Effects of some isoprostanes on the human umbilical artery in vitro

Cumulative concentration‐effect curves for the selective prostanoid TP receptor agonist U46619 and six isoprostanes were constructed in the human isolated umbilical artery. All compounds except 8‐iso‐PGF 3α produced concentration‐dependent contractions. The contractile response to the isoprostanes increased with each cumulative addition up to a point, after which subsequent addition reduced the contraction below the previous level. This [downturn] in the concentration‐effect curve did not occur with U46619. The potencies of the compounds tested were as follows ( p EC 50 ±s.e.mean): U46619, 6.7±0.2; 8‐iso‐PGE 2 , 6.5±0.1; 8‐iso‐PGF 2α , 5.8±0.2; 8‐iso‐PGE 1 , 5.4±0.1; 8‐iso‐PGF 1α , 5.0±0.1; 8‐iso‐PGF 2β > 4.8; 8‐iso‐PGF 3α >> 4.8 ( n =4–17). Neither 8‐iso‐PGF 2β nor 8‐iso‐PGF 3α at 44 μ M had a significant effect on cumulative concentration‐effect curves to U46619. The selective TP receptor antagonist GR32191 (0.1 μ M ) caused rightward shifts in the concentration‐effect curves to all the active compounds. p A 2 values for GR32191 against U46619, 8‐iso‐PGE 2 , 8‐iso‐PGF 2α , 8‐iso‐PGE 1 were 7.6±0.2, 9±1, 8.2±0.3 and 7.7±0.3, respectively ( n =4). Neither Nω‐nitro‐ L ‐arginine methyl ester (100 μ M ) nor the selective DP receptor antagonist BW A868C (50 n M ) affected the complex concentration‐effect curve to 8‐iso‐PGE 2 ( n =3). Stable contractions to U46619 (1–3 μ M ) were unaffected by anandamide at concentrations up to 60 μ M .British Journal of Pharmacology (2000) 129 , 509–514; doi: 10.1038/sj.bjp.0703083