VASOREGULATORY PROSTANOID GENERATION PROCEEDS VIA CYCLOOXYGENASE-2 INNONINFLAMED RAT LUNGS

Prostanoids have been implicated in the regulation of lung Vascular to ne both under physiological and inflammatory conditions. The conversio n of arachidonic acid (AA) to prostaglandin H-2 is catalyzed at least by two isoforms of cyclooxygenase, named Cox-1 and Cox-2. Cox-1 is tho ught to be ubiquitously expressed, enrolled in physiological processes , whereas Cox-2 is mostly assumed to be dynamically regulated, respond ing to inflammatory conditions. We have recently shown by immunohistoc hemistry that Cox-2 is constitutively expressed in control rat lungs, with a predominant localization in smooth muscle cells of partially mu scular vessels. We now asked whether Cox-2 is basically involved in th e physiological regulation of pulmonary vascular tone. Isolated perfus ed rat lungs were challenged with intravascular bolus application of f ree AA to elicit thromboxane-related vasoconstrictor responses and to investigate the effects of three different selective Cox-2 inhibitors (NS-398, DUP697, SC-236). AA induced the liberation of prostaglandin I , and thromboxane A, into the intravascular space, and it provoked mar ked pulmonary artery pressure responses and concomitant lung edema for mation. All events were dose-dependently inhibited by 1 to 50 mu mol/l iter NS-398, whereas control vasoconstrictor responses to angiotensin II and the stable thromboxane analogue U46619 were not affected by thi s agent. Similarly, marked inhibition of the AA elicited presser respo nse was achieved by 25 mu mol/l DUP697 and by 10 mu mol/l SC-236. Thes e data suggest a physiological role of Cox-2 rather than Cox-1 in the regulation of vascular tone in rat lungs.