Effect of oxitropium bromide (Ba253) on increased airway resistance induced by various agonists and antigen in the guinea pig.

Effects of oxitropium bromide (Ba253), which was administered by inhalation, on the resting and stimulus-induced airway resistance were examined in the artificially ventilated guinea pig and compared with those of ipratropium bromide (Sch1000), atropine and isoproterenol. Results obtained were as follows: 1) Ba253 as well as other reference compounds hardly affected the resting resistance. 2) Ba253 strongly and persistently inhibited the acetylcholine (ACh)-induced resistance. Sch1000 caused a similar but relatively weaker inhibition than Ba253. Either atropine or isoproterenol caused only a transient inhibition. 3) The increase in resistance induced by histamine, serotonin, leukotriene D4 or antigen was prevented by Ba253. Atropine, Sch1000 and isoproterenol also inhibited these reactions, but the effects and the duration were generally weaker and shorter than those of Ba253. 4) Repeated inhalations of Ba253 for 7 days did not influence the inhibition of the ACh-induced increase in airway resistance by this drug. However, isoproterenol tended to attenuate the suppression of the resistance by the drug. From these results, it is suggested that Ba253 is a useful inhalant drug for asthma.

Effect of oxitropium bromide (Ba253) on isolated respiratory smooth muscle and release of chemical mediators from passively sensitized lung fragments.

The effect of oxitropium bromide (Ba253), a quaternary scopolamine derivative, on the resting tonus and agonist-induced contraction of isolated guinea pig airway smooth muscle and on the anaphylactic release of histamine and immunoreactive leukotrienes (i-LTs) from lung fragments were investigated and compared with those of Sch1000, atropine and isoproterenol. Ba253 dose-dependently inhibited the acetylcholine (ACh)-induced contraction of the isolated trachea and lung parenchyma. The degree of inhibitory potency was similar to that of Sch1000 and 10 times higher than that of atropine. Ba253 minimally influenced the resting tonus or contractions induced by other agonists including histamine, serotonin and LTD4. Sch1000 and atropine had similar or slightly stronger inhibitory effects on the tonus and contractions than Ba253. On the other hand, low concentrations of isoproterenol solely relaxed the resting tonus and inhibited the the agonist-induced contractions of both preparations. Neither Ba253 nor Sch1000 inhibited the anaphylactic release of histamine and LTs from both guinea pig and human lung fragments, but both mediator releases from either species were slightly inhibited with dose-dependency by atropine and potently inhibited by isoproterenol. From these results, it is suggested that Ba253 is a relatively specific antagonist to cholinergic receptors and might be possibly effective as an inhalant for asthma.

Effect of AA-861, a selective 5-lipoxygenase inhibitor, on models of allergy in several species.

The effects of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861), a selective 5-lipoxygenase inhibitor, on immunological or non-immunological release of slow reacting substance of anaphylaxis (SRS-A) and histamine and its effects on experimental asthma were investigated. AA-861 showed a dose-dependent inhibition of SRS-A release, with no effect on histamine release from passively sensitized guinea pig, monkey (M. irus) and human lung fragments. An analysis of the anaphylactic diffusate from the human lung fragments, using the combined technique of high performance liquid chromatography and radioimmunoassay, revealed that AA-861 markedly suppresses biosynthesis of the leukotrienes. However, this drug inhibits the release of histamine as well as SRS-A from lung fragments of anaphylactic monkey (M. mulatta) and in the Ca ionophore-stimulated rat peritoneal cavity. AA-861 suppressed the anaphylactically-induced airway resistance in mepyramine- and cimetidine-treated guinea pigs. These results suggest that AA-861 may be clinically effective for treating allergy-related asthma by modulating the 5-lipoxygenase pathway and that an inhibitory mechanism of histamine release by AA-861 may be present in some species.

Lack of involvement of leukotriene and platelet activating factor in passive cutaneous anaphylaxis in rats.

Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.

Effect of butyl 3-(1H-tetrazol-5-Yl) oxanilate (MTB) on immunological or non-immunological histamine and SRS(-A) release from guinea-pig, monkey and human lung tissue.

We investigated the influence of butyl 3-(1H-tetrazol-5-yl) oxanilate (MTB) on the release of histamine and slow reacting substance of anaphylaxis (SRS-A) in vitro. MTB dose-dependently inhibited the release of not only histamine but also SRS-A from passively sensitized guinea-pig lung, while disodium cromoglycate (DSCG) hardly affected either release. MTB also resulted in a dose-dependent inhibition of the release of these mediators from the passively sensitized cynomolgus and rhesus monkey and that from human lung at concentrations similar to those inhibiting the release in the guinea-pig. Relatively lower inhibitory activities on the releases of both mediators from the cynomolgus monkey and human lung, but no effects on those from the rhesus monkey were observed with DSCG. MTB dose-dependently inhibited only SRS release from guinea-pig lung induced by phospholipase A2, although the compound did not show any inhibitory activity on the release of those from the calcium ionophore (A23187)-stimulated one. On the other hand, the release of SRS, but not that of histamine from the lung stimulated with A23187 as well as phospholipase A2 was inhibited by N-(3,4-dimethoxycinnamoyl)-anthranilic acid (tranilast, N-5'). From these results, MTB was a potent inhibitor of the anaphylactic release of the mediators, particularly SRS-A. It was suggested that the inhibitory mechanism of MTB is different from those of DSCG and N-5'.

Effects of the new antiallergic drug 11-oxo-11H-pyrido[2,1-b] quinazoline-2-carboxylic acid on type I allergic reactions.

Antiallergic effects of the newly synthesized, quinazoline derivative 11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid (Sm 857) were investigated. The following results were obtained. 1. Anaphylactic and non-immunologic histamine and slow reacting substance of anaphylaxis (SRS-A) release from guinea pig lung fragments was dose-dependently inhibited by 10(-6)-10(-4) and 10(-7) -10(-4) g/ml of Sm 857, respectively. Similar inhibition of the mediator release by the compound was obtained from the experiments of passively sensitized monkey and human lung fragments by antigen. 2. Seven-day passive cutaneous anaphylaxis of guinea pigs was not inhibited at 1-20 mg/kg (i.v.) of Sm 857, but inhibited at 20-100 mg/kg (p.o.) in some experiments without dose dependency. 3. Cutaneous anaphylaxis and histamine-induced cutaneous reaction in guinea pigs were hardly affected by the treatment of 50 and 100 mg/kg (p.o.) of Sm 857. 4. Passive systemic anaphylaxis in guinea pigs was not inhibited at 50-200 mg/kg (p.o.) of Sm 857. 5. Arthus reaction in rabbits was slightly and dose-dependently enhanced at 50-200 mg/kg given twice p.o. 6. Sm 857 (10(-6)-10(-4) g/ml) exhibited antispasmogenic activity against histamine and leukotriene D4 in isolated human bronchi and guinea pig trachea, however, this activity is attributable to non-specific musculotropic smooth muscle relaxation. From these results it may be concluded that Sm 857 exerts preferential effect on the respiratory system and that it might be useful in allergic asthma.