Molsidomine inhibits the chemoattractant-induced respiratory burst in human neutrophils via a no-independent mechanism.
3-Morpholino-sydnonimine (SIN-1) is a NO-releasing compound which mimics the effects of cGMP through activation of soluble guanylyl cyclase. Its prodrug, molsidomine (SIN-10), does not release NO but does modulate various cell functions. These findings prompted us to study the effects of SIN-10 and SIN-1 on the respiratory burst in human neutrophils. SIN-10 was more effective than SIN-1 in inhibiting superoxide anion (O2-) formation induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe) and by C5a. The effects of SIN-1 and SIN-10 on O2- formation were additive or less than additive, indicating the sydnonimines acted through a common mechanism. The sydnonimines showed no effect on O2- formations induced by gamma-hexachlorocyclohexane, arachidonic acid and a phorbol ester. They did not inhibit O2- formation induced by xanthine oxidase, by autoxidation of pyrogallol and in a cell-free system from HL-60 leukemic cells. Neutrophils did not convert SIN-10 to SIN-1 as assessed by O2 consumption which accompanies NO release from SIN-1. The cell-permeant analogue of cGMP, N2,2'-O-dibutyryl guanosine 3':5'-monophosphate (Bt2cGMP), and SIN-10 but not SIN-1 inhibited fMet-Leu-Phe-induced O2 consumption. SIN-1 and SIN-10 slightly enhanced agonist binding to formyl peptide receptors, whereas Bt2cGMP was inhibitory. The sydnonimines did not affect GTP hydrolysis of heterotrimeric regulatory guanine nucleotide-binding proteins in HL-60 membranes. SIN-1 but not SIN-10 stimulated ADP-ribosylation of a 39-kDa protein in the cytosol of HL-60 cells. SIN-10 reduced fMet-Leu-Phe-induced rises in cytosolic Ca2+ concentration in neutrophils. These data suggest that SIN-10 inhibits the respiratory burst via a NO-independent mechanism which may involve inhibition of rises in cytosolic Ca2+ concentration.
Ervens
J
J
Institut für Pharmakologie, Freie Universität Berlin, Germany.
Seifert
R
R
D000085:Acetates / Q000494:pharmacology; D019342:Acetic Acid; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002474:Cell-Free System; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide; D010101:Oxygen Consumption / Q000187:drug effects; D016897:Respiratory Burst / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000085:Acetates; D013481:Superoxides; D009569:Nitric Oxide; D009240:N-Formylmethionine Leucyl-Phenylalanine; C002385:linsidomine; D008981:Molsidomine; D020558:GTP Phosphohydrolases; D019342:Acetic Acid; D002118:Calcium