pyrimidinones and staurosporine-aglycone

To assess the role of protein kinase C (PKC) in the respiratory burst of adherent human polymorphonuclear leukocytes (PMNL), reduction of ferricytochrome C by cells triggered with a phorbol ester (PMA), ionophore A23187, serum-treated zymosan (STZ) or three lipid derivatives, 3-decanoyl-sn-glycerol (G-3-OCOC9), (R,R)-1,4-diethyl-2-O-decyl-L-tartrate (Tt-2-OC10) and 3-decyloxy-5-hydroxymethylphenol (DHP) was examined in a microtiter plate procedure in the presence of inhibitors of PKC and, for comparison, inhibitors of calmodulin, diacylglycerol and myosin light chain kinases and the peptidyl-prolyl cis-trans isomerase activity of fujiphilin. 1) Of the protein kinase inhibitors examined, Ro 31-7549 and staurosporine reduced responses to all stimuli except possibly STZ; in contrast, K252a and the myosin light chain kinase inhibitors ML-7 and ML-9 blocked responses to A23187 and STZ better than those triggered by PMA. H-7 reduced responses to A23187, DHP and G-3-OCOC9, and calphostin, palmitoyl carnitine, sphingosine and the multifunctional drugs TMB-8 and W-7 reduced A23187; they also, when examined, reduced decane derivative-induced O2- production more effectively than PMA- and STZ-triggered responses. Polymyxin B, 4 alpha-PMA and retinal displayed no inhibitory capacity. 2) Of the selective calmodulin antagonists, CGS 9343B, Ro 22-4839 and calmidazolium did not inhibit the oxidative response irrespective of the stimulus used, whereas metofenazate reduced those evoked by A23187, DHP, G-3-OCOC9 and STZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Isomerases; Basophils; Calmodulin; Carbazoles; Carrier Proteins; Diacylglycerol Kinase; Histamine Release; Humans; Indole Alkaloids; Myosin-Light-Chain Kinase; Neutrophils; Peptidylprolyl Isomerase; Phosphotransferases; Protein Kinase C; Pyrimidinones; Superoxides; Tacrolimus; Tetradecanoylphorbol Acetate; Thiazoles

The effects of monosodium urate and calcium pyrophosphate dihydrate crystals on the levels of cytoplasmic free calcium and on the oxidative burst in normal human blood neutrophils were examined. The pattern of sensitivity to granulocyte-macrophage colony-stimulating factor, colchicine, cytochalasin B, pertussis toxin, diglyceride kinase, and protein kinase C inhibitors differentiated the mechanism(s) of neutrophil activation by the crystals from that involved in the responses to soluble chemotactic factors and indicated that individual crystals can use several activation pathways.

Topics: Alkaloids; Calcium; Calcium Pyrophosphate; Carbazoles; Cholera Toxin; Colchicine; Crystallization; Cytochalasin B; Cytoplasm; Diacylglycerol Kinase; Drug Interactions; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Indole Alkaloids; Neutrophils; Oxidation-Reduction; Pertussis Toxin; Phosphotransferases; Protein Kinase C; Pyrimidinones; Staurosporine; Superoxides; Thiazoles; Uric Acid; Virulence Factors, Bordetella