title: Inhibitory effect of HSR-6071, a new anti-allergic agent, on experimental asthma in rats and guinea-pigs.
abstract: The experimental asthma caused by IgE antibody in rats was inhibited by HSR-6071 (6-(1-pyrrolidinyl)-N-(1H-tetrazol-5-yl)-2-pyrazinecarboxamide) (0.01-0.1 mg kg-1 i.v.) in a dose-dependent manner. The inhibitory activity of HSR-6071 was more potent than those of disodium cromoglycate and ketotifen, and equipotent with amlexanox. The bronchoconstriction mediated by IgE or IgG antibody in guinea-pigs was also prevented by HSR-6071 (0.3, 1 and 3 mg kg-1 i.v.), amlexanox (3, 10 and 30 mg kg-1 i.v.) and ketotifen (0.1 mg kg-1 i.v.) but not by disodium cromoglycate (10 mg kg-1 i.v.). HSR-6071 was more potent than amlexanox, but less potent than ketotifen. HSR-6071 suppressed antigen-induced histamine and SRS-A release from minced lung tissues of guinea-pigs sensitized passively with rabbit anti-EA serum and was a more potent inhibitor of the release of SRS-A than of histamine. On the other hand, histamine- or acetylcholine-induced bronchoconstriction in guinea-pigs was scarcely affected by HSR-6071 at doses sufficient to inhibit the experimental asthma, but LTD4-induced bronchoconstriction was dramatically inhibited. These results indicate that the inhibitory action on experimental allergic asthma of HSR-6071 may be due to suppression of antigen-induced histamine and SRS-A release from lung tissues and to antagonism of SRS-A action. In addition, HSR-6071 inhibited cyclic AMP phosphodiesterase activity and produced relaxation of the guinea-pig isolated trachea. These pharmacological actions may contribute to the production of the anti-allergic action of HSR-6071.
authors.affiliation: Central Research Laboratories, Hokuriku Seiyaku Co. Ltd., Fukui, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Makino
authors.forename: T
authors.initials: T
authors.lastname: Ohashi
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: A
authors.initials: A
authors.lastname: Koda
authors.forename: H
authors.initials: H
authors.lastname: Azuma
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001393:Azoles / Q000627:therapeutic use*; D001980:Bronchi / Q000187:drug effects; D004205:Cromolyn Sodium / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006967:Hypersensitivity / Q000188:drug therapy; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D007665:Ketotifen / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011759:Pyrrolidines / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000097:blood / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D000631:Aminopyridines; D001393:Azoles; D011759:Pyrrolidines; D013189:SRS-A; D013777:Tetrazoles; C063147:HSR 6071; D007073:Immunoglobulin E; D006632:Histamine; C045742:amlexanox; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D004205:Cromolyn Sodium; D007665:Ketotifen