Yasushi Miyake

Effect of a thromboxane A2 receptor antagonist (AA-2414) on bronchial hyperresponsiveness to methacholine in subjects with asthma

Bronchial hyperresponsiveness (BHR) to various stimuli is one of the major clinical features of bronchial asthma. In this study, the effect of a thromboxane A2 (TXA2) receptor antagonist, AA-2414, on BHR to methacholine was evaluated in 15 patients with asthma. The methacholine inhalation test was performed before and after oral administration of AA-2414 for 4 days (20 or 40 mg/day). The provocative concentration of methacholine producing a 20% fall in FEV1 (PC20) was measured as an index of BHR. There was a significant increase in PC20 (p less than 0.01) from 0.43 (geometric SEM, 1.42) mg/ml to 0.93 (geometric SEM, 1.43) mg/ml after 40 mg/day of AA-2414, whereas baseline values of FVC and FEV1 were not changed by the treatment. Twenty milligrams per day of AA-2414 did not alter the PC20 value nor the parameter of baseline pulmonary functions. These findings might support our hypothesis that the subthreshold concentration of TXA2 in the bronchial tissues, which has no effect on bronchomotor tone per se, may be involved in BHR in asthma. Further studies with more potent and specific TXA2 receptor antagonists are needed to confirm the conclusion.

INHIBITORY EFFECT OF INHALED PROCATEROL ON ANAPHYLACTIC BRONCHOCONSTRICTION AND THROMBOXANE A2 PRODUCTION IN GUINEA-PIGS

This study was designed to examine whether an inhaled β2‐agonist, procaterol, inhibits thromboxane A2 (TXA2) production induced by antigen challenge in passively sensitized guinea‐pigs in vivo. Antigen‐induced bronchoconstriction was markedly inhibited by pre‐treatment with procaterol. Inhaled procaterol significantly reduced in a dose‐dependent manner the increment in TXB2 concentration in bronchoalveolar lavage fluid obtained 5 min after antigen challenge. Aerosol administration of procaterol significantly inhibited bronchoconstriction induced by inhaled hislainine. These results suggest that inhalation of procalerol has an inhibitory effect on antigen‐induced TXA2 production as well as a protective effect against bronchoconstriction induced by bronchoactive agents.

Bronchoconstrictive Properties and Potentiating Effect on Bronchial Responsiveness of Inhaled Thromboxane A2 Analogue (STA2) in Guinea Pigs

Effect of subthreshold concentration of inhaled STA2, a thromboxane A2 (TXA2) analogue, on bronchial responsiveness to histamine was investigated in anesthetized and artificially ventilated guinea pigs. Percent increase in pressure of the airway opening (Pao) by aerosol histamine (50, 100 micrograms/ml) was significantly potentiated by subthreshold dose of aerosol STA2 (0.10 micrograms/ml) which was determined by dose-response curve of % increase in Pao by inhaled STA2 (0.033, 0.10, 0.33, 1.0 micrograms/ml). These results demonstrated that thromboxane A2 could contribute to bronchial hyperresponsiveness which is one of the major clinical features of bronchial asthma.

Secondary release of thromboxane A2 in aerosol leukotriene C4-induced bronchoconstriction in guinea pigs

Effect of a thromboxane synthetase inhibitor (OKY-046) on bronchoconstriction induced by aerosol leukotriene C4 and histamine was studied in anesthetized, artificially ventilated guinea pigs in order to examine whether secondary release of thromboxane A2 is produced by aerosol leukotriene C4 or not. 0.01-1.0 micrograms/ml of leukotriene C4 and 12.5-400 micrograms/ml of histamine inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with intravenous OKY-046 (100mg/kg) significantly reduced the airway responses produced by inhalation of 0.1, 0.33 and 1.0 micrograms/ml of leukotriene C4, while the pretreatment did not affect the histamine dose-response curve. Based on these findings and previous reports (6,7), it is suggested that aerosol leukotriene C4 activates arachidonate cyclooxygenase pathway including thromboxane A2 synthesis and the released cyclooxygenase products have bronchodilating effect as a whole.

Involvement of arachidonate cyclooxygenase products in bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) in guinea pigs.

Saito M, Fujimura M, Sakamoto S, Miyake Y, Shintani H, Yasui M, Matsuda T. Involvement of arachidonate cyclooxygenase products in bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) in guinea pigs.

Inhibitory effect of inhalation of a thromboxane synthetase inhibitor on bronchoconstriction induced by aerosolized leukotriene C4 and thromboxane A2 analogue in anesthetized guinea pigs

Effect of aerosol administration of a thromboxane synthetase inhibitor (OKY‐046) on bronchoconstriction induced by aerosol leukotriene C4, histamine and a thromboxane A2 analogue (STA2) was studied In anesthetized, artificially ventilated guinea pigs in order to evaluate the effectiveness of inhalation of OKY‐046 on an unfavorable mechanism of secondary release of thromboxane A2 0.01‐1.0 μg/ml leukotriene C4, 25‐400 μg/ml histamine and 0.033‐1.0 μg/ml STA2 inhaled from an ultrasonic nebulizer developed for small animals caused a dose‐dependent increase of pressure at the airway opening (Pao), which is considered to be an index representing bronchial response. Pretreatment of the animals with aerosol OKY‐046 (0.035 and 0.35 mg/animal) significantly reduced the airway responses produced by inhalation of leukotriene C4 and STA2, in a dose‐dependent manner, while the pretreatment did not affect the histamine dose‐response curve. These findings suggest that aerosol leukotriene C4 and STA2 activate thromboxane synthesis in the airway, and inhalation of OKY‐046 may be useful for preventing the secondary release of thromboxane A2, which is an unfavorable mechanism in asthma.

Inhibitory effect of aerosol WP871 on SRS-A mediated bronchoconstriction in the guinea pig in vivo

Slow‐reacting substance of anaphylaxis (SRS‐A) is an important factor mediating bronchoconstriction in asthma. We developed a guinea pig model for SRS‐A mediated bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled WP871, a new anti‐allergic drug, on bronchoconstriction. Aerosol WP871 (0.01 and 0.033%) to some extent inhibited the antigen‐induced bronchoconstriction in a dose‐dependent fashion, but high‐dose WP871 (0.1%) inhalation itself produced a non‐specific bronchoconstriction. However, aerosol WP871 (0.033%) showed no inhibitory effect on bronchoconstriction caused by direct inhalation of leukotriene C4, a component of SRS‐A. These findings indicate that aerosol WP871 does not antagonize SRS‐A, but inhibits synthesis and/or release of SRS‐A and has some non‐specific bronchoconstrictive effect in high concentration.