Inhibitory effect of the newly synthesized pyridazinone derivative NZ-107 on bronchoconstriction induced by slow reacting substance of anaphylaxis in the guinea pig.

Hibi, Morihide; Shikada, Ken-ichi; Iwama, Tetsuo; Yamamoto, Akira; Sakashita, Mitsuaki; Tanaka, Sakuya

doi:10.1254/jjp.51.411

Cited by 16 publications

(8 citation statements)

References 17 publications

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“…4-Bromo-5-(3-ethoxy-4-mcthoxybenzylamino)-3(2H)-pyridazinone (NZ-107) is a newly synthesized pyridazinone derivative which has a potent antilcukotriene activity [4] and mast cell stabilizing activity equivalent to SCG. The present study was, therefore, conducted to research the effects of NZ-107 on antigen-induced bronchoconstriction and PAF-induced airway hyperresponsiveness in guinea pigs.…”

Section: Introductionmentioning

confidence: 99%

Effects of NZ-107 on Bronchoconstriction in Guinea Pigs

Suda¹,

Nagai²,

Iwama³

et al. 1992

Int Arch Allergy Immunol

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The effect of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on bronchoconstriction in guinea pigs was studied (1). The antigen-induced bronchoconstriction was studied in guinea pigs which had been passively sensitized by intravenous injection of antiserum containing anti-benzylpenicilloyl bovine-γ-globulin IgE antibody. The sensitized guinea pigs were divided into two groups; one group was pretreated with metyrapone (11β-hydroxylase inhibitor in glucocorticoid metabolism) and the other with saline. The antigen-induced bronchoconstriction in the metyrapone-treated animals was more severe than that in the saline-treated animals. The asthmatic respiratory changes, in terms of prolongation of the ratio between expiration and inspiration, was also dramatically increased. NZ-107 at doses of 25 and 50 mg/kg significantly inhibited antigen-induced bronchoconstriction in both the saline-and metyrapone-treated animals. NZ-107 showed a tendency to inhibit accelerated severe asthmatic respiration more strongly in metyrapone-treated animals than in those treated with saline. Salbutamol inhibited antigen-induced bronchoconstriction in saline-treated animals, but its efficacy decreased in metyrapone-treated animals. Unlike salbutamol, prednisolone and hydrocortisone showed the reverse effect, inhibiting bronchoconstriction in metyrapone-but not in saline-treated animals. Sodium cromoglycate inhibited antigen-induced bronchoconstriction in both saline- and metyrapone-treated animals (2). When a subthrehold dose of platelet-activating factor was injected into guinea pigs, airway responsiveness against histamine was clearly increased. NZ-107 at a dose of 0.2 mg/kg i.v. inhibited PAF-induced airway hyperreactivity. These data suggest that NZ-107 inhibited antigen-induced bronchoconstriction in guinea pigs pretreated with both saline and metyrapone, as well as platelet-activating factor induced airway hyperreactivity.

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Section: Introductionmentioning

confidence: 99%

Effects of NZ-107 on Bronchoconstriction in Guinea Pigs

Suda¹,

Nagai²,

Iwama³

et al. 1992

Int Arch Allergy Immunol

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“…NZ 107, however, did not affect the contractile re sponse of PGD2, another constrictor PG. The reason for the inability of NZ-107 to inhibit the PGD2 response is not clear, but it may be related to the different contractile mechanism between PGD2 and PGF2a, because we have previously found that PGF2a -induced contrac tion is partly conducted by LT-like substances in the guinea pig trachea (21) and NZ-107 is an inhibitor of LTD4 contraction of the guinea pig trachea (1). Therefore, it is a possible in terpretation that NZ-107 predominantly blocks LTD4 contraction through the involvement of PGF2a rather than PGDZ.…”

Section: Discussionmentioning

confidence: 99%

“…NZ-107 is an orally active and potent inhibi tor of bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A) in the guinea pig (1). In isolated trachea and lung parenchyma, NZ-107 more selectively in hibited antigen-induced contraction than that induced by the calcium ionophore A23187, and it also selectively inhibited antigen-in duced SRS-A release from lung fragments (2).…”

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confidence: 99%

Effects of NZ-107 on Tracheal Responses to Adenosine in the Guinea Pig.

et al. 1991

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ABSTRACT-We have investigated the effect of NZ-107, an inhibitor of bronchocon striction induced by slow reacting substance of anaphylaxis (SRS-A), on tracheal re sponses to adenosine in the guinea pig. In the presence of an adenosine uptake inhibi tor, dipyridamole (1 ,u M), NZ-107 (0.3-1 uM) enhanced adenosine-induced relaxa tion in 30 nM leukotriene D4 (LTD4)-precontracted trachea, whereas aminophylline (AP, 10-30 uM), an adenosine receptor antagonist, markedly inhibited it. NZ-107 (1 p M) also enhanced the relaxation induced by forskolin, an adenylate cyclase activa tor, but not that by nitroprusside (NP), a guanylate cyclase activator. AP (30 PM) affected neither forskolin nor NP-induced relaxation. NZ-107 (1 UM) and AP (30 pM) inhibited to about the same extent the contractile response to an adenosine A, receptor agonist, the R(-)-enantiomer of N6-(2-phenylisopropyl)-adenosine (R-PIA). The R-PIA-induced contraction was completely blocked by 5 pM indomethacin. NZ 107 (1 pM) did not affect the contraction induced by PGD2, but significantly reduced that of PGF2a . AP (30 p M) had no effect on PGF20 and PGD2-induced contractions. These results suggest that NZ-107 may have a unique profile for adenosine responses in bronchial asthma.

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“…) is a newly synthesized substance which shows an inhibitory effect on bronchoconstriction caused by several different stimuli in guinea pigs [1][2][3][4]. In vivo experiments, NZ-107 inhibited the antigen-induced slow reacting substance of anaphylaxis (SRS-A)-, leukotriene D4 (LTD4)-, U46619-and PAF-induced broncho constriction in guinea pigs.…”

Section: -Bromo-5-(3-ethoxy-4-mcthoxybcnzylamino)-3(2h)-pyridazinoncmentioning

confidence: 99%

Effect of NZ-107, a Newly Synthesized Pyridazinone Derivative, on Antigen-Induced Contraction of Human Bronchial Strips and Histamine Release from Human Lung Fragments or Leukocytes

Nagai

Suda²,

Iwama³

et al. 1992

Int Arch Allergy Immunol

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The effects of a newly synthesized pyridazinone derivative, NZ-107, 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone, and two well-known antiasthmatic drugs, amlexanox (orally active disodium cromoglycate-like drug) and disodium cromoglycate (DSCG) on antigen-, histamine- and leukotriene C₄ (LTC₄)-induced constriction of isolated human tracheal muscle, and histamine release from human lung tissues and leukocytes were investigated in vitro. In some experiments, salbutamol was used as a reference drug. NZ-107 inhibited antigen-, histamine- and LTC₄-induced contraction of tracheal muscle. Amlexanox and DSCG did not affect the contractile response of tracheal muscle caused by each stimulant. Salbutamol inhibited antigen-induced contraction of tracheal muscle. NZ-107, amlexanox, DSCG and salbutamol clearly inhibited the antigen-induced release of histamine and LTC₄ from human lung tissue. The antigen-induced histamine release from atopic human leukocytes was inhibited by NZ-107 and amlexanox, but not by DSCG. Pre-treatment with IL-3 did not alter antigen-induced contraction of tracheal muscle and histamine release from lung tissue, but antigen- or calcium ionophore A 23187-induced histamine release from leukocytes was clearly enhanced. Amlexanox inhibited the IL-3-induced enhancement of histamine release from leukocytes in the case of both stimuli, but NZ-107 and DSCG had no effect. These data suggest that NZ-107 has potent anti-allergic actions based on the inhibition of antigen-induced contraction of human tracheal muscle and mediator release from human lung tissue and leukocytes.

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Inhibitory effect of the newly synthesized pyridazinone derivative NZ-107 on bronchoconstriction induced by slow reacting substance of anaphylaxis in the guinea pig.

Cited by 16 publications

References 17 publications

Effects of NZ-107 on Bronchoconstriction in Guinea Pigs

Effects of NZ-107 on Bronchoconstriction in Guinea Pigs

Effects of NZ-107 on Tracheal Responses to Adenosine in the Guinea Pig.

Effect of NZ-107, a Newly Synthesized Pyridazinone Derivative, on Antigen-Induced Contraction of Human Bronchial Strips and Histamine Release from Human Lung Fragments or Leukocytes

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