The inhibitory effect of rolipram on TNF-alpha production in mouse blood ex vivo is dependent upon the release of corticosterone and adrenaline.
Intraperitoneal administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram (1-30 mg/kg) caused a dose-dependent increase in the circulating levels of both corticosterone and adrenaline in male Balb/c mice. These increases were maximal 0.5-1 h after administration of rolipram and had declined to control levels by 4 h. Rolipram (10 mg/kg i.p.) substantially inhibited the production of tumour necrosis factor alpha (TNF-alpha) ex vivo in blood from normal mice but was ineffective in adrenalectomized mice, suggesting that the inhibitory effect of rolipram is dependent on intact adrenal function. The corticosterone antagonist, RU 486, and the beta-adrenoceptor antagonist, propranolol, both partially reversed the inhibitory activity of rolipram while the combination of RU 486 and popranolol abrogated the effect of the rolipram to the same degree as adrenalectomy. These data suggest the release of both corticosterone and adrenaline contribute to the ability of rolipram to inhibit TNF-alpha production in mouse blood ex vivo.
Pettipher
E R
ER
Central Research Division, Pfizer Inc., Groton, CT, 06340, USA.
Eskra
J D
JD
Labasi
J M
JM
D000315:Adrenalectomy; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000502:physiology*; D004837:Epinephrine / Q000097:blood / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000319:Adrenergic beta-Antagonists; D006727:Hormone Antagonists; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D011433:Propranolol; D020889:Rolipram; D003345:Corticosterone; D004837:Epinephrine