Effects of the phosphodiesterase inhibitor rolipram on streptococcal cell wall-induced arthritis in rats.
The phosphodiesterase-IV (PDE-IV) inhibitor, rolipram, is antiinflammatory in a number of animal models and inhibits the release of a variety of cytokines, including TNFalpha. Arthritis induced in rats by systemic reactivation with streptococcal cell walls (SCW) following intraarticular sensitization is a TNFalpha-dependent, delayed-type hypersensitivity (DTH) reaction. Rolipram administered during the reactivation phase dose-dependently inhibited hind paw edema through day 24, the day of peak swelling. PMN and T-cell recruitment to the arthritic joint were also attenuated in rolipram-treated rats. Histologic examination of ankle sections from rolipram-treated animals showed a marked attenuation of synovial inflammation. Mechanistic studies to determine the role of glucocorticoids in mediating rolipram action showed that the inhibitory effect of rolipram on swelling was not reversed by RU 486, a glucocorticoid antagonist. In contrast, RU 486 reversed the inhibitory effects of rolipram on TNFalpha secretion. To further evaluate the role of cAMP in the model, the beta-adrenergic receptor (betaAR) agonist isoproterenol was tested, and found to inhibit swelling but not the release of TNFalpha. These results are consistent with the view that the inhibitory effects of rolipram may be partially mediated by cAMP-dependent, but TNFalpha-independent, mechanisms. The betaAR antagonists propranolol and nadolol had no appreciable affect on the antiinflammatory effect of rolipram. However, rolipram reversed the lethal effects of the antagonists observed when either was administered alone. Apparently, beta-adrenergic mechanisms moderate the response to challenge, and rolipram treatment, presumably as a result of its effects on cAMP levels, reverses the toxic effect of the antagonists.
Laemont
K D
KD
Department of Inflammation Therapeutics, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor MI 48105, USA.
Schaefer
C J
CJ
Juneau
P L
PL
Schrier
D J
DJ
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001170:Arthritis, Infectious / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006614:Hindlimb; D006727:Hormone Antagonists / Q000627:therapeutic use; D007545:Isoproterenol / Q000627:therapeutic use; D015735:Mifepristone / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D020889:Rolipram / Q000627:therapeutic use*; D013290:Streptococcal Infections / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D006727:Hormone Antagonists; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D000242:Cyclic AMP; D020889:Rolipram; D007545:Isoproterenol