Selective Inhibitors of Cyclooxygenase 1 & 2 Decrease 5,6‐EET‐Induced Contraction of Rabbit Intralobar Pulmonary Arteries

Abstract

Previously, we reported that 5,6-epoxyeicosatrienoic acid (EET) increased tension in small intralobar rabbit pulmonary arteries (IPAs). The non-selective cyclooxygenase (COX) inhibitor indomethacin decreased EET-induced IPA contraction. COX-1 and COX-2 isoforms have been reported to be expressed constitutively in rabbit lung. We hypothesized that both COX isoforms are expressed in rabbit pulmonary vasculature and contribute to the 5,6-EET-induced IPA responses. IPA (1-3 mm od) rings were suspended from force displacement transducers in physiological salt solution gassed with 95% O2, 5% CO2. The presence of COX-1 and COX-2 in IPAs was verified by Western immunoblotting. COX-1 and COX-2 metabolized [14C]-5,6-EET at the rates of 0.8 ± 0.2 and 0.5 ± 0.3 μmole · protein −1 · min−1, respectively (n=3). Administration of 5,6-EET resulted in IPA contractions of 0.35 ± 0.21 g at 0.3 μM and 1.17 ± 0.23 g at 3 μM. In the presence of a selective COX-1 inhibitor, SC-560 (300 nM), these contractions were completely abolished (n=6, P<0.05). In contrast, in the presence of a selective COX-2 inhibitor, NS-398 (3 μM) contractions to 0.3 μM 5,6-EET were also abolished, but contractions to 3 μM 5,6-EET were only reduced from 1.13 ± 0.4 to 0.23 ± 0.05 g (n=7, P<0.05), suggesting a greater dependence of 5,6-EET-induced contraction on COX-1 than COX-2 activity. We conclude that IPAs constitutively express both COX isoforms, COX-1 and COX-2 metabolize 5,6-EET at similar rates, and 5,6-EET-induced contraction of rabbit IPA is dependent on the activities of both COX-1 and COX-2. Supported by NIH grants: HL-52675 and HL-64180.