Inhibition of bronchial hyperresponsiveness to histamine induced by intravenous administration of leukotriene C4 by novel thromboxane A2 receptor antagonists ONO-NT-126 and ONO-8809 in guinea-pigs.
We studied the effect of intravenous administration of leukotriene (LT) C4 on bronchial responsiveness to histamine and airway wall thickening in guinea-pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded sections of the lungs were stained and the airways that were cut in transverse sections were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of LTC4. Intravenous administration of 3 microg/kg LTC4 for 1 hr induced an increase of the relative thickness of the airway wall in peripheral bronchi by the histological examination. In analysis of airway function, intravenous administration of 3 microg/kg LTC4 for 1 hr induced airway hyperresponsiveness to histamine with airway wall thickening. Thromboxane A2 receptor antagonists ONO-NT-126 and ONO-8809 inhibited the LTC4-induced airway hyperresponsiveness to histamine in a dose-dependent manner, but not the airway wall thickening induced by LTC4, suggesting that the effect of LTC4 on bronchial hyperresponsiveness is likely to be mediated through TXA2.
Kurosawa
M
M
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Yodonawa
S
S
Tsukagoshi
H
H
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents / Q000633:toxicity*; D004306:Dose-Response Relationship, Immunologic; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006632:Histamine / Q000633:toxicity*; D007275:Injections, Intravenous; D017997:Leukotriene C4 / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D015394:Molecular Structure; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D016085:Bronchoconstrictor Agents; D005229:Fatty Acids, Monounsaturated; D017482:Receptors, Thromboxane; C067427:ONO 8809; C067520:ONO-NT 126; D017997:Leukotriene C4; D006632:Histamine