ovalbumin and thioperamide

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Topics: Administration, Oral; Aerosols; Albuterol; Analysis of Variance; Animals; Antitussive Agents; Capsaicin; Chlorpheniramine; Cimetidine; Codeine; Cough; Drug Hypersensitivity; Guinea Pigs; Hexamethonium; Histamine Antagonists; Indomethacin; Injections, Subcutaneous; Ipratropium; Loratadine; Male; Ovalbumin; Piperidines; Receptors, Histamine H1; Receptors, Histamine H2

The effects of a histamine H3-receptor antagonist on the bronchoconstrictor response to antigen challenge were studied in sensitized guinea pigs. We monitored airway opening pressure as an index of airway caliber, and the provocative dose of intravenous ovalbumin (OA) required to produce 200% increase in airway opening pressure (PD200) was determined. Animals were pretreated with propranolol to inhibit adrenergic bronchodilation. OA (1 to 100 micrograms/kg intravenously) challenge caused significant bronchoconstriction with a PD200 of 28.8 micrograms/kg (geometric mean). The selective H3-antagonist, thioperamide (5 mg/kg intraperitoneally), significantly enhanced the OA-induced bronchoconstriction with the PD200 value decreased to 4.0 micrograms/kg (p less than 0.001). The H2-antagonist, cimetidine (10 mg/kg intraperitoneally), had no significant effect on OA-induced response (PD200, 18.2 micrograms/kg). The H1-antagonist, mepyramine (10 mg/kg intraperitoneally), almost completely blocked the effect of OA, suggesting that OA-induced bronchoconstrictor responses are histamine (H1 receptor) mediated. Thioperamide did not alter the dose-response curve to exogenous histamine (0.3 to 3 micrograms/kg intravenously). We conclude that H3 receptors might play a role in regulation of antigen-induced response in the airways.

Topics: Animals; Antigens; Bronchoconstriction; Cimetidine; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Guinea Pigs; Histamine; Immunization; Male; Ovalbumin; Piperidines; Pyrilamine; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Skin Tests