Involvement of TP and EP3 Receptors in Vasoconstrictor Responses to Isoprostanes in Pulmonary Vasculature
Journal Articles
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
Although isoprostanes generally act on smooth muscle via TXA(2)-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 E(2) (PGE(2)) was the most potent and efficacious of the isoprostanes, with a log EC(50) 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-PGE(2) were both approximately 2 nM, indicating that isoprostane-evoked responses involve primarily TP receptors. Only 8-iso-PGE(2) was able to evoke substantial contractions in the presence of ICI 192605 and only in the pulmonary vein. The EC(50) of these ICI 192605-insensitive responses was -6.1 +/- 0.2. Using a variety of prostanoid agonists, we found the pulmonary vein lacked excitatory PGF(2alpha)-selective prostanoid receptor (FP) or PGD(2)-selective prostanoid receptor (DP) but expressed excitatory EP(3) receptors. The ICI 192605-insensitive responses to 8-iso-PGE(2) were unaffected by the EP(1) 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/EP(1)/EP(2) antagonist AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; 10(-5) M) or by cyclopiazonic acid (10(-5) M; depletes the internal Ca(2+) store). Our data indicate that, whereas 8-iso-PGE(2) constricts pulmonary vasculature primarily through TP receptors, a substantial portion of this response is also directed through EP(3) receptors or possibly a novel isoprostane receptor.
