8-epi-PGF(2 alpha), a novel noncyclooxygenase-derived prostaglandin, constricts airways in vitro

8-Epi-prostaglandin F-2 alpha (8-epi-PGF(2 alpha)) is an F-2-isoprostane formed via a noncyclooxygenase pathway. We investigated whether 8-epi-PGF(2 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-PGF(2 alpha) in the absence or presence of prostanoid TP- and EP(1)-receptors antagonists (ICI 192,605 and AH 6809, respectively) were compared with the responses to U46619 (a thromboxane A(2) mimetic) and PGF(2 alpha). 8-epi-PGF(2 alpha) contracted airway smooth muscle with a rank order of potency of U46619 > PGF(2 alpha) > 8-epi-PGF(2 alpha) for guinea pig and U46619 > 8-epi-PGF(2 alpha) > PGF(2 alpha) for human smooth muscle. ICI 192,605 inhibited guinea-pig tracheal contraction produced by U46619 (pA(2) = 10.0) with a similar potency to its inhibition of the contraction induced by 8-epi-PGF(2 alpha) (apparent pK(B) = 10.2, 10.3), but not that induced by PGF(2 alpha) (apparent pK(B) = 6.6). AH 6809 inhibited contraction induced by PGF(2 alpha) (pA(2) = 6.6) with a greater potency than contraction induced by U46619 (apparent pK(B) = 5.1, 5.2) or 8-epi-PGF(2 alpha) (apparent pK(B) = 5.3). In human airways, ICI 192,605 inhibited contraction induced by U46619 and 8-epi-PGF(2 alpha) with apparent pK(B) values of 9.5 and 9.4, respectively, and AH 6809 inhibited contraction induced by 8-epi-PGF(2 alpha) with apparent pK(B) values of 5.7 and 5.4. We conclude that 8-epi-PGF(2 alpha) contracts human and guinea-pig airways via prostanoid TP receptors. However, if 8-epi-PGF(2 alpha) is formed in asthma, its production, unlike that of other prostanoids, would not be inhibited by cyclooxygenase inhibitors.