Release Of SRS-A Research Articles

The relation between effects of adenosine, theophylline and enprofylline on the contractility of sensitized guinea-pig lung strips

Contractile responses of lung parenchymal strips from ovalbumin-sensitized guinea-pigs to cumulative addition of antigen were significantly potentiated by 10 min pretreatment with adenosine 10 microM. This potentiation was unaffected by the adenosine uptake inhibitor, dipyridamole, 2 microM. Cumulative addition of adenosine 0.1-100 microM to parenchymal strips without antigen produced variable responses, unrelated to sensitization, some contracting, some relaxing. Theophylline 100 microM caused relaxation of parenchymal strips and significantly inhibited the antigen-induced contraction with a parallel shift of the log concentration-response line. It also inhibited the adenosine-induced potentiation of contraction. Enprofylline 100 microM caused a greater relaxation of the tissue than theophylline. While it inhibited the adenosine-induced potentiation of the response, enprofylline, in contrast to theophylline, failed to inhibit the antigen-induced contraction of guinea-pig parenchyma. At these concentrations, theophylline and enprofylline each inhibited the antigen-induced release of SRSA (leukotrienes C4, D4 and E4), and of histamine, from sensitized guinea-pig lung fragments.

The discovery of cromolyn sodium and its effect on research and practice in allergy and immunology

The discovery of cromolyn sodium and its effect on research and practice in allergy and immunology

Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives

We have synthesized many pyrimidine amide derivatives. Novel pyrimidine bis-glycolic amide derivatives showed moderate inhibition in the rat passive cutaneous anaphylaxis (PCA) assay by oral administration. Among these compounds, 2,4-bis(methoxyacetylamino)-6-piperidinopyrirnidine (2i) exhibited significant inhibition. However the compound (2i) did not inhibit antigen-induced histamine or SRS-A release from lung fragments of the guinea-pig at less than 10−4 M. Derivatives of 2i have also notable or moderate activity in the rat PCA assay. Compound 2h which has no oxygen atom at the α-position of the amide carbonyl group and, compound 17 which has no amide carbonyl group, showed no inhibition in the rat PCA assay. We supposed that both the amide carbonyl group and the oxygen atom at α-position of the amide carbonyl group play an important role in inhibiting the rat PCA reaction. These pyrimidine bis-glycolic amide derivatives have a novel structure and unique activity which suggests they may be potentially useful in the treatment of allergic diseases.

虚血性脳浮腫に及ぼすロイコトリエンの影響

虚血性脳浮腫に及ぼすロイコトリエンの影響

Effect of an Anti-SRS-A Agent, NZ-107, on Airway Responses Induced by Ovalbumin and A23187 in the Guinea-pig

The effects of the anti-SRS-A agent NZ-107 on antigen-(ovalbumin) and calcium ionophore A23187-induced airway responses in the guinea-pig have been investigated. In the presence of 5 microM indomethacin, NZ-107 (3 microM) did not affect the peak response in ovalbumin-induced contraction but did inhibit the prolonged response following the peak response in the tracheal strip. A higher concentration of NZ-107 (10 microM) completely blocked both peak and prolonged responses. Inhibitory effects of NZ-107 on ovalbumin responses were less in the lung parenchymal strip. The potency of NZ-107 in inhibiting ovalbumin-induced tracheal contraction was not changed in the absence of indomethacin but was reduced in the presence of 45 mM serine-borate, an inhibitor of the conversion of LTC4 to LTD4. NZ-107 inhibited A23187-induced contractions in both tracheal and parenchymal strips but in both cases the inhibitory potency was less than that on ovalbumin response. NZ-107 was a more potent inhibitor of ovalbumin-induced SRS-A release than histamine release in lung fragments but was ineffective in inhibiting A23187-induced SRS-A and histamine release. NZ-107 at a concentration of 10 microM more effectively inhibited LTC4- and histamine-induced tracheal contractions than it did LTC4 in the presence of 45 mM serine-borate. These results suggest that NZ-107 selectively inhibits antigen-induced SRS-A responses in airway tissues of the guinea-pig.

Inhibitory Effect of HSR-6071, A New Anti-allergic Agent, on Experimental Asthma in Rats and Guinea-pigs

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.

特異的Ｔｈｒｏｍｂｏｘａｎｅ（ＴＸ）Ａ２合成酵素阻害剤（Ｅ）‐３‐〔ｐ‐（１Ｈ‐ｉｍｉｄａｚｏｌ‐１‐ｙｌｍｅｔｈｙｌ）ｐｈｅｎｙｌ〕‐２‐ｐｒｏｐｅｎｏｉｃ ａｃｉｄ（ＯＫＹ‐０４６）の抗アルルギー作用 （第１報） Ｉ型アレルギー反応に対する作用

We studied the effects of OKY-046 on type I allergic reactions. OKY-046 (100 mg/kg) given orally suppressed antigen-induced bronchoconstriction and TXB2 generation in broncho alveolar lavage fluid in rats passively sensitized with anti-DNP-As monoclonal IgE. At the dose of 30 mg/kg given intraduodenally, it also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti DNP-As serum and actively sensitized with ovalbumin. However, aspirin (30 mg/kg) didn't suppressed them significantly. Azelastine (10 mg/kg) inhibited bronchoconstriction in passively sensitized rats and actively sensitized guinea pigs. In 48 hour homologous PCA reactions of rats and mice, oral administration of OKY-046 (300 mg/kg) and tranilast (100 mg/kg) suppressed the extravasated dye in the skin. OKY-046 decreased histamine release from passively sensitized rat peritoneal exudate cells. There was no effect of OKY-046 on SRS-A and leukotriene release from actively sensitized guinea pig lungs and passively sensitized rats. In conclusion, we think that OKY-046 should be an useful asthmatic drug or anti-allergic drug by oral administration.

Antiallergy agents. 1. Substituted 1,8-naphthyridin-2(1H)-ones as inhibitors of SRS-A release.

A novel class of antiallergy agents, the substituted 1,8-naphthyridin-2(1H)-ones, is described. The present compounds are orally active, potent inhibitors of allergic and nonallergic bronchospasm in animal models. Structure-activity studies of the lead compound in this series, 1-phenyl-3-n-butyl-4-hydroxynaphthyridin-2(1H)-one (11), identified three compounds of interest, 1-phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one (12), 1-(3'-chlorophenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H )-one (87), and 1-(3'-methoxyphenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1 H)-one (89). The mechanism of antiallergy activity may involve inhibition of the release of the sulfidopeptide leukotrienes. 1-Phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one, Sch 33303 (12), was selected for preclinical development as an antiallergy agent.

Alloimmune B-lymphocytes modify the myocardium contractility-inducing release of SRS-A

It has been previously demonstrated that murine alloimmune lymphoid cells were able to exert positive or negative inotropic effects on isolated mouse atria depending on the cellular type used. Here we show that BALB/c anti-C 3H B-cells induced positive inotropic action on C 3H mouse atria. Supernatants of alloimmunized B-cells co-cultivated with C 3H myocardium exerted the same biological effect as alloimmune B-cells, indicating that a soluble factor is involved. Inhibitors of lipoxygenase(s) of arachidonic acid metabolism and a SRS-A blocker inhibited the positive effect of immune cells or its supernatants. The effect was prevented when we inhibited the atria lipoxygenase activity. On the other hand, when the inhibitors were applied to effector cells the response was not modified. In addition, supernatants of B-cells cultured with alloextracts were inactive. Supernatants from alloimmune B-cells plus myocardium release higher amounts of LTC 4 than those from normal B-cells. It is proposed that SRS-A synthesis is induced in the atria by direct contact with alloimmune B-cells upon recognition of alloantigens expressed by atria cells; which in turn, triggers the positive inotropic effect.

MY-5116のアレルギー性鼻炎に対する効果の検討I

MY-5116 is a newly synthesized antiallergic agent and the metabolite, of which MY-1250, inhibits the release of chemical mediators from mast cells in animals.This paper describes the inhibitory effect of MY-1250 on the release of histamine and SRS-A from allergen-stimulated human basophils collected from patients with al- lergic rhinitis induced by the pollen of Cryptomeria Japonica D. Don (PCJ). Basophils purified from a donor's peripheral blood were passively sensitized with the same donor's reaginic serum containing anti-PCJIgE class antibodies (aPCJIgEAb).1) Added before antigen stimulation, MY-1250 produced a dose dependent inhibition with an ED50 10-8-10-8g/ml of specific antigen (PCJ) induced histamine and SRS-A release from human peripheral basophils passively sensitized with aPCJ-IgEAb.2) MY-1250 also inhibited Ca2+ ior. ophore A23187 induced histamine and SRS-A release from non passively sensitized human peripheral basophils in a dose dependent manner when added to these cells before A23187 stimulation.3) It has been reported that the oral administration of 150 mg of MY-5116 in humans gives a maximum plasma MY-1250 level of 1.5×10-8g/ml. Considering the in vitro efficacy of MY-1250 in this experiment and the reported human plasma. level, MY-5116 should be a useful prophylactic drug for various type I allergic diseases, including allergic rhinitis.

Antiallergic Effects of Terfenadine on Immediate Type Hypersensitivity Reactions

Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity. The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.

ｐｒａｎｏｐｒｏｆｅｎ（Ｎｉｆｌａｎ）のＳＲＳ‐（Ａ）産生に及ぼす作用

Clinical studies in humans have shown that pranoprofen is an active anti-inflammatory, antipyretic, analgesic agent which is well tolerated by asthmatic patients with minimal side effects. This study was performed in animals in order to confirm its clinical superiority. Pranoprofen (1 mg/kg, i.v.) inhibited the SRS-A related phase in passive anaphylactic bronchoconstriction in guinea pigs pretreated with mepyramine. In IgE-mediated rat passive peritoneal anaphylaxis, pranoprofen (0.01-1mg/rat, i.p.) inhibited the release of SRS-A and histamine dose-dependently. Pranoprofen also inhibited the production of a prostaglandin E2 like substance, but did not increase the SRS- (A) production from rat peritoneal leucocytes which phagocytize killed bacteria in vitro. On the other hand, indomethacin distinctly enhanced SRS- (A) related reactions in these models. These results indicate that the low adverse effects of pranoprofen seen in treating asthma may be related to its inability to potentiate SRS- (A) production.

The effect of prednisolone and ketotifen on the antigen-induced bronchoconstriction and mediator release in rat isolated lungs.

Using a new method for inducing IgE-mediated, systemic anaphylaxis in the rat both prednisolone and ketotifen had been shown previously to be effective in suppressing the bronchial anaphylaxis in vivo. In order to study the mode of action underlying their bronchoprotective effect, both agents were also tested on the antigen-induced bronchoconstriction in rat isolated lungs in relation to the mediator release in the lung-effluent. The presence of histamine, 5-hydroxytryptamine (5-HT) and SRS-A could be detected biologically in the lung-effluent during bronchoconstriction. Histamine and 5-HT were determined quantitatively by means of h.p.l.c. with fluorimetric detection, whereas SRS-A was determined using the guinea-pig ileum in a cascade set-up. Although both prednisolone and ketotifen inhibited the antigen-induced bronchoconstriction effectively, it appeared that only prednisolone suppressed the release of histamine, 5-HT and SRS-A in the lung-effluent significantly, whereas ketotifen had no effect. On account of these data it is suggested that the bronchoprotective effect of prednisolone is mainly based on inhibition of the release of the mediators involved, whereas the effect of ketotifen may be based on receptor antagonism.

Reduction of antigen-induced contraction of sensitized guinea-pig tracheal smooth muscle in vitro by calmodulin inhibitors.

