Vasoregulatory prostanoid generation proceeds via cyclooxygenase-2 in noninflamed rat lungs.
Prostanoids have been implicated in the regulation of lung vascular tone both under physiological and inflammatory conditions. The conversion of arachidonic acid (AA) to prostaglandin H2 is catalyzed at least by two isoforms of cyclooxygenase, named Cox-1 and Cox-2. Cox-1 is thought to be ubiquitously expressed, enrolled in physiological processes, whereas Cox-2 is mostly assumed to be dynamically regulated, responding to inflammatory conditions. We have recently shown by immunohistochemistry that Cox-2 is constitutively expressed in control rat lungs, with a predominant localization in smooth muscle cells of partially muscular vessels. We now asked whether Cox-2 is basically involved in the physiological regulation of pulmonary vascular tone. Isolated perfused rat lungs were challenged with intravascular bolus application of free 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 I2 and thromboxane A2 into the intravascular space, and it provoked marked pulmonary artery pressure responses and concomitant lung edema formation. All events were dose-dependently inhibited by 1 to 50 micromol/liter NS-398, whereas control vasoconstrictor responses to angiotensin II and the stable thromboxane analogue U46619 were not affected by this agent. Similarly, marked inhibition of the AA elicited pressor response was achieved by 25 micromol/l DUP697 and by 10 micromol/l SC-236. These data suggest a physiological role of Cox-2 rather than Cox-1 in the regulation of vascular tone in rat lungs.
Ermert
L
L
Department of Pathology, Justus-Liebig-University Giessen, 35385 Giessen, Germany.
Ermert
M
M
Althoff
A
A
Merkle
M
M
Grimminger
F
F
Seeger
W
W
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000502:physiology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D007527:Isoenzymes; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases