Effects of NZ-107 on Bronchoconstriction in Guinea Pigs

et al. 1993

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ABSTRACT-Effects of R[+]-8-{[1-[3,4-dimethoxyphenyl]-2-hydroxyethyl]amino}-3,7-dihydro-7-[2 methoxyethyl]-1,3-dimethyl-lH-purine-2,6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 1) MKS-492 inhibited antigen-induced bron choconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-in duced bronchoconstriction and inhibited the increase in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle in vitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen and phospholipase A2 induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced 02 generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.

Section: Antigen-induced Bronchoconstrictionmentioning

confidence: 99%

Effects of MKS-492 on Antigen-Induced Bronchoconstriction and Allergic Reaction in Guinea Pigs and Rats

Nagai

Sakurai

et al. 1993

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“…NIP-502 inhibited the antigen-induced bronchoconstriction, one of the main symptoms of asthma, even in the presence of metyrapone. Metyrapone treatment causes a decrease in the concentration of cortisol (16,20), and an increase in the level of antigen-induced bronchoconstriction in guinea pigs (8). Furthermore, the enhanced bronchoconstriction and the deteriorated respiratory parameters were observed within 30 min after the antigen challenge in metyrapone treated guinea pigs and they were not influenced by the a-stimulant salbutamol and were effectively inhibited by prednisolone or hydrocortisone (8).…”

Section: Srbc-induced Delayed Type Hypersensitivity In Micementioning

confidence: 96%

“…In a separate experiment, we examined the effect of NIP-502 on metyrapone-pretreated guinea pigs. We have previously reported that pretreatment with metyrapone, which inhibits 11 jl-hydroxylase in glucocorticoid biosynthesis (14,15), tended to reduce plasma cortisol (16) and dramatically increases the ratio between the time required for expiration and inspiration (8). Metyrapone (10 mg/kg, i.v.)…”

Section: Antigens and Antiseramentioning

confidence: 99%

“…Metyrapone treatment causes a decrease in the concentration of cortisol (16,20), and an increase in the level of antigen-induced bronchoconstriction in guinea pigs (8). Furthermore, the enhanced bronchoconstriction and the deteriorated respiratory parameters were observed within 30 min after the antigen challenge in metyrapone treated guinea pigs and they were not influenced by the a-stimulant salbutamol and were effectively inhibited by prednisolone or hydrocortisone (8). Nakazawa (21) reported that in asthmatic patients who show late asthmatic responses (LAR), the plasma cortisol level was decreased when LAR appeared.…”

Section: Srbc-induced Delayed Type Hypersensitivity In Micementioning

confidence: 99%

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Effects of NIP-502 on Antigen-Induced Bronchial Responses and Allergic Reactions in Animal Models

Yamamoto

Takeda

et al. 1995

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ABSTRACT-We examined the effect of a newly synthesized pyridazinone derivative, NIP-502 [4-chloro-5-(3-ethoxy)-4-phenoxybenzamine)-3(2H)-pyridazinone], on antigen-induced bronchial responses and allergic reactions in several animal models. NIP-502 (10 mg/kg, p.o.) inhibited the antigen-induced immediate asthmatic response in passively sensitized guinea pigs. The inhibitory effect was also observed in metyrapone (an inhibitor of 11(3-hydroxylase)-pretreated guinea pigs. NIP-502 improved ovalbumin (OA)-induced airway hyperresponsiveness to acetylcholine and inhibited the OA-induced increase in the number of inflammatory leukocytes in the bronchoalveolar lavage fluid. These inhibitory effects on OA-induced responses were similar to those of prednisolone. NIP-502 also showed an inhibitory effect on the passive cutaneous anaphylactic reaction in rats but did not inhibit the reversed cutaneous anaphylactic reaction, reversed Arthus reaction or delayed type hypersensitivity reaction. On the other hand, prednisolone showed broad inhibitory effects except for the reversed cutaneous anaphylactic reaction. In the in vitro study, NIP-502 (30 pM) significantly inhibited Formyl-Met-Leu-Phe-induced superoxide anion production by the guinea pig alveolar macrophages. These results indicate that the inhibitory effects of NIP-502 on bronchial responses are similar to those of prednisolone, but this compound seemed to act more selectively on the respiratory tract than prednisolone. Because of its effectiveness against a variety of bronchial responses, NIP-502 may be useful in the treatment of bronchial asthma.

“…The procedure has been described previously (15). In brief, guinea pigs were passively sensitized by an i.v.…”

Section: Antigen-induced Immediate Asthmatic Response (Jar) In Guineamentioning

confidence: 99%

Studies on Anti-allergic Action of AH 21-132, a Novel Isozyme-Selective Phosphodiesterase Inhibitor in Airways

Nagai

Takeda

et al. 1995

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ABSTRACT-The effects of AH 21-132, a type III and IV phosphodiesterase (PDE) inhibitor, on allergic reactions in the airway were studied by comparing them with the effects of rolipram, a type IV PDE inhibitor, and aminophylline, a non-selective PDE inhibitor. The following results were obtained: 1) AH 21-132, rolipram and aminophylline inhibited the antigen-induced contraction of isolated guinea pig tracheal muscle in vitro. 2) AH 21-132 and aminophylline inhibited antigen-induced histamine release from human lung tissue fragments. 3) Antigen-induced accumulation of inflammatory cells including eosinophils and macrophages in mice bronchoalveolar lavage fluid was clearly inhibited by AH 21-132 and rolipram, but not by aminophylline. 4) AH 21-132, rolipram and aminophylline inhibited immediate phase bronchoconstriction induced by either an intravenous or an aerosol challenge of antigen in guinea pigs. 5) AH 21-132 and rolipram inhibited the aeroantigen challenge-induced late phase increase in the airway resistance in guinea pigs, but aminophylline did not. These results suggest that AH 21-132 has an anti-allergic effect in the airway and that these actions may be beneficial for the treatment of allergic bronchial asthma.