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

• Published in: European journal of pharmacology Vol. 567; no. 1; pp. 43 - 49
• Main Authors: Borges de Oliveira-Junior, Edgar, Thomazzi, Sara Maria, Rehder, Jussara, Antunes, Edson, Condino-Neto, Antonio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 12.07.2007; Elsevier
• Subjects: BAY 41-2272; Biological and medical sciences; cAMP; Cell Line; Cell Survival - drug effects; cGMP; Cyclic AMP - biosynthesis; Cyclic GMP - biosynthesis; Enzyme Activation; gp91 phox; Guanylate Cyclase - metabolism; Human macrophage; Humans; Medical sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - physiology; Myeloid cell; NADPH oxidase; NADPH Oxidase 2; NADPH Oxidases - biosynthesis; NADPH Oxidases - physiology; Nitric Oxide - physiology; Phagocyte; Pharmacology. Drug treatments; Pyrazoles - pharmacology; Pyridines - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Soluble Guanylyl Cyclase; Superoxides - metabolism; gp91 phox; NADPH oxidase; cGMP; BAY 41-2272; cAMP; Myeloid cell; Human macrophage; Phagocyte; Human; Enzyme; Phosphorus-oxygen lyases; Cyclic AMP; 3',5'-GMP; Lyases; Guanylate cyclase; In vitro; NAD(P)H oxidase; Nitric oxide; Oxidoreductases; gp91phox; Macrophage
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.04.018

We investigated the effects of the 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1 H-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 μM) 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 1 H-[1,2,4] oxidiazolo[4,3-α] quinoxalin-1-one (ODQ), the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl) adenine (SQ 22,536) or the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester (l-NAME). In addition, BAY 41-2272 (3 and 10 μM; 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.