The ability of phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity.
Elevation of cyclic AMP (cAMP) content inhibits eosinophil function. Because phosphodiesterase IV (PDE IV) appears to be the major PDE isozyme present in eosinophils, inhibitors of this isozyme should suppress eosinophil activation. Previous studies on PDE IV have revealed that this enzyme possesses both cAMP catalytic activity that is inhibitable by rolipram, a prototypical PDE IV inhibitor, and a high-affinity binding site for rolipram. The function of this high-affinity rolipram binding site relative to the inhibitory action of compounds is not clear because the rank order potency of PDE IV inhibitors for competing with [3H]-rolipram binding is distinct from that for inhibiting cAMP hydrolysis. Consequently, the present experiments were carried out to fulfill the following objectives: 1) to determine whether PDE IV inhibitors suppress eosinophil function and, if so, 2) to establish a correlation between this functional activity and inhibition of PDE IV catalytic activity or interaction with the high-affinity rolipram binding site. Various PDE inhibitors produced approximately 60% maximal inhibition of formylmethionine-leucine-phenylalanine-induced superoxide anion production, so that IC30 concentrations were used as a basis to compare the potency of various PDE inhibitors. Selective PDE IV inhibitors were the most potent compounds tested. PDE inhibitors selective for other isozymes were devoid of activity or considerably less potent.(ABSTRACT TRUNCATED AT 250 WORDS)
Barnette
M S
MS
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Manning
C D
CD
Cieslinski
L B
LB
Burman
M
M
Christensen
S B
SB
Torphy
T J
TJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram