THE PHOSPHODIESTERASE TYPE-4 (PDE4) INHIBITOR CP-80,633 ELEVATES PLASMA CYCLIC-AMP LEVELS AND DECREASES TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) PRODUCTION IN MICE - EFFECT OF ADRENALECTOMY

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 ph osphodiesterase (PDE4) inhibitor, has been shown to augment intracellu lar cAMP levels and to inhibit TNF alpha 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 alpha production in mice with and without adrenal glands. CP-80,633 dose-de pendently (3-32 mg/kg p.o.) elevated plasma cAMP levels and decreased systemic TNF alpha production in response to i.p. injection of lipopol ysaccharide. Elevated plasma cAMP levels can be detected for up to 4 h r. CP-80,633 (10 mg/kg p.o.) caused a 6-fold increase in the plasma cA MP level, a 2-fold increase in the plasma epinephrine level and a grea ter than 95% reduction in TNF alpha production. Unlike CP-80,633, neit her 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 respon se and completely blocked the epinephrine response; however, the level s of plasma cAMP in the CP-80,633-treated mice (10 mg/kg p.o.) remaine d 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 mic e with propranolol, which demonstrates that beta adrenoreceptors contr ibute to the cAMP response. Removal of adrenal glands significantly in creased the LPS-induced elevation of serum TNF alpha. The ability of C P-80,633 to block the TNF alpha response was only slightly affected by adrenalectomy (ED(50) = 1.2 mg/kg in controls vs. 3.9 mg/kg in adrena lectomized mice). Taken together, these results show that CP-80,633, w hen given p.o. to mice, is capable of elevating plasma cAMP and inhibi ting TNF alpha production and that adrenal catecholamines contribute s ignificantly to the effect of CP-80,633 on the cAMP response but only slightly to its effect on the systemic TNF alpha response.