The granulocyte response to the phosphodiesterase inhibitor RO 20-1724 in asthma.
Isolated human granulocytes secrete the lysosomal enzyme beta glucuronidase when incubated with complement-activated zymosan particles. Isoproterenol inhibits this release, and the beta adrenergic response is associated with an increase in granulocyte cyclic adenosine monophosphate (cAMP) levels. In asthma, the beta adrenergic responsiveness is impaired. Cyclic AMP concentration in the granulocyte is also influenced by phosphodiesterase hydrolysis of this cyclic nucleotide. We found that the potent phosphodiesterase inhibitor, RO 20-1724, inhibited zymosan-stimulated beta glucuronidase release from granulocytes in a dose-dependent fashion (10(-8) to 10(-4) M). The inhibition of lysosomal enzyme release by RO 20-1724 was associated with an increase in granulocyte cAMP. Granulocytes were also isolated from asthmatic patients and the RO 20-1724 inhibition of beta glucuronidase release was compared with the response in normal subjects. The negative log molar median effective dose (ED50) value (mean +/- SE) was 5.98 +/- 0.69 in normal subjects and 5.90 +/- 0.63 in asthmatics. These observations suggest that the granulocyte metabolism modulated by the RO 20-1724-sensitive phosphodiesterase is equally responsive to this potent phosphodiesterase inhibitor in normal and asthmatic leukocytes.
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D001249:Asthma / Q000378:metabolism*; D000242:Cyclic AMP; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors; D015054:Zymosan / Q000494:pharmacology
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D015054:Zymosan; D000242:Cyclic AMP; D005966:Glucuronidase