Cheng J B, Watson J W, Pazoles C J, Eskra J D, Griffiths R J, Cohan V L, Turner C R, Showell H J, Pettipher E R
Department of Cancer, Immunology and Infectious Diseases, Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
J Pharmacol Exp Ther. 1997 Feb;280(2):621-6.
Rolipram was previously reported to elevate plasma cyclic adenosine 3',5'-monophosphate (cAMP) and inhibit serum tumor necrosis factor-alpha (TNF-alpha) production in mice. CP-80,633, a new cyclic nucleotide phosphodiesterase (PDE4) inhibitor, has been shown to augment intracellular cAMP levels and to inhibit TNFalpha release from human monocytes in vitro. This study was undertaken to determine the effect of p.o. CP-80,633 on plasma cAMP levels and lipopolysaccharide-induced TNFalpha production in mice with and without adrenal glands. CP-80,633 dose-dependently (3-32 mg/kg p.o.) elevated plasma cAMP levels and decreased systemic TNFalpha production in response to i.p. injection of lipopolysaccharide. Elevated plasma cAMP levels can be detected for up to 4 hr. CP-80,633 (10 mg/kg p.o.) caused a 6-fold increase in the plasma cAMP level, a 2-fold increase in the plasma epinephrine level and a greater than 95% reduction in TNFalpha production. Unlike CP-80,633, neither vinpocetine, dipyridamole, SKB-94,120 nor zaprinast, at 100 mg/kg p.o., modified the cAMP response, which suggests that this response is mediated by inhibition of PDE4. Adrenalectomy reduced the cAMP response and completely blocked the epinephrine response; however, the levels of plasma cAMP in the CP-80,633-treated mice (10 mg/kg p.o.) remained elevated (vehicle: 47.3 +/- 6.8 vs. CP-80,633: 98.4 +/- 10.3 pmol/ml, n = 7, P < .05). This effect is mimicked by treatment of control mice with propranolol, which demonstrates that beta adrenoreceptors contribute to the cAMP response. Removal of adrenal glands significantly increased the LPS-induced elevation of serum TNFalpha. The ability of CP-80,633 to block the TNFalpha response was only slightly affected by adrenalectomy (ED50 = 1.2 mg/kg in controls vs. 3.9 mg/kg in adrenalectomized mice). Taken together, these results show that CP-80,633, when given p.o. to mice, is capable of elevating plasma cAMP and inhibiting TNFalpha production and that adrenal catecholamines contribute significantly to the effect of CP-80,633 on the cAMP response but only slightly to its effect on the systemic TNFalpha response.
罗匹尼罗曾被报道可提高小鼠血浆环磷腺苷（cAMP）水平，并抑制血清肿瘤坏死因子-α（TNF-α）的产生。CP-80,633是一种新型环核苷酸磷酸二酯酶（PDE4）抑制剂，已被证明可提高细胞内cAMP水平，并在体外抑制人单核细胞释放TNF-α。本研究旨在确定口服CP-80,633对有肾上腺和无肾上腺小鼠血浆cAMP水平以及脂多糖诱导的TNF-α产生的影响。CP-80,633剂量依赖性地（口服3 - 32 mg/kg）提高血浆cAMP水平，并降低腹腔注射脂多糖后全身TNF-α的产生。血浆cAMP水平升高可持续检测长达4小时。CP-80,633（口服10 mg/kg）使血浆cAMP水平增加6倍，血浆肾上腺素水平增加2倍，并使TNF-α产生减少超过95%。与CP-80,633不同，口服100 mg/kg的长春西汀、双嘧达莫、SKB-94,120或扎普司特均未改变cAMP反应，这表明该反应是由PDE4抑制介导的。肾上腺切除术降低了cAMP反应并完全阻断了肾上腺素反应；然而，CP-80,633处理的小鼠（口服10 mg/kg）血浆cAMP水平仍保持升高（溶剂对照组：47.3±6.8 vs. CP-80,633组：98.4±10.3 pmol/ml，n = 7，P <.05）。用普萘洛尔处理对照小鼠可模拟这种效应，这表明β肾上腺素能受体参与了cAMP反应。摘除肾上腺显著增加了脂多糖诱导的血清TNF-α升高。CP-80,633阻断TNF-α反应的能力仅受到肾上腺切除术的轻微影响（对照组ED50 = 1.2 mg/kg，肾上腺切除小鼠组为3.9 mg/kg）。综上所述，这些结果表明，口服CP-80,633给小鼠后，能够提高血浆cAMP水平并抑制TNF-α产生，并且肾上腺儿茶酚胺对CP-80,633对cAMP反应的影响有显著贡献，但对其对全身TNF-α反应的影响贡献较小。
