Cyclooxygenase (COX)-1 and COX-2 participate in 5,6-epoxyeicosatrienoic acid-induced contraction of rabbit intralobar pulmonary arteries.
Epoxyeicosatrienoic acids (EETs) have been reported to contract intralobar pulmonary arteries (PA) of the rabbit in a cyclooxygenase (COX)-dependent manner. In the present study, we observed that COX-1 and COX-2 isoforms were expressed in freshly isolated PA of healthy rabbits. We examined the hypothesis that both COX isoforms participate in 5,6-EET-induced contraction of rabbit intralobar PA. Selective inhibition of COX-1 with 300 nM 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) prevented 5,6-EET (1x10(-8)-1x10(-5) M)-induced contractions of isolated intralobar rabbit PA rings in a manner similar to that observed with the nonselective cyclooxygenase inhibitor indomethacin at 10 microM. Selective inhibition of COX-2 with either 100 nM 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl) thiophene (DUP-697) or 3 microM N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) shifted the EC50 value of 5,6-EET-induced PA contraction to the right but with considerably lower efficacy than SC-560. In rabbit PA, 5,6-EET-induced contraction was primarily dependent on COX-1 activity. Differential metabolism of 5,6-EET by COX-1 and COX-2 does not explain the primary dependence of PA contraction on COX-1 activity because 5,6-EET was metabolized similarly by both COX isoforms. COX-1 and -2 were expressed primarily in PA endothelium where COX-1 expression was dense and uniform, whereas COX-2 expression was sparse and nonuniform. 5,6-EET-induced PA contraction was endothelium-dependent. These results suggest that 5,6-EET-induced contraction is primarily dependent on COX-1 activity.
Moreland
K Trent
KT
Department of Pharmacological and Physiological Science, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
Procknow
Jesse D
JD
Sprague
Randy S
RS
Iverson
Jennifer L
JL
Lonigro
Andrew J
AJ
Stephenson
Alan H
AH
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015126:8,11,14-Eicosatrienoic Acid