Effects of some isoprostanes on the human umbilical artery in vitro

1 Cumulative concentration-effect curves for the selective prostanoid TP re ceptor agonist U46619 and six isoprostanes were constructed in the human is olated umbilical artery. 2 All compounds except 8-iso-PGF(3 alpha) produced concentration-dependent contractions. The contractile response to the isoprostanes increased with e ach cumulative addition up to a point, after which subsequent addition redu ced the contraction below the previous level. This 'downturn' in the concen tration-effect curve did not occur with U46619. 3 The potencies of the compounds tested were as follows (pEC(50) +/- s.e.me an): U46619, 6.7 +/- 0.2; 8-iso-PGE(2), 6.5 +/- 0.1; 9-iso-PGF(2 alpha), 5. 8 +/- 0.2; 8-iso-PGE(1), 5.4 +/- 0.1; 8-iso-PGF(1 alpha), 5.0 +/- 0.1; 8-is o-PGF(2 beta)> 4.8; 8-iso-PGF(3 alpha)> > 4.8 (n = 4-17). Neither 8-iso-PGF (2 beta) nor 8-iso-PGF(3 alpha) at 44 mu M had a significant effect on cumu lative concentration-effect curves to U46619. 4 The selective TP receptor antagonist GR32191 (0.1 mu M) caused rightward shifts in the concentration-effect curves to all the active compounds. pA(2 ) Values for GR32191 against U46619, 9-iso-PGE(2), 8-iso-PGF(2 alpha), 8-is o-PGE(1), were 7.6 +/- 0.2, 9 +/- 1, 8.2 +/- 0.3 and 7.7 +/- 0.3, respectiv ely (n = 4). 5 Neither N omega-nitro-L-arginine methyl ester (100 mu M) nor the selectiv e DP receptor antagonist BW A868C (50 nM) affected the complex concentratio n-effect curve to 8-iso-PGE(2) (n = 3). 6 Stable contractions to U46619 (1-3 mu M) were unaffected by anandamide at concentrations up to 60 mu M.