Howell R E, Sickels B D, Woeppel S L
Inflammation/Bone Metabolism Division, Wyeth-Ayerst Research, Princeton, New Jersey.
J Pharmacol Exp Ther. 1993 Feb;264(2):609-15.
The effectiveness of theophylline (aminophylline) in treating asthma may result in part from nonselective inhibition of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE). The roles for inhibition of different PDE isozymes in the pulmonary antiallergic and bronchodilator effects of theophylline were investigated in anesthetized and ventilated guinea pigs by using the PDE-III-selective inhibitor Cl-930, the PDE-IV-selective inhibitor rolipram and the PDE-V-selective inhibitor zaprinast. Aminophylline, Cl-930 and rolipram inhibited aerosol ovalbumin-induced full [leukotriene (LT) + histamine] and LT-dependent bronchoconstriction, but zaprinast was inactive. At doses producing an equieffective inhibition of antigen-induced full bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of aerosol histamine-induced bronchoconstriction, whereas rolipram produced much less inhibition of histamine-induced bronchoconstriction. At doses producing an equieffective inhibition of antigen-induced LT-dependent bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of i.v. LTD4-induced bronchoconstriction, whereas rolipram did not inhibit LTD4-induced bronchoconstriction. Acute airway hyperreactivity was evidenced by significant leftward shifts in dose-response curves to i.v. methacholine-induced bronchoconstriction 24 hr after aerosol ovalbumin challenge. Aminophylline and rolipram prevented airway hyperreactivity without causing residual bronchodilation 24 hr after antigen challenge. In contrast, Cl-930 failed to inhibit airway hyperreactivity, but produced substantial residual bronchodilation. The results indicate that PDE-IV inhibition produces pulmonary antiallergic effects in vivo, including the apparent inhibition of LT release, which may contribute to the antiasthmatic actions of theophylline. The results also support previous suggestions that PDE-III inhibition contributes to the bronchodilator effect of theophylline.
茶碱（氨茶碱）治疗哮喘的有效性可能部分源于其对环核苷酸磷酸二酯酶（PDE）多种同工酶的非选择性抑制。通过使用PDE-III选择性抑制剂Cl-930、PDE-IV选择性抑制剂咯利普兰和PDE-V选择性抑制剂扎普司特，在麻醉通气的豚鼠中研究了抑制不同PDE同工酶在茶碱肺部抗过敏和支气管扩张作用中的作用。氨茶碱、Cl-930和咯利普兰抑制雾化卵清蛋白诱导的完全性[白三烯（LT）+组胺]和LT依赖性支气管收缩，但扎普司特无活性。在产生等效抑制抗原诱导的完全性支气管收缩的剂量下，氨茶碱和Cl-930对雾化组胺诱导的支气管收缩产生相似的抑制作用，而咯利普兰对组胺诱导的支气管收缩的抑制作用则小得多。在产生等效抑制抗原诱导的LT依赖性支气管收缩的剂量下，氨茶碱和Cl-930对静脉注射LTD4诱导的支气管收缩产生相似的抑制作用，而咯利普兰不抑制LTD4诱导的支气管收缩。雾化卵清蛋白激发后24小时，静脉注射乙酰甲胆碱诱导的支气管收缩剂量反应曲线显著左移，证明存在急性气道高反应性。氨茶碱和咯利普兰可预防气道高反应性，且在抗原激发后24小时不会引起残留支气管扩张。相比之下，Cl-930未能抑制气道高反应性，但产生了显著的残留支气管扩张。结果表明，抑制PDE-IV在体内产生肺部抗过敏作用，包括明显抑制LT释放，这可能有助于茶碱的抗哮喘作用。结果还支持先前的观点，即抑制PDE-III有助于茶碱的支气管扩张作用。
