cAMP-specific phosphodiesterase inhibitor, rolipram, reduces eosinophil infiltration evoked by leukotrienes or by histamine in guinea pig conjunctiva.
The effect of rolipram, an isozyme IV-selective inhibitor of cAMP-specific phosphodiesterase, was evaluated in a guinea pig eye model of tissue eosinophilia. (R)-rolipram was administered by gavage to guinea pigs 1 h prior to topical ocular challenge with a mixture of leukotrienes (LTs) (10 ng LTB4 + 1000 ng LTD4/eye) or with histamine dihydrochloride (1 mg/eye). Conjunctivae were evaluated histologically 6 h after challenge. Eosinophil counts per millimeter of conjunctival epithelium in LT-challenged animals that received (R)-rolipram at dosages of 0.1, 0.3, 1, 3, or 10 mg/kg were reduced by 63, 63, 84, 81 and 90% respectively, compared to LT-challenged controls. Reduction was statistically significant (P < 0.05) at all dosages. Eosinophil counts per millimeter of epithelium in histamine-challenged animals that received 10 mg/kg (R)-rolipram were reduced by 79% compared to histamine-challenged controls (P < 0.01). The results indicate that (R)-rolipram inhibits the response to two distinct classes of mediator in this model of eosinophil infiltration, adding support to the contention that isozyme IV-selective cAMP phosphodiesterase inhibitors offer therapeutic potential for human asthma.
Department of Toxicology SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
S J
SJ
Newsholme
L
L
Schwartz
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D003228:Conjunctiva / Q000187:drug effects*; D003231:Conjunctivitis / Q000139:chemically induced / Q000517:prevention & control*; D004802:Eosinophilia / Q000139:chemically induced / Q000517:prevention & control*; D004804:Eosinophils / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology* / Q000633:toxicity; D007527:Isoenzymes / Q000187:drug effects; D015289:Leukotrienes / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram
D007527:Isoenzymes; D015289:Leukotrienes; D011760:Pyrrolidinones; D006632:Histamine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram