EFFECTS OF PHOSPHODIESTERASE INHIBITORS AND SALBUTAMOL ON MICROVASCULAR LEAKAGE IN GUINEA-PIG TRACHEA

The aim of this study was to investigate the effects of selective phos phodiesterase inhibitors and their combination with salbutamol on anti gen-induced microvascular leakage in the trachea. in actively sensitiz ed anaesthetized guinea-pigs, the non-selective phosphodiesterase inhi bitor theophylline (100 mg/kg p.o.) and the selective phosphodiesteras e type 4 inhibitor Ro 20-1724 (30 mg/kg p.o.) inhibited antigen-induce d microvascular leakage (-73.8% and -44.1%, respectively) as demonstra ted by a reduced extravasation of plasma proteins measured by the use of Evans blue dye. No significant reduction in microvascular leakage w as seen with (a) the selective phosphodiesterase type 4 inhibitor roli pram (10 mg/kg p.o.), (b) the selective phosphodiesterase type 3 inhib itors milrinone (30 mg/kg p.o.) and SK and F 94-836 (30 mg/kg p.o.) or (c) the selective phosphodiesterase type 1/5 inhibitor zaprinast (30 mg/kg p.o.). Neither Ro 20-1724 nor rolipram and theophylline inhibite d microvascular leakage induced by either substance P or histamine. Pr etreatment with aerosolized salbutamol (10 mu g/ml) potentiated the in hibitory effects of theophylline (-49.8% at 30 mg/kg p.o.) and Ro 20-1 724 (-52.6% at 10 mg/kg p.o.) versus antigen-induced microvascular lea kage. Furthermore, a significant inhibitory effect of rolipram (10 mg/ kg, p.o.) was obtained following pretreatment with this concentration of aerosolized salbutamol. Even at higher concentrations (0.3-2 mg/ml) salbutamol did not augment the corresponding inhibitory effects of ro lipram and Ro 20-1724 versus microvascular leakage induced by either h istamine or substance P. Theophylline had no effect versus substance P -induced microvascular leakage, but did inhibit it significantly(P < 0 .05) after pretreatment with aerosolized salbutamol (0.3 mg/ml). The p otentiation by salbutamol of the inhibitory effects of both non-select ive and selective phosphodiesterase type 4 inhibitors versus antigen-i nduced microvascular leakage probably results from a synergistic reduc tion in the release of anaphylactic mediators. (C) 1998 Elsevier Scien ce B.V.