Keiichi Mizuhashi

Role of leukotrienes in post‐allergic propranolol‐induced bronchoconstriction in guinea‐pigs

Background Administration of propranolol can provoke bronchoconstriction only in asthmatic patients. Recently we developed an animal model for propranolol‐induced bronchoconstriction (PIB). Our working hypothesis is that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction.

Effect of a 5-lipoxygenase inhibitor, AL-3264, on propranolol-induced bronchoconstriction in guinea-pigs

The administration of propranolol can provoke bronchoconstriction in asthmatic patients. We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. We investigated the effect of AL-3264, a 5-lipoxygenase inhibitor, on propranolol-induced bronchoconstriction (PIB) after antigen inhalation in passively sensitized and artificially ventilated guinea-pigs. Our goal was to determine whether products of arachidonate 5-lipoxygenase are involved in such PIB. Bronchoconstriction occurred when 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. Pretreatment with AL-3264 given in intravenous doses of 0.01 and 0.1 mg/kg 15 min after the antigen challenge significantly reduced PIB in a dose-dependent manner. Pretreatment with 0.1 mg/kg of AL-3264 10 min before antigen challenge significantly inhibited both the immediate allergic bronchoconstriction and PIB, although the effect was minimal. Results suggest that arachidonate 5-lipoxygenase products (such as leukotriene B4, C4, D4 or E4) are involved in the pathophysiology of PIB but their contribution may be small. Further studies using selective antagonists for each of these leukotrienes are needed to clarify their role.

Interaction of thromboxane A2 and leukotrienes in guinea pig airways in vivo.

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused 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 inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.

Addition of a 2-month low-dose course of levofloxacin to long-term erythromycin therapy in sinobronchial syndrome

Background: We previously reported that a 6‐month low‐dose course of ofloxacin combined with long‐term low‐dose erythromycin therapy (EM therapy) was superior to EM therapy alone for sinobronchial syndrome (SBS), especially during the initial 2 months of treatment. However, there was no data as to whether discontinuation of low‐dose ofloxacin after 2 months results in symptom relapse. This study was designed to clarify this issue.

Effects of aerosol administration of a thromboxane receptor antagonist (S-1452) on experimental asthma in guinea pigs.

The importance of thromboxane A2(TXA2), one of the arachidonate metabolites, in the pathogenesis of bronchial asthma has been emphasized recently. Because aerosolized administration of antiasthmatic drugs is effective and safe, this study examined the effect of aerosolized TXA‐2 receptor antagonist (S‐1542) on allergic bronchoconstriction in passively sensitized and mechanically ventilated guinea pigs. Under the cover of antihistamine, antigen‐induced bronchoconstriction was markedly inhibited by pretreatment with aerosolized S‐1452 inhalation in a dose‐dependent manner. Although aerosolized S‐1452 itself provoked weak bronchoconstriction for its partial agonist effect, bronchial responsiveness to inhaled histamine did not change 10 min after S‐1452 inhalation. These results indicate that aerosolized S‐1452 may be useful in treating bronchial asthma.