EFFECT OF THE ISOPROSTANES, 8-ISO PROSTAGLANDIN E(2) AND 8-ISO PROSTAGLANDIN-F2-ALPHA ON THE RABBIT LUNG IN-VIVO

8-Iso-prostaglandin (PG)E(2) and 8-iso-PGF(2 alpha) are members of the isoprostane class of prostanoids which are formed by free radical med iated oxidation of arachidonic acid. Both E(2)-and F-2-isoprostanes ar e potent vasoconstrictors and are believed to act through the prostano id TP-receptors or a closely related receptor. In lightly anaesthetise d, spontaneously breathing rabbits, aerosolised administration of hist amine (1.25-40 mg ml(-1), n = 8) caused a modest dose-dependent increa se in total lung resistance (R(L)) and a concomitant fall in dynamic l ung compliance (C-L dyn). Aerosolised methacholine (0.625-20 mg ml(-1) , n = 6) caused considerable bronchoconstriction, with a dose-dependen t increase in R(L), and a corresponding fall in C-L dyn. In contrast, intratracheal administration of either 8-iso PGE(2) or 8-iso-PGF(2 alp ha) (1ng ml(-1)-100 mu g ml(-1), n = 8) had no significant effect on l ung function. The TP-receptor agonist, U-46619, was similarly inactive in this model when given by aerosol. Intravenous administration of hi stamine or 8-iso PGF(2 alpha), had no significant effect on the lung i ndices, R(L) and C-L dyn, or on the pulmonary and systemic vasculature (n = 4 per drug group). 8-Iso PGE(2) caused a concentration-dependent decrease in the right ventricular systolic pressure from 3 nmol kg(-1 ) to 100 nmol kg(-1) (n = 4, p < 0.05), but showed no other activity. In contrast, U-46619 given intravenously caused an increase in transpu lmonary pressure (n = 4, p < 0.05), but had no effect on airflow. At h igher doses, it did cause a significant drop in both systemic and righ t ventricular systolic pressures (n = 4, p < 0.05), which were probabl y due to an interaction with platelets. The isoprostanes had no effect on the rabbit airway up to a concentration of 3 mu M. In contrast, 3 mu M U-46619 caused a modest contraction of tracheal smooth muscle, wh ilst 3 mu M methacholine was at least five-fold more potent in contrac ting the same tissues. We conclude that the aerosolised isoprostanes a re not bronchoconstricting agents in the rabbit in vivo. (C) 1997 Else vier Science Inc.