Ca2+/calmodulin-dependent protein kinase II inhibitors potentiate superoxide production in polymorphonuclear leukocytes.
The possible role of Ca2+/calmodulin-dependent protein kinase II (CaMK II) in superoxide anion (O2-) production induced by formyl-methionyl-leucyl-phenylalanine (FMLP) was investigated in mouse polymorphonuclear leukocytes (PMNs). KN-93 and KN-62, specific CaMK II inhibitors, augmented FMLP-induced O2- production. KN-92, an analogue which did not inhibit CaMK II, did not affect O2- production. W-7, a calmodulin inhibitor, augmented O2- production when administered at 30 mM for 5 min. KN-93 and recombinant mouse tumour necrosis factor-alpha (rmTNF-alpha) each augmented the maximal production of O2- induced by FMLP, and an additive effect of a combination of KN-93 and rmTNF-alpha was observed. CaMK II activity in the PMNs was increased by FMLP, and the increase was inhibited by KN-93 but not by rmTNF-alpha. These results suggest that the inhibition of CaMK II resulted in the augmentation of FMLP-induced O2- production in PMNs by a mechanism different from that of the augmentation shown by TNF-alpha.
Watanabe
M
M
Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Kaihatsu
T
T
Miwa
M
M
Maeda
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000096926:Benzenesulfonamides
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013449:Sulfonamides; D013481:Superoxides; D014409:Tumor Necrosis Factor-alpha; C072105:KN 93; D000096926:Benzenesulfonamides; C063302:KN 62