8-Epi-PGF2 alpha, a novel noncyclooxygenase-derived prostaglandin, constricts airways in vitro.
8-Epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) is an F2-isoprostane formed via a noncyclooxygenase pathway. We investigated whether 8-epi-PGF2 alpha has any effects on isolated guinea-pig and human airway smooth-muscle tone, and characterized the receptor involved in these effects. Cumulative concentration responses to 8-epi-PGF2 alpha in the absence or presence of prostanoid TP- and EP1-receptors antagonists (ICI 192, 605 and AH 6809, respectively) were compared with the responses to U46619 (a thromboxane A2 mimetic) and PGF2 alpha. 8-epi-PGF2 alpha contracted airway smooth muscle with a rank order of potency of U46619 > PGF alpha > 8-epi-PGF2 alpha for guinea pig and U46619 > 8-epi-PGF2 alpha > PGF2 alpha for human smooth muscle. ICI 192,605 inhibited guinea-pig tracheal contraction produced by U46619 (pA2 = 10.0) with a similar potency to its inhibition of the contraction induced by 8-epi-PGF2 alpha (apparent pKB = 10.2, 10.3), but not that induced by PGF2 alpha (apparent pKB = 6.6). AH 6809 inhibited contraction induced by PGF2 alpha (pA2 = 6.6) with a greater potency than contraction induced by U46619 (apparent pKB = 5.1, 5.2) or 8-epi-PGF2 alpha (apparent pKB = 5.3). In human airways, ICI 192,605 inhibited contraction induced by U46619 and 8-epi-PGF2 alpha with apparent pKB values of 9.5 and 9.4, respectively, and AH 6809 inhibited contraction induced by 8-epi-PGF2 alpha with apparent pKB values of 5.7 and 5.4. We conclude that 8-epi-PGF2 alpha contracts human and guinea-pig airways via prostanoid TP receptors. However, if 8-epi-PGF2 alpha is formed in asthma, its production, unlike that of other prostanoids, would not be inhibited by cyclooxygenase inhibitors.
Kawikova
I
I
Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
Barnes
P J
PJ
Takahashi
T
T
Tadjkarimi
S
S
Yacoub
M H
MH
Belvisi
M G
MG
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000293:Adolescent; D000328:Adult; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D004146:Dioxanes; D028441:F2-Isoprostanes; D011448:Prostaglandin Antagonists; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D014966:Xanthenes; D044004:Xanthones; C057498:ICI 192605; C075750:8-epi-prostaglandin F2alpha; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost