TY - JOUR T1 - Involvement of TP and EP<sub>3</sub> Receptors in Vasoconstrictor Responses to Isoprostanes in Pulmonary Vasculature JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1060 LP - 1066 DO - 10.1124/jpet.301.3.1060 VL - 301 IS - 3 AU - Luke J. Janssen AU - Tracy Tazzeo Y1 - 2002/06/01 UR - http://jpet.aspetjournals.org/content/301/3/1060.abstract N2 - Although isoprostanes generally act on smooth muscle via TXA2-selective prostanoid receptors (TPs), some suggest other prostanoid receptors or possibly even a novel isoprostane-selective receptor might be involved. We studied contractions to several isoprostanes in porcine pulmonary vasculature using organ bath techniques. 8-iso-prostaglandin E2(PGE2) was the most potent and efficacious of the isoprostanes, with a log EC50 of −7.0 ± 0.2 in the pulmonary artery and −6.8 ± 0.2 in the pulmonary vein. The responses to all the isoprostanes were essentially completely blocked by the TP receptor antagonist ICI 192605 [4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid], and the equilibrium dissociation constants for ICI 192605 competing with U46619 or 8-iso-PGE2 were both ≈2 nM, indicating that isoprostane-evoked responses involve primarily TP receptors. Only 8-iso-PGE2 was able to evoke substantial contractions in the presence of ICI 192605 and only in the pulmonary vein. The EC50 of these ICI 192605-insensitive responses was −6.1 ± 0.2. Using a variety of prostanoid agonists, we found the pulmonary vein lacked excitatory PGF2α-selective prostanoid receptor (FP) or PGD2-selective prostanoid receptor (DP) but expressed excitatory EP3 receptors. The ICI 192605-insensitive responses to 8-iso-PGE2 were unaffected by the EP1 antagonist SC-19220 [8-chloro-debenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl) hydrazine; 10−5 M] but were antagonized by the less selective DP/EP1/EP2 antagonist AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; 10−5 M) or by cyclopiazonic acid (10−5 M; depletes the internal Ca2+ store). Our data indicate that, whereas 8-iso-PGE2 constricts pulmonary vasculature primarily through TP receptors, a substantial portion of this response is also directed through EP3 receptors or possibly a novel isoprostane receptor. The American Society for Pharmacology and Experimental Therapeutics ER -