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Effects of SCA40 on human isolated bronchus and human polymorphonuclear leukocytes: comparison with rolipram, SKF94120 and levcromakalim
Author(s) -
Cortijo J.,
Villagrasa V.,
Navarrete C.,
Sanz C.,
Berto L.,
Michel A.,
Bonnet P.A.,
Morcillo E.J.
Publication year - 1996
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.1476-5381.1996.tb15682.x
Subject(s) - superoxide , chemistry , rolipram , ic50 , elastase , n formylmethionine leucyl phenylalanine , ec50 , leukotriene b4 , phosphodiesterase , biochemistry , pharmacology , in vitro , enzyme , biology , immunology , inflammation
1 SCA40 (0.1 nM‐0.1 mM) produced concentration‐dependent suppression of the spontaneous tone of human isolated bronchus (‐log EC 50 = 6.85 ± 0.09; n = 10) and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (‐log EC 50 values) of SCA40 compared to other relaxants was rolipram (7.44 ± 0.12; n = 9) > SCA40 ≥ levcromakalim (6.49 ± 0.04; n = 6) > SKF94120 (5.87 ± 0.10; n = 9). 2 When tested against the activity of the isoenzymes of cyclic nucleotide phosphodiesterase (PDE) isolated from human bronchus, SCA40 proved highly potent against PDE III (‐log IC 50 = 6.47 ± 0.16; n = 4). It was markedly less potent against PDE IV (4.82 ± 0.18; n = 4) and PDE V (4.32 ± 0.11; n = 4). 3 Human polymorphonuclear leukocytes (PMNs) stimulated with N ‐formylmethionyl‐leucyl‐phenylalanine (FMLP) produced a concentration‐dependent superoxide anion generation and elastase release. SCA40 (1 nM‐10 μ m ) produced a concentration‐related inhibition of FMLP (30 nM ∼ EC 50 )‐induced superoxide production (‐log IC 50 = 5.48 ± 0.10; n = 6) and elastase release (‐log IC 50 = 5.50 ± 0.26; n = 6). Rolipram was an effective inhibitor of superoxide generation and elastase release (‐log IC 50 values ∼8) while SKF94120 and levcromakalim were scarcely effective. 4 FMLP (30 nM) and thimerosal (20 μ m ) induced leukotriene B 4 production and elevation of intracellular calcium concentration in human PMNs. The production of leukotriene B 4 was inhibited by SCA40 in a concentration‐related manner (‐log IC 50 = 5.94 α 0.22; n = 6) but SCA40 was less effective against the elevation of intracellular calcium. Rolipram was an effective inhibitor of leukotriene B 4 synthesis (‐log IC 50 ∼7) and intracellular calcium elevation (‐log IC 50 ∼6) while SKF94120 and levcromakalim were scarcely effective. 5 It is concluded that SCA40 is an effective inhibitor of the inherent tone of human isolated bronchus. The bronchodilatation produced by SCA40 appears mainly related to PDE inhibition since the potency of SCA40 as a relaxant of human isolated bronchus was found to be close to its potency as inhibitor of PDE III activity isolated from human bronchus. In addition, SCA40 exhibited inhibitory effects on human PMN function stimulated by FMLP. These effects may be related to the ability of SCA40 to inhibit PDE IV from human PMNs while the contribution of PDE V inhibition is uncertain. We found no evidence of a role for levcromakalim‐sensitive plasmalemmal K + ‐channels in human PMNs.