Antigen-induced Bronchoconstriction In Guinea Pigs Research Articles

Adrenal Influences on the Inhibitory Effects of Procaterol, a Selective Beta-Two-Adrenoceptor Agonist, on Antigen-Induced Airway Microvascular Leakage and Bronchoconstriction in Guinea Pigs

While the guinea pig has been the preferred choice for use as a model of allergic bronchial asthma in the evaluation of anti-asthmatic drugs, it has been shown that antigen-induced bronchoconstriction in guinea pigs is attenuated by epinephrine released from the adrenal gland. In order to investigate the possible influence of the adrenal gland on the effects of antiexudative and bronchodilative drugs on antigen-induced airway responses, we examined the inhibitory effects of procaterol, a selective β₂-adrenoceptor agonist, on antigen-induced airway microvascular leakage and bronchoconstriction in adrenalectomized guinea pigs and compared them with the drug’s effects in sham-operated animals. Guinea pigs sensitized passively with anti-ovalbumin (OA) guinea-pig serum were adrenalectomized or sham-operated under urethane anesthesia and examined 30 min after surgery in the following experiments. (1) Animals were intravenously administered Evans blue dye to quantify airway plasma exudation, and then OA was inhaled for 10 min while measuring pulmonary inflation pressure, a parameter of bronchoconstriction. Procaterol (1, 3, 10, or 30 µg/kg) or saline (control) was administered into the airways 10 min prior to OA inhalation. The amount of extravasated Evans blue dye in the airways was calculated. (2) Venous blood samples were collected during OA or saline inhalation and plasma catecholamine levels were compared. In control animals, OA-induced increases in both the amount of Evans blue dye and in pulmonary inflation pressure were markedly greater in adrenalectomized animals than in sham-operated animals. Procaterol dose-dependently inhibited OA-induced airway microvascular leakage and bronchoconstriction, and its effects were more potent in adrenalectomized animals (significant at 1 µg/kg and higher) than in sham-operated animals (significant at 10 µg/kg and higher). Although the plasma concentration of epinephrine during OA inhalation was approximately 3 times higher than that during saline inhalation in sham-operated animals, no difference was seen in adrenalectomized animals. In conclusion, while procaterol essentially possesses pronounced inhibitory effects on antigen-induced airway microvascular leakage and bronchoconstriction in guinea pigs, the effects are considerably masked by epinephrine released from the adrenal gland.

Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea-pigs in vivo.

Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear. The present study examined the effects of repeated exposure to FA on methacholine- and antigen-induced bronchoconstriction in guinea-pigs in vivo. First, non-sensitized guinea-pigs were transnasally treated with 0.1 or 1.0% FA or saline three times a week for 6 weeks, and increasing concentrations of methacholine (50, 100, and 200 microg/mL) were inhaled at 5-min intervals. Second, guinea-pigs pre-treated with transnasal administration of FA or saline using the same protocol were passively sensitized with anti-ovalbumin (OA) serum 7 days before antigen challenge. Third, guinea-pigs were actively sensitized with OA and pre-treated with transnasal administration of FA or saline using the same protocol. The lateral pressure of the tracheal tube (Pao) was measured under anesthesia and artificial ventilation. The antigen-induced increase in Pao in actively sensitized guinea-pigs was significantly potentiated by FA exposure in a dose-dependent manner. The dose-response curve of the methacholine-induced increase in Pao in non-sensitized guinea-pigs or of the antigen-induced increase in Pao in passively sensitized guinea-pigs was not altered by FA exposure. Transnasal administration of FA significantly increased the serum anti-OA homocytotropic antibody titre (IgG) as measured by the passive cutaneous anaphylaxis reaction in actively sensitized guinea-pigs. The results suggest that repeated exposure to FA worsens allergic bronchoconstriction through enhancing antigen sensitization.

