icatibant and Bronchial-Hyperreactivity

Icatibant, a bradykinin B(2) receptor antagonist, inhibits the reduction in nasal patency after challenge with house dust mite antigen in sensitive subjects and abolishes the nasal hyperresponsiveness induced by platelet-activating factor in nonatopic subjects.. We sought to investigate the effect of icatibant on the response to nasal antigen challenge in subjects with seasonal allergic rhinitis.. Patients allergic to grass pollen antigen (n = 9-13) were included in a double-blind, randomized-block, placebo-controlled, crossover study outside the pollen season. Subjects first received an intranasal spray of icatibant (200 microg per nostril) or a saline control. Subjects were then challenged with antigen or diluent (control), and their responses were monitored by using acoustic rhinometry. Six hours later, nasal lavage fluid was collected and quantified for inflammatory cells and various inflammatory mediators (kinin, eosinophil cationic protein, IL-5, and IL-8). At 24 hours, the response of the nasal airways to 200 microg of histamine was assessed, and a further nasal lavage was carried out.. Antigen challenge caused a significant increase in nasal obstruction and albumin extravasation, which was not affected by icatibant. Nasal hyperresponsiveness to histamine was present 24 hours after antigen and was abolished by pretreatment with icatibant. Icatibant also reduced the antigen-induced increase in eosinophils, eosinophil cationic protein, kinin, and IL-8 in nasal lavage fluid.. Pretreatment with icatibant does not affect the acute inflammatory response in seasonal allergic rhinitis. However, our results imply the involvement of kinins and the bradykinin B(2) receptor in the development of antigen-induced hyperresponsiveness and the associated eosinophilia in the human nasal airway.

Topics: Adult; Aerosols; Antigens; Bradykinin; Bradykinin Receptor Antagonists; Bronchial Hyperreactivity; Cross-Over Studies; Eosinophilia; Humans; Kinins; Middle Aged; Nasal Cavity; Nasal Provocation Tests; Rhinitis; Rhinitis, Allergic, Seasonal; Time Factors

1. The effects of inhibitors of nitric oxide synthase (NOS) on the responsiveness of the human nasal airway were investigated, by measuring the nasal response to histamine and bradykinin. 2. Repeated intranasal administration of N(G)-nitro-L-arginine methyl ester (L-NAME) or N(G)-monomethyl-L-arginine (L-NMMA), 1 micromol per nostril every 30 min for 6 h, increased the nasal obstruction induced by histamine, 50 - 500 microg, and bradykinin, 200 microg per nostril. A single administration of L-NAME, 1 micromol per nostril did not induce hyperresponsiveness to histamine. 3. Pretreatment with L-arginine, 30 micromol, abolished the hyperresponsiveness to histamine caused by L-NAME, 1 micromol. Pretreatment with N(G)-nitro-D-arginine methyl ester (D-NAME), 1 micromol, did not induce hyperresponsiveness to histamine. 4. Repeated administration of L-NAME, 1 micromol, caused a significant reduction in the amount of nitric oxide measured in the nasal cavity. 5. Neither L-NMMA, 1 micromol, nor L-arginine, 30 micromol, altered the nasal hyperresponsiveness induced by platelet activating factor (PAF), 60 microg. PAF did not alter the levels of nitric oxide in the nasal cavity. 6. The results suggest that inhibition of nitric oxide synthase induces a hyperresponsiveness in the human nasal airway, and that this occurs by a mechanism different from that involved in PAF-induced hyperresponsiveness.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Bronchial Hyperreactivity; Cross-Over Studies; Double-Blind Method; Drug Interactions; Enzyme Inhibitors; Humans; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Platelet Activating Factor; Receptor, Bradykinin B2

The involvement of bradykinin in virus-induced airway hyperresponsiveness (AHR) in guinea pig airways in vivo was determined with the B(2)-receptor antagonist Hoe 140. The efficacy of Hoe 140 treatment was assessed through its effect on the bradykinin-induced (up to 2.5 microgram/100 g B.W. administered intravenously) decrease in blood pressure (BP). Hoe 140 (0.1 micromol/kg), administered subcutaneously twice a day for 5 d almost completely blocked bradykinin-induced changes in BP. Four days after parainfluenza-3 (PI-3) virus infection, guinea pigs showed AHR; excessive airway contraction was found with histamine-receptor stimulation. This hyperresponsiveness was completely inhibited by pretreatment with Hoe 140 (0.1 micromol/kg) administered subcutaneously twice a day for five consecutive days, starting 1 d before virus inoculation. Interestingly, nebulized delivery of bradykinin itself to captopril-treated animals induced an AHR comparable to that observed in virus-treated guinea pigs. Viral infection also caused influx of bronchoalveolar cells into the lungs. Both histologic examinations and lung lavage experiments showed that this cell influx could not be inhibited by pretreatment with Hoe 140. In summary, the results of the study show that bradykinin is involved in a cascade of events leading to AHR after a viral infection in guinea pigs, without affecting bronchoalveolar cell influx.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Count; Guinea Pigs; Lung; Male; Parainfluenza Virus 3, Human; Respiratory Tract Infections; Respirovirus Infections

Bradykinin (BK) is a peptide mediator generated at sites of inflammation and its effects are mediated through constitutively expressed B(2) receptor or through induction of B(1) receptors. We examined the role of these receptors in bronchial hyperresponsiveness (BHR). Brown-Norway rats sensitized with ovalbumin (OA) and Al(OH)(3) intraperitoneally, were exposed 3 wk later to either saline or OA aerosol. B(1) receptor antagonist desArg(10)[Hoe140] (200 nmol/kg or 1 micromol/kg, intraperitoneally) or B(2) receptor antagonist Hoe140 (200 nmol/kg, intraperitoneally) was administered 30 min before allergen exposure. Hoe140 had no effect on OA-induced BHR to acetylcholine (ACh) and bronchoalveolar lavage fluid (BALF) cellular profiles, but inhibited bronchoconstriction to BK (p < 0.04). At both doses, desArg(10)[Hoe140] dose-dependently inhibited allergen-induced BHR to ACh (p < 0.01), but had no effect on bronchoconstriction to BK or baseline ACh responsiveness. The inflammatory cells in BALF were not affected apart from reduced lymphocyte numbers at the highest dose. B(1) receptor mRNA expression measured by Northern analysis was increased after allergen exposure in sensitized lungs, with a peak at 2 to 6 h after exposure, whereas B(2) receptor mRNA expression remained unchanged. Newly induced BK B(1) receptors may be involved in allergen-induced BHR to ACh, whereas constitutive B(2) receptors mediate BK-induced bronchoconstriction.

Topics: Acetylcholine; Allergens; Animals; Blotting, Northern; Bradykinin; Bradykinin Receptor Antagonists; Bronchi; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Male; Ovalbumin; Rats; Rats, Inbred BN; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin