Biochemical pharmacology

Inhibition of superoxide anion generation by YC-1 in rat neutrophils through cyclic GMP-dependent and -independent mechanisms.

PMID 11992625


3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a soluble guanylyl cyclase (sGC) activator, inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O(2)*(-)) generation and O(2) consumption in rat neutrophils (IC(50) values of 12.7+/-3.1 and 17.7+/-6.9 microM, respectively). Inhibition of O(2)*(-) generation by YC-1 was partially reversed by the cyclic GMP-lowering agent 6-anilinoquinoline-5,8-quinone (LY83583) and by the Rp isomer of 8-(4-chlorophenylthio)guanosine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), a cyclic GMP-dependent protein kinase inhibitor. In cell-free systems, YC-1 failed to alter O(2)*(-) generation during dihydroxyfumaric acid autoxidation, phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparation, and arachidonic acid-induced NADPH oxidase activation. YC-1 increased cellular cyclic GMP levels through the activation of sGC and the inhibition of cyclic GMP-hydrolyzing phosphodiesterase activity. The plateau phase, but not the initial spike, of fMLP-induced [Ca(2+)](i) changes was inhibited by YC-1 (IC(50) about 15 microM). fMLP- but not PMA-induced phospholipase D activation was inhibited by YC-1 (IC(50) about 28 microM). Membrane-associated ADP-ribosylation factor and Rho A in cell activation was also reduced by YC-1 at a similar concentration range. Neither cytosolic protein kinase C (PKC) activity nor PKC membrane translocation was altered by YC-1. YC-1 did not affect either fMLP-induced phosphatidylinositol 3-kinase activation or p38 mitogen-activated protein kinase phosphorylation, but slightly attenuated the phosphorylation of extracellular signal-regulated kinase. Collectively, these results indicate that the inhibition of the fMLP-induced respiratory burst by YC-1 is mediated by cyclic GMP-dependent and -independent signaling mechanisms.

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6-Anilinoquinoline-5,8-quinone, ≥95% (TLC), solid