ono-nt-126 and Bronchial-Hyperreactivity

We studied the effect of intravenous administration of 13,14-dihydro-15-keto-prostaglandin (PG) F2 alpha on airway 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 section 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 13,14-dihydro-15-keto-PGF2 alpha. Intravenous administration of 10 micrograms/kg 13,14-dihydro-15-keto-PGF2 alpha for 1 h did not induce an increase of the relative thickness of the airway wall by the histological examination. In analysis of airway function, intravenous administration of 10 micrograms/kg 13,14-dihydro-15-keto-PGF2 alpha for 1 h induced airway hyperresponsiveness to histamine without airway wall thickening. Thromboxane A2 (TXA2) receptor antagonists ONO-NT-126 and ONO-8809 inhibited the 13,14-dihydro-15-keto-PGF2 alpha-induced airway hyperresponsiveness to histamine, suggesting that the effect of 13,14-dihydro-15-keto-PGF2 alpha on bronchial hyperresponsiveness is likely to be mediated through TXA2.

Topics: Animals; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Dinoprost; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Thromboxane A2

Prostaglandin F2 alpha (PGF2 alpha) has been suggested to play a role in the pathogenesis of bronchial asthma. In this study, the effects of intravenous administration of 13,14-dihydro-15-keto-PGF2 alpha, a stable metabolite of PGF2 alpha, on bronchial smooth muscle in guinea pigs were investigated by measuring dynamic respiratory resistance using a formula that excludes the effects of differences in airway wall thickness. With this formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of 13,14-dihydro-15-keto-PGF2 alpha did not induce airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was significantly enhanced by the administration of 13,14-dihydro-15-keto-PGF2 alpha. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of 13,14-dihydro-15-keto-PGF2 alpha administration. These results suggest that 13,14-dihydro-15-keto-PGF2 alpha can be important mediators affecting bronchial hyperresponsiveness, and TXA2 may play a part in the 13,14-dihydro-15-keto-PGF2 alpha-induced bronchial hyperresponsiveness.

Topics: Administration, Oral; Animals; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Dinoprost; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Injections, Intravenous; Male; Thromboxane A2

We studied the effect of intravenous administration of 9 alpha,11 beta-prostaglandin F2 on bronchial responsiveness to histamine and airway wall thickening in guinea pigs. The infusion of 9 alpha,11 beta-prostaglandin F2 induced an increase of the relative thickness of the airway wall in peripheral bronchi demonstrable by histological examination. Analysis of airway function showed that the infusion of 9 alpha,11 beta-prostaglandin F2 induced airway hyperresponsiveness to histamine with airway wall thickening. The thromboxane A2 receptor antagonists, ONO-NT-126 (5(Z)-6-[(1R,2R,3R,4S)-3-(n-4-bromobenzenesulfonyl-aminomethyl) bicyclo[2.2.1]heptane-2-yl]hex-5-enoic acid) and ONO-8809 (n-decyl(Z)-6-[(1S,2S,3R,4R)-3-(4-bromobenzenesulfonylaminomethyl) bicyclo[2.2.1]hept-2-yl]-5-hexenoate), inhibited these effects of 9 alpha,11 beta-prostaglandin F2 in a dose-dependent manner.

Topics: Airway Resistance; Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Dinoprost; Dose-Response Relationship, Drug; Drug Interactions; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; Receptors, Thromboxane

Effects of TXA2 antagonists on bronchial hyperresponsiveness induced by intravenous administration of LTC4 in guinea pigs were investigated by measurement of dynamic compliance and dynamic respiratory resistance, using a formula to exclude the effects of changes in airway wall thickness. With the formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness to histamine. Administration of LTC4 induced airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was enhanced by the administration of LTC4. TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the increased ratio of bronchial smooth muscle constriction of LTC4. On the other hand, the antagonists showed no significant effects on airway wall edema by LTC4. These results suggest TXA2 may play a role in LTC4-induced bronchial hyperresponsiveness to histamine.

Topics: Animals; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; SRS-A; Thromboxane A2

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.

Topics: Airway Resistance; Animals; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Dose-Response Relationship, Immunologic; Edema; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Injections, Intravenous; Leukotriene C4; Male; Molecular Structure; Receptors, Thromboxane

Prostaglandin D2 (PGD2) and thromboxane A2 (TXA2) have been suggested to play important roles in the pathogenesis of bronchial asthma. In the present study, effects of i.v.-administration of PGD2 on bronchial hyperresponsiveness in guinea pigs were investigated by the measurement of dynamic compliance and dynamic respiratory resistance with formulae which can exclude the effects of changes of the airway wall thickness. With these formulae, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of PGD2 induced airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was enhanced with the administration of PGD2. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of PGD2 administration.

Topics: Airway Resistance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Edema; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Thromboxane A2

Thromboxane A2 (TXA2) has been suggested to play an important role in the pathogenesis of bronchial asthma. In this study the effects of intravenous administration of TXA2 on bronchial smooth muscle in guinea-pigs were investigated by measuring dynamic compliance and dynamic respiratory resistance, using a formula to exclude the effects of differences in airway wall thickness. Using this formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of TXA2 did not induce airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was significantly (p less than 0.01) enhanced by the administration of TXA2. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of TXA2 administration. These results suggest that TXA2 is an important mediator affecting bronchial hyperresponsiveness.

Topics: Airway Resistance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Lung Compliance; Muscle Contraction; Muscle, Smooth; Thromboxane A2