Comparative pharmacology of chemically distinct NADPH oxidase inhibitors
Open Access
- 17 June 2010
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 161 (4), 885-898
- https://doi.org/10.1111/j.1476-5381.2010.00920.x
Abstract
BACKGROUND AND PURPOSE Oxidative stress [i.e. increased levels of reactive oxygen species (ROS)] has been suggested as a pathomechanism of different diseases, although the disease-relevant sources of ROS remain to be identified. One of these sources may be NADPH oxidases. However, due to increasing concerns about the specificity of the compounds commonly used as NADPH oxidase inhibitors, data obtained with these compounds may have to be re-interpreted. EXPERIMENTAL APPROACH We compared the pharmacological profiles of the commonly used NADPH oxidase inhibitors, diphenylene iodonium (DPI), apocynin and 4-(2-amino-ethyl)-benzolsulphonyl-fluoride (AEBSF), as well as the novel triazolo pyrimidine VAS3947. We used several assays for detecting cellular and tissue ROS, as none of them is specific and artefact free. KEY RESULTS DPI abolished NADPH oxidase-mediated ROS formation, but also inhibited other flavo-enzymes such as NO synthase (NOS) and xanthine oxidase (XOD). Apocynin interfered with ROS detection and varied considerably in efficacy and potency, as did AEBSF. Conversely, the novel NADPH oxidase inhibitor, VAS3947, consistently inhibited NADPH oxidase activity in low micromolar concentrations, and interfered neither with ROS detection nor with XOD or eNOS activities. VAS3947 attenuated ROS formation in aortas of spontaneously hypertensive rats (SHRs), where NOS or XOD inhibitors were without effect. CONCLUSIONS AND IMPLICATIONS Our data suggest that triazolo pyrimidines such as VAS3947 are specific NADPH oxidase inhibitors, while DPI and apocynin can no longer be recommended. Based on the effects of VAS3947, NADPH oxidases appear to be a major source of ROS in aortas of SHRs.Keywords
This publication has 48 references indexed in Scilit:
- The NADPH oxidase inhibitor diphenyleneiodonium is also a potent inhibitor of cholinesterases and the internal Ca2+ pumpBritish Journal of Pharmacology, 2009
- A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafishNature, 2009
- Mechanisms of Vascular Smooth Muscle NADPH Oxidase 1 (Nox1) Contribution to Injury-Induced Neointimal FormationArteriosclerosis, Thrombosis, and Vascular Biology, 2009
- Measurement of Reactive Oxygen Species in Cardiovascular StudiesHypertension, 2007
- Regulation of Nox and Duox enzymatic activity and expressionFree Radical Biology & Medicine, 2007
- Calcium-Dependent Protein Kinases Regulate the Production of Reactive Oxygen Species by Potato NADPH OxidasePlant Cell, 2007
- Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation☆Cardiovascular Research, 2006
- NADPH Oxidases in Cardiovascular Health and DiseaseAntioxidants and Redox Signaling, 2006
- Novel Nox inhibitor of oxLDL-induced reactive oxygen species formation in human endothelial cellsBiochemical and Biophysical Research Communications, 2006
- Sensitive Superoxide Detection in Vascular Cells by the New Chemiluminescence Dye L-012Journal of Vascular Research, 1999