The effect of two calmodulin inhibitors, 1-[bis(p-chlorophenyl)methyl]-3-[2,4-dichloro-beta-(2,4-dichlorobenzylox y) phenethyl]imidazolinium chloride (R 24571) and chlorpromazine (CPZ) on antigen-induced contraction of guinea-pig tracheal smooth muscle was studied. Ketotifen, an anti-allergic compound, was used as a comparative drug. Contraction of sensitized guinea-pig trachea induced by antigen challenge was reduced by all three agents. The two calmodulin inhibitors effected relaxation of contraction of guinea-pig trachea induced by histamine and leukotriene D4 (LTD4). Ketotifen relaxed histamine-induced contraction, but hardly affected LTD4-induced tone. Contrary to chemical mediator induced tone, all examined agents had no effect on resting tone. These three agents shifted histamine- and LTD4-induced concentration-contraction curves to the right. They produced a downward displacement of the maximum, without a parallel shift in histamine- and LTD4-induced concentration-contraction curves. The two calmodulin inhibitors did not affect the antigen-induced release of histamine and SRS-A from sensitized guinea-pig lung tissue. Ketotifen slightly inhibited the release of histamine. These results suggest that R 24571 and CPZ, calmodulin inhibitors, reduced an antigen-induced contraction of sensitized guinea-pig trachea in vitro mainly by affecting the contractility of tracheal smooth muscle by chemical mediators but not by interfering with the release of mediators.

Effect of clenbuterol, a new β2 selective adrenoceptor stimulant, on the release of histamine and SRS-A from passively sensitized guinea-pig chopped lungs

1. Effect of clenbuterol on the release of histamine and SRS-A from passively sensitized guinea-pig lungs was studied in a superfused-cascade bioassay system, and compared with isoproterenol and salbutamol. 2. One-week-old guinea-pig lungs were used, since histamine and SRS-A were released more in these than in 6- or 12-week old lungs during anaphylaxis. 3. Clenbuterol, isoproterenol and salbutamol (10 -8−10 −7M) were found to inhibit the releases of histamine and SRS-A. 4. These actions were inhibited by propranolol. 5. These results suggest that clenbuterol inhibits the releases of histamine and SRS-A via the β-andrenoceptor.

Determination of SRS-A release from guinea-pig lungs by a radioimmunoassay

A sensitive radioimmunoassay for leukotrienes (LTs) has been developed. Rabbits were immunized with a conjugate of LTD 4 and bovine serum albumin, prepared by using 1,5-difluoro-2,4-dinitrobenzene as the coupling agent. The assay can detect 0.045 pmol LTD 4 at a final plasma dilution of 1:72. 50% displacement of bound 3H-LTD 4 was obtained with 0.43±0.03 pmol LTD 4. LTC 4, LTE 4 and LTF 4 cross-react 159%, 57% and 85%, respectively, whereas LTB 4, 5-HETE and prostaglandins did not. The assay was validated by measuring the antigen-induced release of LTs from sensitized guinea-pig chopped lungs. High correlation (0.9434, p<0.05) was found when LTs were simultaneously determined by this assay and a bioassay on guinea pig ileum.

Effect of fenoterol on immunological release of leukotrienes and histamine from human lung in vitro: Selective antagonism by β-adrenoceptor antagonists

The inhibitory effects of fenoterol, a β 2-adrenoceptor agonist, on the release of SRS-A leukotrienes and histamine from chopped human lung tissue were measured and selective β-adrenoceptor antagonists used to investigate the nature of the receptors involved. Fenoterol 0.01−1.0 μM inhibited the antigen-induced release of SRS-A and histamine, but not the release induced by the calcium ionophore A23187. Propranolol 0.1 and 1.0 μM and butoxamine 10 and 100 μM significantly antagonized the effects of fenoterol 0.1 μM on SRS-A and histamine at concentrations which affect β 2-adrenoceptors, while atenolol 0.1 to 10 μM showed no antagonism at concentrations which affect β 1-adrenoceptors. These results suggest that adrenoceptors in human lung which modulate the immunological release of SRS-A leukotrienes are of the β 2-subtype as for histamine release.

Effect of lipoxygenase inhibitors, AA-861 and T-22083, on chemical mediators released from sensitized guinea-pig lung tissue

Male Hartley strain guinea pigs weighing about 200g were used as the experimental animals. Histamine and SRS-A released from the lung tissue were measured by the bioassay methods. The amount of histamine released from passively sensitized lung tissue by the challenge of antigen showed marked decrease by preincubating with AA-861 or T-22083, and the percentage inhibition by AA-861 was greater than that by T-22083. The amount of SRS-A released from sensitized lung tissue by the challenge with antigen showed marked decrease by preincubation with AA-861 or T-22083, and the percentage inhibition by AA-861 was greater than that by T-22083. The above results suggest that AA-861 and T-22083 have not only an inhibitory action on the release of SRS-A from sensitized lung tissue but also have an inhibitory action on the release of histamine.

Alteration of drug responsiveness in guinea-pig lung anaphylaxis using different antigen challenge concentrations.

Antihistamine-resistant anaphylactic bronchospasm in guinea pigs is increased with increasing doses of antigen (ovalbumin, OA) challenge. This was observed in passively and actively sensitized animals, and by both i.v. and aerosol routes of antigen challenge. At a challenge concentration of 100 mg/kg OA, antihistamines were virtually inactive. Indeed, the resulting bronchospasm was inhibited by isoproterenol, theophylline and ketotifen but not any anticholinergics, anti-5HT, SRS-A antagonists, arachidonic acid lipoxygenase inhibitors or antiallergic drugs. However, in the presence of chlorpheniramine, the response was antagonized by SRS-A antagonists (FPL 55712 and isamoxole), but not the lipoxygenase inhibitors (BW 755C, ETYA, NDGA and phenidone). This suggests that the antihistamine-resistant bronchospasm produced in guinea pigs challenged with high antigen concentrations might be the result of SRS-A release. This is by no means certain since the currently available SRS-A antagonists possess other mechanisms of action; furthermore, the failure of lipoxygenase inhibitors to influence this response is not consistent with a role for SRS-A. Elucidation of the mechanism of the antihistamine-resistant bronchospasm awaits development of more specific SRS-A antagonists.

Effect of anti-allergic drugs on the release of chemical mediators from passively sensitized guinea-pig lung

During anaphylaxis, histamine (His) and SRA-A are the most important chemical mediators. In this paper, a tissue bioassay system was contrived for simultaneous determination of His and SRS-A released from guinea-pig lung during anaphylaxis. The system was composed of two guinea-pig ileums superfused with Krebs Henseleit solution (K.H.sol.) kept at 37°C and gassed with the carbogen. The upper ileum was treated with atropine, 1 μg/ml, alone and the lower one was treated with atropine,1 μg/ml,and chlorpheniramine,1 μg/ml. The guinea-pig lung was incubated for 4 hr in K.H.s0i. containing 4% serum prepared from rabbit sensitized with ovalbumin. The releasing amount of chemical mediators from 1-week-old guinea-pig was much more than that from 6-week or 12-week-old one. The contraction of lower ileum which was markedly inhibited by FPL-55712 was potentiated by pretreatment with indomethacin, 1 μg/ml. As a result, the chemical mediators from guinea-pig lung might be mainly His and SRS-A. Isoproterenol (Iso), salbutamol Sal) andNAB-365 (β2-adrenoceptor stimulant) inhibited the release of His and SRS-A nearly 1000 times as much as theophylline or disodium cromoglycate. As the inhibitory effects of Iso, Sal and NAB-365 were antagonized by propranolol, 3 μg/ml, mediator-release during anaphylaxis can be considered to be inhibited via β- adrenoceptors.