Bronchopulmonary effects of 8-epi-PGF2α in anaesthetised guinea pigs

The compound 8-epi-prostaglandin F-2 alpha (8-epi-PGF(2 alpha)), a F-2-isoprostane formed mainly via a non-cyclooxygenase pathway, has been shown to constrict both human and guinea pig airway smooth muscle in vitro. We investigated whether this compound has any activity on bronchial resistance and plasma exudation in tracheal tissue of anaesthetised guinea pigs. 8-Epi-PGF(2 alpha) (12.5, 25 and 50 mu g kg(-1) i.v.) elicited a dose-dependent increase in intratracheal pressure. Diphenhydramine (2 mg kg(-1) i.v.), indomethacin (1 mg kg(-1) i.v.) and N-G-nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1) i.v.) did not affect the 8-epi-PGF(2 alpha) (25 mu g kg(-1) i.v.)-induced bronchoconstriction. On the contrary, while atropine (0.5 mg kg(-1) i.v.) injected 10 min prior to 8-epi-PGF(2 alpha) (25 mu g kg(-1) i.v.) significantly reduced to 55% (P < 0.05) the increase in intratracheal pressure induced by the isoprostane, the selective thromboxane A(2) receptor antagonist, ICI-192,605 (0.5 mg kg(-1) i.v.) abolished it (95%, P < 0.001). Furthermore, 8-epi-PGF(2 alpha) (50, 100 and 200 mu g kg(-1) i.v.) increased plasma leakage, measured according to the Evans Blue dye technique, in tracheal tissue. This effect was particularly evident when 8-epi-PGF(2 alpha) was injected at the dose of 200 mu g kg(-1) i.v. (105% increase; P < 0.01) and it was markedly reduced by ICI-192,605 (0.5 mg kg(-1) i.v.) (36%; P < 0.01) but not by diphenhydramine (2 mg kg(-1) i.v.). In isolated perfused lungs, 8-epi-PGF(2 alpha) (2.5 mu g ml(-1) min(-1) perfused for 2 min) increased the thromboxane A(2) formation which was significantly reduced by ICI-192,605 (16 mu g ml(-1) min(-1) perfused for 5 min) and abolished by indomethacin (1 mu g ml(-1) min(-1) perfused for 15 min). These data indicate that 8-epi-PGF(2 alpha) induces bronchoconstriction in guinea pig in vivo and that this effect, which seems to be related to activation of thromboxane A(2) receptor, is associated to an augment of vascular permeability with plasma leakage in airway smooth muscle. (C) 1998 The Italian Pharmacological Society.