Effects of theophylline and S 9795 on hyperoxic and hypoxic pulmonary vascular tone in intact dogs

In the literature, it remains uncertain whether methylxanthines inhibit hypoxic pulmonary vasoconstriction. We examined the effects of theophylline and of S 9795, a new methylxanthine derivative, on multipoint mean pulmonary arterial pressure (Ppa)/cardiac index (Q) relationships in 31 intact dogs, ventilated alternately in hyperoxia (fraction of inspired oxygen, FIO2 0.4) and in hypoxia (FIO2 0.1). A sequence of two 5-point Ppa/Q plots at FIO2 0.4 and at FIO2 0.1, consecutively, was performed before and after i.v. administrations of theophylline 10 mg.kg-1 (n = 8) and 25 mg.kg-1 (n = 7), of S 9795 10 mg.kg-1 (n = 8) and of placebo (n = 8). The Ppa/Q plots were rectilinear in all experimental conditions. Over the entire range of Q studied, 2-5 l.min-1.m-2, hypoxia increased Ppa in all animals. Placebo had no effect on these Ppa/Q plots. Theophylline at the lowest dose (plasma levels from 8.4-13.6 micrograms.ml-1) and S 9795 (plasma levels from 3.0-11.2 micrograms.ml-1) did not affect Ppa/Q in hyperoxia or in hypoxia. Theophylline at the highest dose (plasma levels from 17.8-40.4 micrograms.ml-1) reduced hypoxic Ppa at all levels of Q and hyperoxic Ppa at the highest Q, from 3-5 l.min-1.m-2, and inhibited hypoxia-induced increases in Ppa. We conclude that pulmonary vasoconstriction may be preserved after the lowest doses of methylxanthines recommended for the treatment of increased bronchial tone.