Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram.
Selective inhibition of the low Km cyclic AMP-specific phosphodiesterase has been shown to inhibit inflammatory cell function and relax airway smooth muscle. These studies were conducted to characterize the bronchodilator and anti-inflammatory activity of rolipram, an archetypical cyclic AMP-specific phosphodiesterase inhibitor, in in vitro and in vivo guinea pig airway models. In isolated tracheal rings from ovalbumin (OA)-sensitive guinea pigs, both R- and S-enantiomers of rolipram (1 microM) significantly antagonized OA-induced contractions. In contrast, neither enantiomer at concentrations up to 1 microM significantly inhibited histamine- or LTD4-induced contractions. In superfusion and mediator release experiments, both enantiomers of rolipram significantly reduced antigen-induced prostaglandin D2 release, but had minimal effect on histamine release. In anesthetized, ventilated OA-sensitive guinea pigs, racemic rolipram or enantiomers reduced OA-induced bronchoconstriction with ID50 values of approximately 0.25 mg/kg i.v. Histamine- and leukotriene D4-induced bronchoconstriction were not affected by doses of rolipram which abolished the response to OA. Higher doses (3-10 mg/kg) reduced histamine-, but not the leukotriene D4-induced bronchoconstriction. In conscious OA-sensitive guinea pigs, intragastric pretreatment with rolipram dose-dependently reduced both the OA-induced decreases in specific conductance as well as the corresponding pulmonary eosinophil influx as assessed by both bronchoalveolar lavage and histological evaluation. Therefore, rolipram produces significant inhibition of antigen-induced bronchoconstrictor and inflammatory responses, thus providing strong evidence that this pharmacological approach may be of significant therapeutic value in allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Underwood
D C
DC
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Osborn
R R
RR
Novak
L B
LB
Matthews
J K
JK
Newsholme
S J
SJ
Undem
B J
BJ
Hand
J M
JM
Torphy
T J
TJ
D000758:Anesthesia; D000818:Animals; D000941:Antigens; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000276:immunology*; D003243:Consciousness; D000242:Cyclic AMP / Q000378:metabolism*; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects; D006168:Guinea Pigs; D008168:Lung / Q000166:cytology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010047:Ovalbumin; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010991:Plethysmography; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D013237:Stereoisomerism; D013379:Substrate Specificity; D014132:Trachea / Q000187:drug effects
D000941:Antigens; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D010047:Ovalbumin; D000242:Cyclic AMP; D020889:Rolipram