The cyclooxygenase (COX) enzyme in the vascular endothelium has the unique ability to produce both vasodilators and vasoconstrictors (Davidge, 2001). This makes it an important determinant of endothelial function and dysfunction and therefore a double-edged regulator of vascular tone. However, it is not clear, particularly in healthy resistance arteries whether these opposing roles are determined by the relative expression and activity of its isoforms COX-1 and COX-2. Thus we investigated whether the double-edged role of the enzyme in healthy resistance arteries is isoform-specific. Skeletal muscle (SKM) and mesenteric vasa recta (MVR) resistance arteries were isolated from samples obtained from healthy male sheep euthanized in a government-controlled slaughter house in Doha and therefore did not require additional ethics approval. Endothelium-dependent relaxation to Acetylcholine (Ach, 10-10-10-4.5 M) was studied by wire myography in the absence and presence of 10 µM indomethacin (non-selective COX inhibitor), 1 µM FR122047 (COX-1 selective inhibitor) or 4 µM Celecoxib (COX-2 selective inhibitor). Experiments were also carried out in the absence and presence of 100 µM N(ω)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor). Messenger RNA for both isoforms of the enzyme were also measured by RT-PCR. Values are means ± SEM., and comparisons were made with ANOVA or students t-test as appropriate. Both arteries were relaxed by Ach in a dose-dependent manner. Greater maximum relaxation was recorded in SKM arteries (Imax 90.6±1.7 %, n=21) compared with MVR arteries (85.5±4.1 %, n=19, p<0.01). The SKM arteries were also more sensitive to Ach compared with MVR arteries (log IC50 -7.6±0.1 vs. -6.9±0.2 M for SKM vs. MVR, p<0.001). Indomethacin had opposite effects on the relaxation of the two arteries: It attenuated SKM relaxation but enhanced the relaxation of MVR arteries. FR122047 attenuated relaxation of both arteries with significant rightward shift in the curve for SKM arteries (n=8, p<0.001). On the other hand, Celecoxib significantly enhanced the relaxation of MVR arteries (n=5, P<0.01,) but had no noticeable effect on the SKM arteriolar relaxation. In the presence of L-NAME, the curves for both arteries were shifted to the right (n=7-8, p<0.01). COX-1 mRNA was more abundant in SKM arteries compared with MVR arteries (n=6-8, p<0.05). On the other hand, COX-2 mRNA was slightly more abundant in the MVR compared with SKM arteries, although the difference was not statistically significant. These results suggest that the opposing roles of COX in these apparently healthy ovine resistance arteries are isoform-specific, with COX-1 driving positive regulation in SKM arteries, and COX-2 responsible for negative vasomotor regulation of MVR arteries.