Effect of the isoprostanes, 8-iso prostaglandin E 2 and 8-iso prostaglandin F 2α on the rabbit lung in vivo

Abstract

8-Iso-prostaglandin (PG)E 2 and 8-iso-PGF 2α are members of the isoprostane class of prostanoids which are formed by free radical mediated oxidation of arachidonic acid. Both E 2- and F 2-isoprostanes are potent vasoconstrictors and are believed to act through the prostanoid TP-receptors or a closely related receptor. In lightly anaesthetised, spontaneously breathing rabbits, aerosolised administration of histamine ( (1.25–40 mg ml −1, n = 8) caused a modest dose-dependent increase in total lung resistance (R L) and a concomitant fall in dynamic lung compliance (C L dyn). Aerosolised methacholine (0.625 – 20 mg ml −1, n = 6) caused considerable bronchoconstriction, with a dose-dependent 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 2α (1ng ml −1, − 100μg ml −1, n = 8) had no significant effect on lung function. The TP-receptor agonist, U-46619, was similarly inactive in this model when given by aerosol. Intravenous administration of histamine or 8-iso PGF 2α, had no significant effect on the lung indices, 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 transpulmonary pressure (n = 4, p < 0.05), but had no effect on airflow. At higher doses, it did cause a significant drop in both systemic and right ventricular systolic pressures (n = 4, p < 0.05), which were probably due to an interaction with platelets. The isoprostanes had no effect on the rabbit airway up to a concentration of 3μM. In contrast, 3μM U-46619 caused a modest contraction of tracheal smooth muscle, whilst 3μM methacholine was at least five-fold more potent in contracting the same tissues. We conclude that the aerosolised isoprostanes are not broncho-constriciting agents in the rabbit in vivo.