Lack of adrenomedullin on antigen-induced bronchoconstriction in guinea pigs in vivo

Antigen challenge can provoke acute bronchoconstriction, recognized as immediate asthmatic response (IAR), but the evolving events in this reaction are not well defined. Recently, a novel peptide, designated adrenomedullin, was isolated from human pheochromocytoma, and has been shown to have potent systemic and pulmonary vasodilator activity. The purpose of this study was to elucidate the influence of adrenomedullin in the development of IAR. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated. Ovalbumin was inhaled after an intravenous administration of adrenomedullin. Other studies were performed in naive guinea pigs to investigate the airway responses to inhaled methacholine or histamine after an intravenous administration of adrenomedullin. Antigen challenge caused bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the antigen-induced bronchoconstriction in sensitized guinea pigs or the dose-dependent responses to inhaled methacholine or histamine in naive animals in spite of its vasodilating effect. We conclude that an intravenous administration of adrenomedullin does not influence antigen-induced bronchoconstriction or bronchial responsiveness to inhaled methacholine or histamine in vivo.

Effect of thromboxane A 2 (TXA 2) synthase inhibitor and TXA 2 receptor antagonist alone and in combination on antigen-induced bronchoconstriction in guinea pigs

Thromboxane A 2 (TXA 2) causes bronchoconstriction and bronchial hyperresponsiveness. Two types of TXA 2 modifiers, one synthase inhibitor and one receptor antagonist, are widely used for the treatment of asthma in Japan. Although the target of TXA 2 modifiers is to inhibit bioactivity of TXA 2, the pharmacological properties are somewhat different between these drugs. We studied the inhibitory effects of the TXA 2 synthase inhibitor CS-518 and the TXA 2 receptor antagonist S-1452 alone and in combination on antigen-induced bronchoconstriction in passively sensitized guinea pigs treated with diphenhydramine. Both CS-518 and S-1452 inhibited the antigen-induced bronchoconstriction dose-dependently with the plateau. The combination of these drugs at the maximal inhibitory doses did not have any more effect compared with each single dosing. The combination at the submaximal doses tended to show an additive effect, but the effect was not significant. These findings suggest that other prostanoids such as PGE 2, PGI 2, PGD 2 and PGF 2α may not take an important role in the antiasthmatic effects of TXA 2 modifiers.

Effects of intravenous theophylline, aminophylline and ethylenediamine on antigen-induced bronchoconstriction in guinea pigs.

The antiasthmatic effect of i.v. injection of theophylline was compared with that of aminophylline by using an antigen-induced bronchoconstriction model in sensitized guinea pigs. Both theophylline and aminophylline showed dose-dependent inhibition of antigen-induced bronchoconstriction. Statistically significant differences were observed at theophylline doses of 20 and 40 mg/kg and at aminophylline doses of 25 and 50 mg/kg. Thus, antiasthmatic effects of both drugs appeared to be similar. In addition, intravenous ethylenediamine did not influence either airflow in normal guinea pigs or bronchoconstriction induced by antigen at doses up to 30 mg/kg. In conclusion, the ethylenediamine in aminophylline may not influence the antiasthmatic action of theophylline, and the therapeutic effects of theophylline and aminophylline are suggested to be similar.

Antiallergic Action of Betotastine Besilate (TAU-284) in Animal Models: A Comparison with Ketotifen

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (R_rs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3–10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.

Research and development of ozagrel, a highly selective inhibitor of TXA2 synthase

Highly selective inhibitors of thromboxane (TX) A2 synthase were noted as a therapeutic agent for ischemic heart diseases, thromboembolic disorders, cerebral circulatory disorders, and asthma. The 1-substituted imidazoles and beta-substituted pyridines showed high inhibitory potency on TXA2 synthase. The structure-activity relationships of the imidazole and pyridine derivatives as inhibitors of TXA2 synthase were investigated. Introduction of various substituents into the carboxy-bearing side chain of 1-(7-carboxyheptyl) imidazole and beta-(7-carboxyheptyl) pyridine was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum in the region of 8.5 to 10 A for the inhibitory potency on TXA2 synthase. Among the tested imidazole and pyridine derivatives, (E)-4-(1-imidazolylmethyl)cinnamic acid (44) and (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methylacrylic acid (56) showed the highest potency (IC50 = 1.1 x 10(-8) and 3 x 10(-9) M). The inhibition by these derivatives was highly selective for TXA2 synthase, since other enzymes which are involved in the arachidonic acid cascade, such as fatty acid cyclooxygenase, 5-lipoxygenase, prostacyclin (PGI2) synthase, and PGE2 isomerase were not affected. On the basis of the results obtained from the pharmacological, physicochemical and toxicological studies on the two compounds (44 and 56), (E)-4-(1-imidazolylmethyl) cinnamic acid (44; OKY-046, ozagrel) was selected as the best compound of highly selective inhibitors of TXA2 synthase. The pharmacological properties of ozagrel are as follows. The inhibition of TXA2 synthase by ozagrel was more effective on human and rabbit enzymes than those of other species. Ozagrel increased 6-keto-PGF1 alpha, one of stable metabolites of PGI2, in various isolated cells and tissues perhaps via accumulated PG endoperoxides resulted by the inhibition of TXA2 synthase. Such an increase in PGI2 production by ozagrel was also observed in various experimental animals. We obtained the suggestion that, by the reduction of TXA2 production and increment of PGI2 production, ozagrel inhibits the spasms of basilar artery and the decreases in regional cerebral blood flow in dogs which received autologous blood into cisterna magna, and inhibits the decreases in motor function and regional cerebral blood flow, and the formation of infarcted area in the animals of cerebral ischemic treatment. It was also suggested that ozagrel inhibits leukotriene-, platelet-activating factor-, and antigen-induced bronchoconstriction in guinea-pigs and inhibits the induction of airway hyperresponsiveness by various stimuli in several species of animals by both mechanisms. The summarized results of ADME, toxicological, and clinical studies were also described.

Involvement of neurogenic inflammation in antigen-induced bronchoconstriction in guinea pigs.

The role of tachykinins released from sensory nerves in bronchoconstriction induced by antigen was studied in sensitized guinea pigs anesthetized with pentobarbital sodium and pretreated with atropine. The combination of NK2 (SR-48968) and NK1 (CP-96,345) tachykinin-receptor antagonists abolished the increase in total pulmonary resistance (RL) evoked by intravenous capsaicin but did not affect the response evoked by intravenous histamine. A small dose of aerosolized ovalbumin (OVA, 0.1%) produced a small increase in RL that was further increased and markedly prolonged by the neutral endopeptidase (NEP) inhibitor phosphoramidon; this bronchoconstrictor effect of OVA was markedly reduced by the NK2-receptor antagonist and was abolished by the combination of the NK1 and NK2-receptor antagonists together. When a larger dose of OVA (0.5%) was used, a maximal bronchoconstrictor response was obtained. Phosphoramidon did not potentiate this response significantly. The combination of NK1- and NK2-receptor antagonists blunted the response at 5 min only slightly but markedly attenuated the later (10-20 min) response. These results show that tachykinins released from sensory nerves play a significant role in antigen-induced bronchoconstriction in guinea pigs. This effect is exaggerated when the normal modulation of neuropeptides by NEP is inhibited and is mediated predominantly by NK2-receptor activation, with a smaller contribution by NK1 receptors.

The effect of a novel thromboxane A 2 (TXA 2) receptor antagonist (S-1452) on the antigen-induced bronchocostriction and airway hyperresponsiveness in guinea pigs

The effect of a novel thromboxane A 2 (TXA 2) receptor antagonist (S-1452) on antigen-induced bronchoconstriction and airway hyperresponsiveness in guinea pigs was studied. Ketotifen was used as a reference drug. S-1452 at doses of 1 and 3 mg/kg (per oral administration, 1 h before the injection of U-46619) clearly inhibited U-46619-induced pulmonary pressure increase. Ketotifen at a dose of 10 mg/kg did not affect U-46619-induced bronchoconstriction. S-1452 at doses of 3 and 10 mg/kg and ketotifen at a dose of 10 mg/kg inhibited the antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. S-1452 at a dose of 10 mg/kg inhibited repeated antigen provocation-induced airway hyperresponsiveness in guinea pigs. The accumulation of inflammatory cells by antigen provocation in bronchial alveolar lavage fluid (BALF) was inhibited by ketotifen but not by S-1452. These results indicate the efficacy of S-1452 on antigen-induced bronchoconstriction and antigen-induced airway hyperresponsiveness in guinea pigs.

