Abstract
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.
Footnotes
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These studies were supported by operating funds from the Canadian Institutes of Health Research and the Ontario Thoracic Society, and a Scientist Award from the Medical Research Council of Canada.
- Abbreviations:
- ICI 192605
- 4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid
- SC-19220
- 8-chloro-dibenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide
- AH6809
- 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
- PG
- prostaglandin
- CPA
- cyclopiazonic acid
- SQ 29548
- [1S-(1α,2β-(5Z)-3β,4α)]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid
- L 670596
- (−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid
- L 657925
- 9,11-dimethyl-methano-11,12-methano-16-(3-iodo-4-hydroxyl)-13-aza-15α,β-ω-tetranorthromboxane A2
- GR 32191
- [1R- [1α(Z)-2β,3β,5α-(+)-7-[[1,1′-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-4-heptanoic acid] hydrochloride
- BMS 180291
- [1S-(exo,exo)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid
- BW245C
- (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidine heptanoic acid
- Received October 31, 2001.
- Accepted February 11, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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