The Phosphodiesterase Type 4 (PDE4) Inhibitor CP-80,633 Elevates Plasma Cyclic AMP Levels and Decreases Tumor Necrosis Factor-α (TNFα) Production in Mice: Effect of Adrenalectomy

• Published in: The Journal of pharmacology and experimental therapeutics 1997-02, Vol.280 (2), p.621
• Main Authors: John B. Cheng, John W. Watson, Christopher J. Pazoles, James D. Eskra, Richard J. Griffiths, Victoria L. Cohan, Claudia R. Turner, Henry J. Showell, E. Roy Pettipher
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103

Rolipram was previously reported to elevate plasma cyclic adenosine 3′,5′-monophosphate (cAMP) and inhibit serum tumor necrosis factor-α (TNFα) production in mice. CP-80,633, a new cyclic nucleotide phosphodiesterase (PDE4) inhibitor, has been shown to augment intracellular cAMP levels and to inhibit TNFα 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 TNFα 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 TNFα 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 TNFα 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 TNFα. The ability of CP-80,633 to block the TNFα response was only slightly affected by adrenalectomy (ED 50 = 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 TNFα 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 TNFα response.