title: Effects of BAY 41-2272, an activator of nitric oxide-independent site of soluble guanylate cyclase, on human NADPH oxidase system from THP-1 cells.
abstract: We investigated the effects of the 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) on the NADPH oxidase activity, gp91(phox) gene expression, cyclic guanosine-3',5'-monophosphate (cGMP) and cyclic adenosine-3',5'-monophosphate (cAMP) levels in the human myelomonocytic THP-1 cell line. THP-1 cells treated with BAY 41-2272 (0.3-10 microM) for 48 h significantly increased the superoxide anion (O(2)(*-)) release. This increase was not affected when cells were pre-treated with the specific cGMP-phosphodiesterase inhibitor zaprinast, the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (ODQ), the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl) adenine (SQ 22,536) or the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). In addition, BAY 41-2272 (3 and 10 microM; 48 h) was able to increase gp91(phox) gene expression on THP-1 cells. The pre-treatment with zaprinast, 3-isobutyl-l-methyl-xanthine (IBMX; 0.5 mM), ODQ, SQ 22,536 or l-NAME caused no additional effect on the expression of gp91(phox) evoked by BAY 41-2272. Treatment of THP-1 cells with BAY 41-2272 caused a significant increase in cGMP and cAMP levels. Our findings show that BAY 41-2272 caused a significant increase on the O(2)(*-) release and gp91(phox) gene expression by THP-1 cells, and an elevation of intracellular cGMP and cAMP levels. However, we could not detect a clear correlation between both O(2)(*-) release and gp91(phox) gene expression with activation of cGMP and cAMP signaling pathways.
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas Medical School, Campinas (SP), Brazil.
authors.forename: Edgar
authors.initials: E
authors.lastname: Borges de Oliveira-Junior
authors.forename: Sara Maria
authors.initials: SM
authors.lastname: Thomazzi
authors.forename: Jussara
authors.initials: J
authors.lastname: Rehder
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D008562:Membrane Glycoproteins; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D013481:Superoxides; D009569:Nitric Oxide; D000242:Cyclic AMP; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP