the remaining two rabbit thromboplastins had intermediate responsiveness. Assay sensitivity to cold-activated FVII varied according to the thromboplastin: the bovine thromboplastin was the most sensitive, the human thromboplastin the least sensitive, of the three rabbit thromboplastins two were relatively sensitive, one was almost insensitive. In conclusion, our results indicate that thromboplastin rather than deficient plasma is the crucial factor in the standardization of FVII assay.

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