kt2-962 and Hypertension--Pulmonary

We investigated whether KT2-962 (thromboxane H2/A2 receptor antagonist) could attenuate increases in pulmonary arterial and airway pressures after antigen challenge in isolated-perfused sensitized rabbit lungs. Sensitized rabbits were immunized intravenously with human O-N type erythrocytes until the agglutination titer against antigen reached above 1:10,000. Nineteen rabbits were divided into three groups. In N group (n = 9), antigen was challenged into perfusate. In KT2 group (n = 5), 1 mg.kg-1 of KT2-962 was given into reservoir 10 min prior to antigen challenge. In Indo group (n = 5), 5 mg.kg-1 of indomethacin was given into reservoir 20 min prior to antigen challenge. Maximal increase in pulmonary arterial pressure after antigen challenge in N group was significantly higher than that in KT2 group or in Indo group (13.4 +/- 3.3 mmHg, 1.5 +/- 0.5mmHg, 1.5 +/- 0.2mmHg, respectively). Maximal increase in airway pressure in N group was higher than that in KT2 group or in Indo group (2.9 +/- 0.8cmH2O, 0.8 +/- 0.2cmH2O, 0.5 +/- 0.2cmH2O, respectively), but this was not significant. Pharmacological potential of KT2-962 to attenuate pulmonary hypertensive responses was estimated 50 times stronger than that of indomethacin. In conclusion, KT2-962 can exert therapeutic effect on pulmonary hypertensive responses induced by immunological reactions.

Topics: Animals; Benzenesulfonates; Cycloheptanes; Erythrocytes; Female; Humans; Hypertension, Pulmonary; In Vitro Techniques; Male; Perfusion; Rabbits; Receptors, Thromboxane

By adding antigen cells into perfusate circulation, a great increase in pulmonary arterial pressure was observed in isolated perfused lung from rabbits previously immunized with human O-N type erythrocytes. To investigate whether thromboxane A2 is the main mediator in pulmonary vasoconstrictive response, we injected antigen erythrocytes into the reservoir after administration of putative inhibition as follows: indomethacin (5 mg/kg, thromboxane A2 synthetase inhibitor), KT2-962 (.1 mg/kg, thromboxane receptor blocker), and pyrilamine (.1 mumol, H1 blocker). Pulmonary vasoconstrictive response after antigen challenge was significantly blocked by both indomethacin and KT2-962, but not by H1 blocker. Although the H1 blocker, pyrilamine, did not significantly block the pulmonary vasoconstrictive response, it did significantly block the bronchoconstrictive response after antigen challenge; however, the bronchoconstrictive response was not blocked by either indomethacin or KT2-962. We conclude that thromboxane is the main mediator in the pulmonary vasoconstrictive response, and histamine is the main mediator in the bronchoconstrictive response.

Topics: Animals; Antigens; Benzenesulfonates; Blood Pressure; Bronchoconstriction; Cycloheptanes; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Erythrocytes; Histamine; Histamine H1 Antagonists; Humans; Hypertension, Pulmonary; In Vitro Techniques; Indomethacin; Perfusion; Pulmonary Artery; Pyrilamine; Rabbits; Receptors, Thromboxane; Thromboxane A2