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Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan‐stimulated respiratory burst by ‘type IV’‐selective PDE inhibitors
Author(s) -
Dent Gordon,
Giembycz Mark A.,
Rabe Klaus F.,
Barnes Peter J.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb09790.x
Subject(s) - rolipram , zaprinast , phosphodiesterase , respiratory burst , chemistry , cyclic nucleotide , zymosan , cyclic nucleotide phosphodiesterase , adenosine , biochemistry , enzyme , nucleotide , in vitro , gene
1 The cyclic nucleotide phosphodiesterase (PDE) of guinea‐pig eosinophils was partially characterized and the effects of selective inhibitors of PDE isoenzymes upon opsonized zymosan (OZ)‐stimulated respiratory burst were studied. 2 PDE activity in eosinophil lysates appeared to be membrane‐associated, displayed substrate specificity for adenosine 3′: 5′ cyclic monophosphate (cyclic AMP) versus guanosine 3′: 5′ cyclic monophosphate (cyclic GMP) and was insensitive to cyclic GMP or Ca 2+ and calmodulin. 3 The non‐selective PDE inhibitor, 3‐isobutyl‐1‐methylxanthine caused a concentration‐dependent inhibition of both OZ‐stimulated hydrogen peroxide (H 2 O 2 ) generation and cyclic AMP hydrolysis. The type IV‐selective PDE inhibitors, rolipram and denbufylline, also inhibited H 2 O 2 generation and cyclic AMP hydrolysis in a concentration‐dependent manner whilst SK&F 94120 and Org 9935 (type III‐selective) and zaprinast (type Ia or V‐selective) were ineffective. 4 Dibutyryl cyclic AMP, a cell‐permeable, non‐hydrolysable analogue of cyclic AMP, caused a concentration‐dependent inhibition of H 2 O 2 generation stimulated by OZ. Dibutyryl cyclic GMP was ineffective. 5 It is concluded that eosinophil respiratory burst activity induced by OZ can be regulated by intracellular cyclic AMP and that the levels of cyclic AMP are controlled exclusively by a rolipram‐ and denbufylline‐sensitive PDE isoenzyme that resembles a type IV species.