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

Effects of R[+]-8-([1-[3,4-dimethoxyphenyl]-2-hydroxyethyl]amino) -3,7-dihydro-7-[2-methoxyethyl]-1,3-dimethyl-1H-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 bronchoconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-induced 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 O2- 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.

Inhibitory Effect of DS-4574 on Leukotriene- or Antigen-Induced Bronchoconstriction in Guinea Pigs

We studied the leukotriene (LT) antagonistic activity of DS-4574 in vivo and the inhibitory effect of this compound on antigen-induced bronchoconstriction in actively sensitized guinea pigs. Bronchoconstriction induced by LTD4 was inhibited by intravenous and oral treatment with DS-4574 in a dose-dependent manner. Orally administered DS-4574 was also able to inhibit the bronchoconstriction mediated by intravenous administration of LTC4 and E4 and that by endogenous LTs. The inhibitory effect of DS-4574 showed similar potency to those of FPL-55712 and LY171883. In contrast, histamine-, acetylcholine- or 5-hydroxytryptamine-induced bronchoconstriction was not significantly affected by DS-4574. Moreover, DS-4574 given orally or intravenously inhibited antigen-induced bronchoconstriction in actively sensitized guinea pigs and this compound prevented antigen-induced mediator release from actively sensitized guinea-pig lung fragments. The anti-asthmatic effect of this compound appears to be associated with LT antagonism and inhibition of the release of chemical mediators. This study therefore shows DS-4574 to have orally effective LT antagonistic and anti-asthmatic activities. This compound may prove useful in the treatment of bronchial asthma.

Effects of Capsaicin on Mechanical, Cellular, and Mediator Responses to Antigen in Sensitized Guinea Pigs

To assess the role of tachykinins (TKs) in immediate hypersensitivity allergic reactions in guinea pigs (GPs), we compared airway mechanics and bronchoalveolar lavage (BAL) cell and inflammatory mediator profiles in three groups of GPs after ovalbumin aerosol challenge: (1) saline-sensitized, noncapsaicinized (control) (n = 9); (2) ovalbumin-sensitized, noncapsaicinized (OS) (n = 9); (3) ovalbumin-sensitized capsaicinized (OSC) (n = 9). Lung resistance (RL), dynamic elastance (EL), BAL cell counts, histamine, and eicosanoid mediator levels were measured at baseline on Day 1, and then on Day 14 after aerosolized antigen challenge. We found significant increases on Day 14 compared with Day 1 in the following: (1) postchallenge RL and EL in OS and OSC GPs, but not in control GPs; (2) BAL total cells and red cells in OS and OSC GPs; (3) BAL prostaglandin D2 (PGD2) thromboxane B2 (TxB2), sulfidopeptide leukotrienes (LTC4/D4/E4), and histamine in OS and OSC animals. Further, when data from all GPs were considered in distributed fashion, we noted positive linear correlations between peak postchallenge RL versus BAL concentrations of each of the following: PGD2, PGF2 alpha, TxB2, LTC4/D4/E4, leukotriene B4 (LTB4), and histamine. We found no significant differences in mediator or cellular responses between OS and OSC GPs. To verify that our method of capsaicinization resulted in TK depletion from the lungs of OSC GPs, substance P (SP) and neurokinin A (NKA) lung tissue levels were measured by ELISA in seven other animals, four treated with capsaicin using the same protocol and three treated with diluent.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of Antigen-Induced Bronchoconstriction in Guinea Pigs by a New Xanthine Derivative (HW A448)

We examined the effect of a new xanthine derivative, HWA448, on antigen-induced bronchoconstriction in actively sensitized guinea pigs. Guinea pigs were sensitized by intraperitoneal injection of bovine serum albumin (BSA) on two occasions, separated by 10 days. Two weeks after the second injection, the animal was placed in a two-chambered whole body plethysmograph and specific airway resistance (SRaw) was monitored for 10 min after an aerosol inhalation of BSA. HWA448 prevented the increase in SRaw after challenge (at 5 and 20 mg/kg i.p.). Aminophylline also prevented the increase in SRaw at 20 mg/kg, but not at a 5-mg/kg dose. The concentration of HWA448, which produced 50% relaxation of the tracheal rings constricted with 0.1 mM of histamine, was 49.9 microM as compared with 18.2 microM in aminophylline. HWA448 has a protective effect on antigen-induced bronchoconstriction in guinea pigs and may be a useful agent in the therapy of bronchial asthma.

466 Attenuation of antigen-induced bronchoconstriction in guinea pigs by a new xanthine derivative of pentoxifylline (HWA-448)

466 Attenuation of antigen-induced bronchoconstriction in guinea pigs by a new xanthine derivative of pentoxifylline (HWA-448)

選択的Ｔｈｒｏｍｂｏｘａｎｅ Ａ２（ＴＸＡ２）合成酵素阻害剤Ｙ‐２０８１１のモルモット気道収縮反応に対する作用

We investigated the effects of Y-20811 on chemical mediator-induced bronchoconstriction and the release of chemical mediators into lung perfusion fluid during arachidonic acid (AA)-induced bronchoconstriction in guinea pigs. Y-20811 (0.01-1 mg/kg, i.v.), like acetylsalicylic acid or indomethacin, dose-dependently suppressed arachidonic acid- and LTD4-induced bronchoconstriction, and it (1 mg/kg, i.v.) also inhibited PAF-induced bronchoconstriction in guinea pigs. However, at a dose of 1 mg/kg, i.v., it was inactive against the bronchoconstriction induced by histamine, serotonin and acetylcholine in guinea pigs. Y-20811 (0.3-10 mg/kg) administered orally also prevented the LTD4-induced bronchoconstriction in a dose-dependent manner. This protective effect of Y-20811 (10 mg/kg, p.o.) persisted for at least 24 hr. Y-20811 (10 mg/kg, p.o.) also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti-ovalbumin guinea pig serum and pretreated with mepyramine. In the perfused and ventilated guinea pig lungs, Y-20811 inhibited AA-induced bronchoconstriction, decreased the release of TXA2 (estimated as TXB2) and increased the release of PGE2 into the perfused lung fluid, significantly (TXB2 and PGE2 were measured by HPLC). Therefore, Y-20811 suppressed various stimulant-induced bronchoconstrictions through the decrease of TXA2 production and the increase of PGE2 production. Thus, Y-20811 should prove useful as an anti-asthmatic drug.

Histamine H 3 receptors modulate antigen-induced bronchoconstriction in guinea pigs

The effects of a histamine H3-receptor antagonist on the bronchoconstrictor response to antigen challenge were studied in sensitized guinea pigs. We monitored airway opening pressure as an index of airway caliber, and the provocative dose of intravenous ovalbumin (OA) required to produce 200% increase in airway opening pressure (PD200) was determined. Animals were pretreated with propranolol to inhibit adrenergic bronchodilation. OA (1 to 100 micrograms/kg intravenously) challenge caused significant bronchoconstriction with a PD200 of 28.8 micrograms/kg (geometric mean). The selective H3-antagonist, thioperamide (5 mg/kg intraperitoneally), significantly enhanced the OA-induced bronchoconstriction with the PD200 value decreased to 4.0 micrograms/kg (p less than 0.001). The H2-antagonist, cimetidine (10 mg/kg intraperitoneally), had no significant effect on OA-induced response (PD200, 18.2 micrograms/kg). The H1-antagonist, mepyramine (10 mg/kg intraperitoneally), almost completely blocked the effect of OA, suggesting that OA-induced bronchoconstrictor responses are histamine (H1 receptor) mediated. Thioperamide did not alter the dose-response curve to exogenous histamine (0.3 to 3 micrograms/kg intravenously). We conclude that H3 receptors might play a role in regulation of antigen-induced response in the airways.

