Vol. 280, Issue 2, 621-626, 1997

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

John B. Cheng, John W. Watson, Christopher J. Pazoles, James D. Eskra, Richard J. Griffiths, Victoria L. Cohan, Claudia R. Turner, Henry J. Showell and E. Roy Pettipher

Department of Cancer, Immunology and Infectious Diseases, Central Research Division, Pfizer Inc., Groton, Connecticut

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