Kazunori Kanamori

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.

Effects of Ca2+ Antagonist, Nicardipine, on Experimental Asthma With Special Reference to Slow Reacting Substance of Anaphylaxis

Slow reacting substance of anaphylaxis (SRS‐A) is an important chemical mediator of bronchial asthma. Leukotriene C4 is a component of SRS‐A and is synthesized from arachidonic acid. Its synthesizing and releasing processes are found to he Ca2+‐dependent. We developed an in vivo inhalation asthma model, mainly mediated by SRS‐A, and elucidated the relationship between a Ca2+‐antagonist, nicardipine, and SRS‐A. In the asthmatic model, mediated by endogenous SRS‐A induced by antigen inhalation, continuous intravenous infusion of nicardipine 7 μg/kg/min depressed the open airway pressure by about 60% compared with the saline‐treated group. Inhibition of mean pulmonary resistance (RL) was about 50% and that of the inverted value of dynamic compliance (1/Cdyn) about 36%. However, the same concentration of nicardipine did not significantly affect the airway response in the asthmatic model induced by the inhalation of leukotriene C4. These results suggest that nicardipine, at the concentration used in the present study, did not block the direct effect of SRS‐A on the smooth muscle, but blocked the Ca2+ influx required for the synthesis of SRS‐A and its release.