Ortiz J L, Vallés J M, Martí-Cabrera M, Cortijo J, Morcillo E J
Department of Pharmacology, University of Valencia, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Jan;353(2):200-6. doi: 10.1007/BF00168758.
There is currently interest in the potential use of selective inhibitors of cyclic nucleotide phosphodiesterases (PDE) in the treatment of asthma. In this study we examined the effects of three selective PDE inhibitors, milrinone (PDE III), rolipram (PDE IV) and zaprinast (PDE V), on the broncoconstriction produced by antigen and histamine, the airway hyperreactivity and microvascular leakage after aerosol exposure to platelet-activating factor (PAF) and antigen, and the antigen-induced eosinophil infiltration in guinea-pig lung. Inhaled rolipram (0.01-10 mg ml-1) inhibited dose dependently the bronchospasm produced by aerosol antigen (5 mg ml-1) an anaesthetised, ventilated guinea-pigs. Rolipram (10 mg ml-1) produced maximal inhibition of antigen-induced bronchoconstriction but only partial inhibition of the response to aerosol histamine (1 mg ml-1). Milrinone and zaprinast (each 10 mg ml-1) showed weak, or no, inhibitory effects against bronchoconstriction produced by aerosol antigen or histamine. Pretreatment with rolipram (10 mg kg-1, i.p.) prevented airway hyperreactivity to histamine which develops 24 h after exposure of conscious guinea-pigs to aerosol PAF (500 micrograms ml-1) or antigen (5 mg ml-1). The pulmonary eosinophil infiltration obtained with 24 h of antigen-exposure was inhibited by rolipram. In contrast, milrinone and zaprinast (each 10 mg kg-1, i.p.) failed to reduce either the airway hyperreactivity of the eosinophil accumulation in these animals. Rolipram (1-10 mg ml-1) reduced the extravasation of Evans blue after aerosol PAF (500 micrograms ml-1) at all airway levels while a lower dose (0.1 mg ml-1) was only effective at intrapulmonary airways. Rolipram (0.01-1 mg ml-1) markedly reduced airway extravasation produced by inhaled antigen (5 mg ml-1). Zaprinast (1-10 mg ml-1) was also effective against airway microvascular leakage produced by aerosol PAF or antigen while milrinone (10 mg ml-1) had no antiexudative effect. These data support previous suggestions that pharmacological inhibition of PDE IV results in anti-spasmogenic and anti-inflammatory effects in the airways and may be useful in the treatment of asthma.
目前，人们对环核苷酸磷酸二酯酶（PDE）选择性抑制剂在哮喘治疗中的潜在应用颇感兴趣。在本研究中，我们检测了三种选择性PDE抑制剂米力农（PDE III）、咯利普兰（PDE IV）和扎普司特（PDE V）对豚鼠肺中抗原和组胺所致支气管收缩、气溶胶暴露于血小板活化因子（PAF）和抗原后气道高反应性及微血管渗漏，以及抗原诱导的嗜酸性粒细胞浸润的影响。吸入咯利普兰（0.01 - 10 mg/ml）可剂量依赖性地抑制麻醉、通气的豚鼠由气溶胶抗原（5 mg/ml）引起的支气管痉挛。咯利普兰（10 mg/ml）可最大程度抑制抗原诱导的支气管收缩，但仅部分抑制对气溶胶组胺（1 mg/ml）的反应。米力农和扎普司特（均为10 mg/ml）对气溶胶抗原或组胺所致支气管收缩显示出微弱或无抑制作用。咯利普兰（10 mg/kg，腹腔注射）预处理可预防清醒豚鼠暴露于气溶胶PAF（500 μg/ml）或抗原（5 mg/ml）24小时后出现的对组胺的气道高反应性增强。咯利普兰可抑制24小时抗原暴露后出现的肺嗜酸性粒细胞浸润。相比之下，米力农和扎普司特（均为10 mg/kg，腹腔注射）未能降低这些动物中嗜酸性粒细胞积聚的气道高反应性。咯利普兰（1 - 10 mg/ml）可降低所有气道水平上气溶胶PAF（500 μg/ml）后伊文思蓝的渗出，而较低剂量（0.1 mg/ml）仅对肺内气道有效。咯利普兰（0.01 - 1 mg/ml）可显著减少吸入抗原（5 mg/ml）引起的气道渗出。扎普司特（1 - 10 mg/ml）对气溶胶PAF或抗原引起的气道微血管渗漏也有效，而米力农（10 mg/ml）无抗渗出作用。这些数据支持了先前的观点，即PDE IV的药理学抑制可导致气道产生抗痉挛和抗炎作用，可能对哮喘治疗有用。
