Effect of the isoprostanes, 8-iso prostaglandin E2 and 8-iso prostaglandin F2α on the rabbit lung in vivo

Abstract

8-Iso-prostaglandin (PG)E₂ 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 E₂- and F₂-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 PGE₂ 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 PGE₂ 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.