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

Version 2

      Publication Details (including relevant citation   information):

      The Journal of Pharmacology and Experimental Therapeutics

      Vol. 321, No. 2, pg. 446–454,   (2007)

      ISSN: 0022-3565

      DOI: 10.1124/jpet.106.107904

      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 300 nM   5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole   (SC-560) prevented 5,6-EET-induced contractions of isolated   intralobar rabbit PA rings in a manner similar to that   observed with the nonselective cyclooxygenase inhibitor   indomethacin at 10 M.  Selective inhibition of COX-2 with   either 100 nM 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl)   thiophene (DUP-697) or 3M 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.

      Address (URL): http://jpet.aspetjournals.org.   doi:10.1124/jpet.106.107904