Inhibitory effect of aerosol WP871 on SRS-A mediated bronchoconstriction in the guinea pig in vivo

Slow-reacting substance of anaphylaxis (SRS-A) is an important factor mediating bronchoconstriction in asthma. We developed a guinea pig model for SRS-A mediated bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled WP871, a new anti-allergic drug, on bronchoconstriction. Aerosol WP871 (0.01 and 0.033%) to some extent inhibited the antigen-induced bronchoconstriction in a dose-dependent fashion, but high-dose WP871 (0.1%) inhalation itself produced a non-specific bronchoconstriction. However, aerosol WP871 (0.033%) showed no inhibitory effect on bronchoconstriction caused by direct inhalation of leukotriene C4, a component of SRS-A. These findings indicate that aerosol WP871 does not antagonize SRS-A, but inhibits synthesis and/or release of SRS-A and has some non-specific bronchoconstrictive effect in high concentration.     

The ‘calcium gating mechanism’ in the anaphylactic histamine release from guinea pig mast cells

Conclusion Our results lend support to the validity of the calcium gating hypothesis [2] also for the histamine release from guinea pig mast cells.     

Inhibitory effect of NZ-107 on anaphylactic bronchoconstriction in guinea pigs and rats.

We studied the effect of NZ-107 in a number of animal models of anaphylactic bronchoconstriction. In conscious guinea pigs, pretreated with indomethacin, pyrilamine and propranolol, passively sensitized with heterologous anti serum, NZ-107 in doses of 10-30 mg/kg per os inhibited the aerosolized antigen-induced cough and collapse. NZ-107 in a high dose of 100 mg/kg per os significantly prevented aerosolized antigen-induced anaphylactic collapse, but not cough in actively or passively sensitized conscious guinea pigs and also significantly protected aerosolized histamine-induced collapse, but not cough in conscious guinea pigs. This compound had little inhibitory effect on aerosolized acetylcholine-induced cough and collapse. In anesthetized animals, the effect of NZ-107 on bronchoconstriction induced by intravenous administration of antigen and various agonists was examined by the method of Konzett and R?ssler. In doses of 10-50 mg/kg per os, NZ-107 inhibited antigen-induced bronchoconstriction in anesthetized guinea pigs. NZ-107 when intravenously administered to the anesthetized guinea pigs inhibited not only leukotriene D4-induced bronchoconstriction, but also thromboxane A2 mimetic U-46619-, platelet-activating factor- and histamine-induced bronchoconstriction. In anesthetized rats, NZ-107 in a dose of 300 mg/kg per os tended to inhibit the antigen-induced bronchoconstriction, but this effect was not significant. These results indicate that NZ-107 acts as a spasmolytic agent which inhibits bronchial responses to antigens or various other bronchoconstrictors in animal models, suggesting that NZ-107 may be potentially beneficial in the treatment of bronchial asthma.     

Mediators of C5a-induced bronchoconstriction in the guinea pig

The effect of intravenous injection of C5a on pulmonary resistance and dynamic lung compliance was determined in anesthetized, artificially respirated guinea pigs. A mixture of C5a plus C5ades arg was purified from yeast-activated guinea pig serum and is referred to as C5a. Intravenous injection of C5a caused a dose-related bronchoconstriction as evidenced by a decrease in compliance and increase in resistance. Conversion of the C5a in the mixture to C5ades arg by carboxypeptidase B digestion did not significantly alter the magnitude of the bronchoconstriction. Pharmacological antagonists were employed to determine if histamine, acetylcholine or products of the arachidonate metabolism were mediators of C5a-induced bronchoconstriction. The histamine H1 antagonist pyrilamine inhibited the C5a-induced bronchoconstriction, suggesting the involvement of histamine. The cholinergic receptor antagonist atropine in combination with pyrilamine caused an inhibition of the C5a-induced increase in resistance but not compliance, suggesting acetylcholine does not play a major role in C5a-induced bronchoconstriction beyond its known role in participating in histamine-induced bronchoconstriction. Involvement of arachidonate metabolites was suggested by the ability of the cyclooxygenase inhibitor, indomethacin, to prevent the C5a-induced bronchoconstriction. Because indomethacin also caused a delay in the leukotriene C4 (LTC4)-induced bronchoconstriction, the participation of peptidoleukotrienes in the C5a-induced bronchoconstriction could not be ruled out. The leukotriene antagonists FPL 55712 and L-649,923 were evaluated for their specificity in inhibiting LTC4-induced bronchoconstriction. FPL 55712 was nonselective since it inhibited prostaglandin D2 and histamine-induced bronchoconstriction as well as LTC4-induced bronchoconstriction. L-649,923 inhibited only the LTC4-induced bronchoconstriction and was without effect on the C5a-induced bronchoconstriction, suggesting that peptidoleukotrienes are not important mediators of C5a-induced bronchoconstriction. Using radioimmunoassay, the change in peptidoleukotriene levels detected in plasma during C5a-induced bronchoconstriction was not significantly different from 0. Thus, these studies have quantitated the C5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance and suggest that histamine and cyclooxygenase products, but not peptidoleukotrienes, play a major role in C5a-induced bronchoconstriction.     

Involvement of PAF-acether in anaphylactic bronchoconstriction induced in guinea pigs by aerosolized antigen

Bronchoconstriction following the aerosolization of PAF-acether or antigen to guinea pigs induces autodesensitization, but the responses to direct spasmogenic substances are not modified. Bronchoconstriction by PAF-acether is not reduced when it is aerosolized to passively sensitized animals previously desensitized by repeated inhalations of the allergen (ovalbumin). In contrast, when passively sensitized animals are initially desensitized to PAF-acether by repeated inhalations of this agonist, ovalbumin aerosolization induces a bronchoconstriction which is significantly reduced when compared with the response obtained in nondesensitized animals though, in this case, the response to aerosolized histamine is not modified. Thus, PAF-acether is released during intrapulmonary anaphylactic shock induced by aerosolized ovalbumin and can be a prime candidate for its development.     

The influence of cyclic nucleotides on histamine release from lungs and on the histamine-induced contraction of guinea pig ileum

Conclusion In conclusion, exogenous cAMP and cGMP exert certain opposite actions on antibody-induced histamine release from guinea pig lungs as well as on histamine or antigen-induced contraction of guinea pig ileum smooth muscle.     

Lack of a role for bradykinin in allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig

We have investigated the role of bradykinin in allergen-induced airway microvascular leakage and bronchoconstriction in sensitized guinea pigs. We used a selective bradykinin B2 receptor antagonist, HOE140, which has been shown to prevent the airway effects induced by bradykinin. Lung resistance (R_L) was measured for 6 min after challenge with allergen. Extravasation of Evans blue dye into airway tissues was used as an index of the airway microvascular leakage. Aerosolized ovalbumin (5 mg/ml, 30 breaths) induced a significant increase in R_L and leakage of dye in the trachea, main bronchi and intrapulmonary airways in the ovalbumin-sensitized guinea pigs. HOE140 given by inhalation (200 M, 60 breaths) had no effect on the airway microvascular leakage and bronchoconstriction induced by the allergen. I.v. HOE140 (200 nmol/kg) did not significantly inhibit these airway responses. We conclude that bradykinin-mediated mechanism may not play a significant role in airway microvascular leakage or bronchoconstriction induced by allergen.accepted by I. Ahnfelt-Rønne     

Time course of morphometric changes after acute allergic bronchoconstriction in the guinea pig

Experimental allergic bronchoconstriction was induced in guinea pigs by passive sensitization with a standard dose of homologous antiserum followed by challenge with aerosolized antigen. Lungs were removed from animals at intervals of up to 6 days thereafter, and several parameters of the reaction were assessed morphometrically by comparison with lungs from unsensitized guinea pigs. We determined all changes in volume of the lung tissue resulting from fixation through to the preparation of histologic sections, but no significant differences were observed between the time course subgroups. The size of both large and small airways was assessed by a point-counting technique, as well as by measurement of the percentage of the diameter of the airways contributed by the mean thickness of the muscular layer. Maximal bronchoconstriction was observed morphometrically to correspond with the peak of a response as determined clinically by the use of a strain gauge around the chest. This was followed by a return to normal of the airway size. The number of mast cells and eosinophils around large and small airways, around branches of the pulmonary artery and in random fields of the lung parenchyma was tabulated. The maximal decrease in mast cells was seen in animals which died immediately following challenge, but the numbers were not restored to the control level even in animals which had survived for 6 days. The greatest increase in eosinophil response occurred in lungs obtained 10 min following challenge. This model will be of value in determining the effects at the tissue level of pharmacological inhibitors of this reaction.