Molsidomine inhibits the chemoattractant-induced respiratory burst in human neutrophils via a no-independent mechanism
Ervens, J.; Seifert, R.
Biochemical Pharmacology 44(4): 637-644
ISSN/ISBN: 0006-2952 PMID: 1324680 DOI: 10.1016/0006-2952(92)90397-2
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.