Received for publication May 24, 2006.
Revised January 29, 2007.
Accepted for publication January 30, 2007.

COX-1 and COX-2 Participate in 5,6-Epoxyeicosatrienoic acid-Induced Contraction of Rabbit Intralobar Pulmonary Arteries

Abstract

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 SC-560 (300 nM) prevented 5,6-EET (1 x 10^-8 to 1 x 10-⁵ M) -induced contractions of isolated intralobar rabbit PA rings in a manner similar to that observed with the non-selective cyclooxygenase inhibitor, indomethacin (10 µM). Selective inhibition of COX-2 with either DUP-697 (100 nM) or NS-398 (3 µM) shifted the EC₅₀ 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 since 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, while COX-2 expression was sparse and non-uniform. 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.

Key words: DUP-697, NS-398, SC-560, cytochrome P-450, indomethacin, lung

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