Influence of the thromboxane antagonist BM 13.177 on the arachidonic acid-induced increase in pulmonary vascular resistance and permeability in rabbit lungs.
In blood-free perfused isolated rabbit lungs increased availability of free arachidonic acid (AA), whether exogenously applied or released from the endogenous membrane phospholipid pool after different stimuli, causes an acute pulmonary artery pressor response and an increase in vascular permeability. Previous experiments suggested that the vasoconstriction is caused primarily by the cyclooxygenase product thromboxane (Tx) A2, whereas an increase in the capillary filtration coefficient must be ascribed to non-cyclooxygenase products of AA. The influence of BM 13.177, a non-prostanoic antagonist of TxA2- and endoperoxide-effects in platelets, on the AA-induced vascular effects in isolated rabbit lungs was investigated. BM 13.177 dose-dependently inhibited the pressor responses evoked by repetitive direct application of AA (IC50 approximately 10(-6) M) or by repetitive stimulation of endogenous AA-release with the calcium-ionophore A 23187 (IC50 approximately 10(-7) M), with maximum reduction of the pressor responses to less than 15%. The generation of TxA2 and of prostaglandin (PG) I2 evoked by these stimuli was, however, not altered. At a concentration of 10(-5) M BM 13.177 did not influence the capillary filtration coefficient, measured during venous pressure challenge, under baseline conditions and after stimulation with AA in presence of indomethacin.


CONCLUSIONS
BM 13.177 acts as TxA2/endoperoxide antagonist with dose-dependent inhibition of AA-induced vasoconstriction in the pulmonary vascular bed.
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000032:analysis; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D001095:Arachidonic Acids; D005343:Fibrinolytic Agents; D013449:Sulfonamides; D016718:Arachidonic Acid; D000001:Calcimycin; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C040624:sulotroban; D007213:Indomethacin