Inhibition of pulmonary thromboxane A2 synthase activity and airway responses by CGS 13080

The effects of CGS 13080, a thromboxane (TXA₂) synthase inhibitor, on airway responses to arachidonic acid (AA) were investigated in the anesthetized cat. Feline and human lung microsomal fraction exhibited prostaglandin I₂ (PGI₂, prostacyclin), and TXA₂ synthase activities, and human platelet microsomal fractions exhibited TXA₂ synthase activity. Cat and human lung microsomal fractions, but not human platelets, exhibited the presence of GSH-dependent PGE₂ isomerase activity. CGS 13080 inhibited TXA₂ synthase activity in all three microsomal fractions in a concentration-dependent manner. The increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance in response to AA were decreased significantly by CGS 13080. These data suggest that the bronchoconstrictor actions of AA are mediated in large part by the formation of TXA₂. The data further indicate that cyclooxygenase products other than TXA₂ are involved in the bronchoconstrictor response to AA since meclofenamate had greater inhibitory activity than did CGS 13080. Moreover, the effects of CGS 13080 were due to inhibition of TXA₂ synthase rather than an effect on TXA₂ receptors, since airway responses to the TXA₂ mimic, U46619, were not altered. The present data show that CGS 13080 inhibits TXA₂ synthase activity without altering cyclooxygenase, PGI₂ synthase, or GSH-dependent PGE₂ isomerase activities. The data further indicate that in vivo administration of CGS 13080 may selectively increase PGI₂ synthase activity.