ozagrel and Hypersensitivity

Our in vivo assay system developed to search for allergy-preventive substances, assesses the blood flow decrease in tail vein microcirculation of mice subjected to sensitization with hen-egg white lysozyme (HEL). The blood flow decrease appears to be regulated by various factors such as nitric oxide (NO), thromboxane (TX) A(2), prostacyclin (PGI(2)) and endothelin (ET)-1 together with cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS), and constitutive nitric oxide synthase (cNOS). In this study, we examined in detail the roles of iNOS in this assay system using an iNOS knockout (KO) mouse. We found that the blood flow decrease in the HEL-sensitized iNOS KO mice was slightly weaker than that in their wild type (WT) mice. This blood flow decrease was not affected by a selective COX-1 inhibitor, a selective COX-2 inhibitor and a PGI(2) agonist unlike the case of the WT mice. However, it was inhibited by a nonselective NOS inhibitor, a specific TXA(2) synthase inhibitor and a specific ET-1 receptor blocker as in the case of the WT mice. The present results indicate that the blood flow decrease occurs via two pathways; one is an iNOS-independent response involving TXA(2) and ET-1, and the other is an iNOS-dependent response involving COX-1, COX-2 and PGI(2). cNOS appears to play some roles in the blood flow decrease and iNOS acts as an exacerbation factor. Our method using HEL-sensitized should be useful for searching for agents that can prevent allergy via new mechanisms.

Topics: Animals; Epoprostenol; Female; Hypersensitivity; Methacrylates; Mice; Mice, Inbred C57BL; Muramidase; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitrobenzenes; Peptides, Cyclic; Regional Blood Flow; Sulfonamides; Thromboxane A2; Veins

The development of an allergic bronchoconstriction model in rats is described. In actively sensitized Donryu strain rats, there was a remarkable biphasic increase in airway resistance within 10 min after antigen challenge on day 9 to day 21. The increase in airway resistance, correlated with the IgE titer and the dose of antigen, was inhibited by disodium cromoglycate (DSCG) or by aminophylline. This bronchoconstriction was remarkably blocked by methysergide (25 and 100 micrograms/kg) while pyrilamine inhibited it partially at the same dose. Serotonin (greater than 30 micrograms/kg) but not histamine (less than 1,000 micrograms/kg) induced a bronchoconstriction. FPL-55712 (1,10 mg/kg) inhibited it significantly. The content of thromboxane B2 (TxB2) in plasma increased during the bronchoconstriction while the content of peptide-leukotrienes (p-LTs) in plasma did not increase significantly. OKY-046 inhibited not only allergic bronchoconstriction but also the increase in TxB2 levels in plasma. The late phase of the bronchoconstriction was more susceptible to OKY-046. In conclusion, this model seems to be useful for the screening of antiasthma drugs because of a relationship with the dose of antigen, IgE titer and the susceptibility to an antiallergic drug or a bronchodilator. It is demonstrated that the major part of this allergic bronchoconstriction depends on serotonin, and it is also suggested that thromboxane A2 may play an important role in the late phase of the bronchoconstriction.

Topics: Airway Resistance; Allergens; Aminophylline; Animals; Bronchial Spasm; Chromones; Cromolyn Sodium; Dose-Response Relationship, Immunologic; Histamine; Hypersensitivity; Leukotrienes; Male; Methacrylates; Methysergide; Pyrilamine; Rats; Rats, Inbred Strains; Serotonin; Thromboxane B2; Time Factors

We studied the effect of a selective thromboxane-synthetase inhibitor, sodium (E)-3-[4-(1-imidazolymethyl)-phenyl]-2-propanoate) (OKY-046) on the late-phase response to antigen in ragweed-sensitized dogs. Skin biopsies were performed before and 1, 6, and 24 hours after ragweed injection. OKY-046 was infused (100 micrograms.kg-1.min) from 1 hour before until 6 hours after intracutaneous ragweed in five dogs. The early clinical response to ragweed (wheal at 20 minutes) was not changed by OKY-046. A late-phase response (induration at 6 hours) was not observed in any of the OKY-046-treated dogs but was present at 6 hours in 4/5 dogs without OKY-046. Typical mast cells responded similarly in both groups with progressive degranulation during 24 hours. Maximal degranulation of atypical mast cells was delayed to 6 hours with OKY-046, whereas these cells responded completely at 1 hour without OKY-046. The inflammatory response to ragweed followed the same pattern in both groups, but the numbers of each cell type were decreased with OKY-046. With OKY-046, the cutaneous response to histamine was not changed significantly from baseline at 6 hours but was increased (p less than 0.05) at 24 hours, whereas without OKY-046, histamine response was significantly increased at 6 hours (p less than 0.001) and 24 hours (p less than 0.01). We conclude that OKY-046 alters the antigen-induced response of atypical mast cells, the subsequent cellular and clinical late-phase response, and prevents the increase in histamine response.

Topics: Acrylates; Animals; Basophils; Biopsy; Dogs; Drug Evaluation, Preclinical; Histamine; Hypersensitivity; Mast Cells; Methacrylates; Pollen; Skin; Skin Tests; Thromboxane-A Synthase; Time Factors

To determine the role of thromboxane A2 in the airway hyperresponsiveness induced by antigen challenge, we studied the effect of a thromboxane synthetase inhibitor, OKY-046, i.e., sodium (E)-3-[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, in 6 ragweed-sensitized dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus total pulmonary resistance before and 6 and 24 h after inhalation with ragweed antigen. This procedure was repeated in each dog during intravenous infusion of OKY-046 (100 micrograms/kg/min). OKY-946 did not alter the acute increase in total pulmonary resistance after antigen. At 6 h, there was a 7-fold increase in airway responsiveness, an effect that was prevented by OKY-046 (p less than 0.001). At 24 h, 18 h after OKY-046 was stopped, hyperresponsiveness was still significantly inhibited. OKY-046 did not alter the influx of neutrophils recovered by bronchoalveolar lavage performed at 6 h after antigen challenge. Antigen-induced airway hyperresponsiveness in dogs may depend upon the thromboxane A2 generation from inflammatory cells (e.g., neutrophils).

Topics: Acrylates; Aerosols; Airway Resistance; Animals; Dogs; Hypersensitivity; Methacrylates; Pollen; Respiratory System; Therapeutic Irrigation; Thromboxane-A Synthase