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 phosphodiesterase inhibitors and their combination with salbutamol on antigen-induced microvascular leakage in the trachea. In actively sensitized anaesthetized guinea-pigs, the non-selective phosphodiesterase inhibitor theophylline (100 mg/kg p.o.) and the selective phosphodiesterase type 4 inhibitor Ro 20-1724 (30 mg/kg p.o.) inhibited antigen-induced microvascular leakage (-73.8% and -44.1%, respectively) as demonstrated by a reduced extravasation of plasma proteins measured by the use of Evans blue dye. No significant reduction in microvascular leakage was seen with (a) the selective phosphodiesterase type 4 inhibitor rolipram (10 mg/kg p.o.), (b) the selective phosphodiesterase type 3 inhibitors 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 inhibited microvascular leakage induced by either substance P or histamine. Pretreatment with aerosolized salbutamol (10 microg/ml) potentiated the inhibitory effects of theophylline (-49.8% at 30 mg/kg p.o.) and Ro 20-1724 (-52.6% at 10 mg/kg p.o.) versus antigen-induced microvascular leakage. 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 rolipram and Ro 20-1724 versus microvascular leakage induced by either histamine 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 potentiation by salbutamol of the inhibitory effects of both non-selective and selective phosphodiesterase type 4 inhibitors versus antigen-induced microvascular leakage probably results from a synergistic reduction in the release of anaphylactic mediators.
Planquois
J M
JM
Department Allergie-Inflammation, Institut de Recherche Jouveinal, Fresnes, France.
Mottin
G
G
Artola
M
M
Lagente
V
V
Payne
A
A
Dahl
S
S
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013373:Substance P / Q000008:administration & dosage; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply*
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D013373:Substance P; D006632:Histamine; D010047:Ovalbumin; D013806:Theophylline; D000420:Albuterol