Planquois J M, Mottin G, Artola M, Lagente V, Payne A, Dahl S
Department Allergie-Inflammation, Institut de Recherche Jouveinal, Fresnes, France.
Eur J Pharmacol. 1998 Feb 26;344(1):59-66. doi: 10.1016/s0014-2999(97)01536-7.
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.
本研究的目的是调查选择性磷酸二酯酶抑制剂及其与沙丁胺醇联合应用对抗原诱导的气管微血管渗漏的影响。在主动致敏的麻醉豚鼠中，非选择性磷酸二酯酶抑制剂茶碱（100mg/kg口服）和选择性4型磷酸二酯酶抑制剂Ro 20-1724（30mg/kg口服）抑制了抗原诱导的微血管渗漏（分别为-73.8%和-44.1%），这通过使用伊文思蓝染料测量血浆蛋白外渗减少得以证明。（a）选择性4型磷酸二酯酶抑制剂咯利普兰（10mg/kg口服）、（b）选择性3型磷酸二酯酶抑制剂米力农（30mg/kg口服）和SK及F 94-836（30mg/kg口服）或（c）选择性1/5型磷酸二酯酶抑制剂扎普司特（30mg/kg口服）均未使微血管渗漏显著减少。Ro 20-1724、咯利普兰和茶碱均未抑制P物质或组胺诱导的微血管渗漏。雾化沙丁胺醇（10μg/ml）预处理增强了茶碱（30mg/kg口服时为-49.8%）和Ro 20-1724（10mg/kg口服时为-52.6%）对抗原诱导的微血管渗漏的抑制作用。此外，用该浓度的雾化沙丁胺醇预处理后，咯利普兰（10mg/kg，口服）产生了显著的抑制作用。即使在较高浓度（0.3 - 2mg/ml）下，沙丁胺醇也未增强咯利普兰和Ro 20-1724对组胺或P物质诱导的微血管渗漏的相应抑制作用。茶碱对P物质诱导的微血管渗漏无作用，但在雾化沙丁胺醇（0.3mg/ml）预处理后对其有显著抑制作用（P < 0.05）。沙丁胺醇增强非选择性和选择性4型磷酸二酯酶抑制剂对抗原诱导的微血管渗漏的抑制作用，可能是由于过敏介质释放的协同减少所致。
