Bronchopulmonary effects of 8-epi-PGF2A in anaesthetised guinea pigs

The compound 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), a F2-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-PGF2 alpha (12.5, 25 and 50 micrograms 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 NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1 i.v.) did not affect the 8-epi-PGF2 alpha (25 micrograms 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-PGF2 alpha (25 micrograms kg-1 i.v.) significantly reduced to 55% (P < 0.05) the increase in intratracheal pressure induced by the isoprostane, the selective thromboxane A2 receptor antagonist, ICI-192,605 (0.5 mg kg-1 i.v.) abolished it (95%, P < 0.001). Furthermore, 8-epi-PGF2 alpha (50, 100 and 200 micrograms 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-PGF2 alpha was injected at the dose of 200 micrograms 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-PGF2 alpha (2.5 micrograms ml-1 min-1 perfused for 2 min) increased the thromboxane A2 formation which was significantly reduced by ICI-192,605 (16 micrograms ml-1 min-1 perfused for 5 min) and abolished by indomethacin (1 microgram ml-1 min-1 perfused for 15 min). These data indicate that 8-epi-PGF2 alpha induces bronchoconstriction in guinea pig in vivo and that this effect, which seems to be related to activation of thromboxane A2 receptor, is associated to an augment of vascular permeability with plasma leakage in airway smooth muscle.