Enhancement of Antigen-Induced Bronchoconstriction in the Guinea Pig after Intravascular Complement Activation with Cobra Venom Factor

The purpose of the present studies was to begin to test the hypothesis that the complement system is important for antigen-induced bronchoconstriction in the guinea pig. The effect of the complement-depleting agent cobra venom factor (CVF) on antigen-induced bronchoconstriction in guinea pigs passively sensitized with IgG or IgE antibody to ovalbumin was determined. Intravenous injection of CVF significantly reduced total hemolytic complement activity (CH50), caused a transient decrease in dynamic lung compliance, an increase in pulmonary resistance, and a decrease in circulating white blood cells with a sustained decrease in platelets. Antigen-induced bronchoconstriction was not inhibited in either IgG- or IgE-sensitized guinea pigs depleted of complement. Thus, a role for the complement system as a contributing factor in antigen-induced bronchoconstriction was not supported. On the contrary, our studies revealed an enhanced antigen-induced bronchoconstriction in guinea pigs depleted of complement with CVF. Our studies were then directed towards characterizing the enhanced response to begin to determine the mechanism responsible. The enhanced antigen-induced bronchoconstriction occurred in both IgG- and IgE-sensitized guinea pigs and was most apparent at lower antigen doses. The enhanced response still occurred in animals treated for 5 min with a dose of CVF (10 U) which caused no demonstrable decrease in CH50, a 30% level of conversion of C3, and a normal response to C5a. These data suggested that the enhanced response was not related to the level of C5a responsiveness of the animal.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The effect of substance P on the antigen-induced bronchoconstriction in guinea pigs.

The effect of substance P (SP) on the antigen-induced bronchoconstriction in vitro and in vivo was investigated in guinea pigs. SP caused the contraction of isolated non-sensitized guinea pig tracheal muscle at concentrations between 10(-9) to 10(-7) g/ml. The elimination of epithelium in the tracheal muscle produced a slight enhancement of SP response as compared to control. Antigen-induced contraction of isolated sensitized guinea pig tracheal muscle was slightly enhanced by the pretreatment with SP at a concentration of 10(-9) g/ml. The SP-induced enhancement of antigen-induced contraction was significantly augmented by the elimination of epithelium of sensitized tracheal muscle. Moreover, the clear bronchoconstriction was observed by the infusion of SP (1 micrograms/min) intravenously, but not by the infusion of SP at the rates between 0.1 and 0.01 micrograms/min. Antigen-induced asthmatic respiratory disorder was accelerated temporarily by the infusion of subthreshold SP (0.1 microgram/min). The reactivity of bronchial smooth muscle measured by repeated injection of acetylcholine was significantly potentiated by the infusion of subthreshold SP (0.1 microgram/min). These results suggest that SP has dual actions in the contractile response of guinea pig airway smooth muscle. One is the direct contractile activity, and the other one is enhancing activity of antigen- and acetylcholine-induced bronchoconstriction.

Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methane sulfonamide) an orally active leukotriene D 4 antagonist: Pharmacological characterization in vitro and in vivo in the guinea pig

The following communicates the pharmacology of Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide) a chemically novel and orally potent leukotriene (LT) D 4 receptor antagonist. In the isolated guinea-pig trachea pretreated with indomethacin (5 μM) and L-cysteine (10 mM), Wy-48,252 antagonized TD 4-induced contraction with a pK B = 7.6. Against LTC 4 on tissues pretreated with IND and glutathione (10 mM), Wy-48,252 had a pK B > 5. Wy-48,252 (10 μM) did not antagonize pilocarpine-, histamine- or PGF 2α-induced tracheal contraction. Further, in the presence of indomethacin and chlorpheniramine (1 μM), Wy-48,252 dose-dependently inhibited the antigen-induced contraction of guinea-pig trachea in a manner consistent with antagonism at the LTD 4 receptor and inhibition of LT synthesis. In the Konzett-Rossler model of i.v. LTD 4-induced bronchoconstriction in indomethacin treated guinea pigs, intragastric Wy-48,252 (2 hr) had and ID 50 of 100 μg/kg and a functionalhalf-life of 5 hr. Against i.v. antigen-induced bronchoconstriction in guinea pigs treated with indomethacin and chlorpheniramine, intragastric Wy-48,252 (2 hr) had an ID 50 of 0.6 mg/kg and a 5 hr half life. Intragastric Wy-48,252 also selectively blocked the cutaneous wheal reaction to intradermal LTD 4 but not histamine. We conclude that Wy-48,252 is distinguished from other selective LTD 4 receptor antagonists by its oral potency and should be useful in ascertaining the role of LTD 4 mediated processes in asthma, allergy and animal models.