Hichami A, Boichot E, Germain N, Legrand A, Moodley I, Lagente V
Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire Faculté des Sciences Pharmaceutiques, Université des Rennes, France.
Eur J Pharmacol. 1995 Oct 15;291(2):91-7. doi: 10.1016/0922-4106(95)90129-9.
The effects of selective phosphodiesterase inhibitors, cyclic AMP (cAMP) elevating agents and stable analogues of cyclic nucleotides, on the release of arachidonate induced by N-formyl-Met-Leu-Phe (fMLP) were investigated on human peripheral blood mononuclear cells. The selective phosphodiesterase IV inhibitors, rolipram and Ro 20-1724, and the non-selective phosphodiesterase inhibitor, theophylline, elicited a concentration-dependent inhibition of arachidonate release (EC50 = 1.3 x 10(-6) M, 3.2 x 10(-6) M and 3.7 x 10(-4) M respectively). The selective phosphodiesterase III inhibitor, milrinone (10(-5) M), only caused a slight effect while the phosphodiesterase V inhibitor, zaprinast (10(-5) M), the beta 2-adrenoceptor agonists, salbutamol and fenoterol (10(-5) M), failed to inhibit arachidonate release. Forskolin (10(-5) M) and N6,2'-O- dibutyryladenosine 3':5'-cyclic monophosphate (db-cAMP), 10(-3) M) elicited a moderate inhibition. Forskolin increased the effects of rolipram and Ro 20-1724 (EC50 = 4.5 10(-7) M and 4 x 10(-7) M respectively). Incubation of the cells with rolipram (10(-8) to 10(-5) M), Ro 20-1724 (10(-8) to 10(-5) M, forskolin (10(-5) M) or salbutamol (10(-5) M) alone, induced a moderate increase or no increase at all in intracellular cAMP. However, in the presence of forskolin, rolipram (10(-8) to 10(-6) M) and Ro 20-1724 (10(-8) to 10(-6) M) induced significant and concentration-dependent increase in intracellular levels of cAMP. These results suggest that the potent inhibition of arachidonate release from mononuclear cells by selective phosphodiesterase IV inhibitors may be due to increases in discrete pools of intracellular cAMP.
在人外周血单核细胞上研究了选择性磷酸二酯酶抑制剂、环磷酸腺苷（cAMP）升高剂和环核苷酸稳定类似物对N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）诱导的花生四烯酸释放的影响。选择性磷酸二酯酶IV抑制剂咯利普兰和Ro 20-1724，以及非选择性磷酸二酯酶抑制剂茶碱，均引起花生四烯酸释放的浓度依赖性抑制（EC50分别为1.3×10⁻⁶ M、3.2×10⁻⁶ M和3.7×10⁻⁴ M）。选择性磷酸二酯酶III抑制剂米力农（10⁻⁵ M）仅产生轻微影响，而磷酸二酯酶V抑制剂扎普司特（10⁻⁵ M）、β2-肾上腺素能激动剂沙丁胺醇和非诺特罗（10⁻⁵ M）未能抑制花生四烯酸释放。福斯高林（10⁻⁵ M）和N6,2'-O-二丁酰环磷腺苷（db-cAMP，10⁻³ M）引起中度抑制。福斯高林增强了咯利普兰和Ro 20-1724的作用（EC50分别为4.5×10⁻⁷ M和4×10⁻⁷ M）。单独用咯利普兰（10⁻⁸至10⁻⁵ M）、Ro 20-1724（10⁻⁸至10⁻⁵ M）、福斯高林（10⁻⁵ M）或沙丁胺醇（10⁻⁵ M）孵育细胞，细胞内cAMP适度增加或根本不增加。然而，在福斯高林存在的情况下，咯利普兰（10⁻⁸至10⁻⁶ M）和Ro 20-1724（10⁻⁸至10⁻⁶ M）诱导细胞内cAMP水平显著且呈浓度依赖性增加。这些结果表明，选择性磷酸二酯酶IV抑制剂对单核细胞花生四烯酸释放的有效抑制可能是由于细胞内离散的cAMP池增加所致。
