Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs - PubMed (original) (raw)
Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs
D J Stuehr et al. FASEB J. 1991 Jan.
Abstract
The cofactor requirements of macrophage nitric oxide (NO.) synthase suggest involvement of an NADPH-dependent flavoprotein. This prompted us to test the effect of the flavoprotein inhibitors diphenyleneiodonium (DPI), di-2-thienyliodonium (DTI), and iodoniumdiphenyl (ID) on the NO. synthases of macrophages and endothelium. DPI, DTI, and ID completely inhibited NO. synthesis by mouse macrophages, their lysates, and partially purified macrophage NO. synthase. Inhibition of NO. synthase by these agents was potent (IC50's 50-150 nM), irreversible, dependent on time and temperature, and independent of enzyme catalysis. The inhibition by DPI was blocked by NADPH, NADP+, or 2'5'-ADP, but not by NADH. Likewise, FAD or FMN, but not riboflavin or adenosine 5-diphosphoribose, protected NO. synthase from inhibition by DPI. Neither NADPH nor FAD reacted with DPI. Once NO. synthase was inhibited by DPI, neither NADPH nor FAD could restore its activity. DPI also inhibited acetylcholine-induced relaxation of norepinephrine-preconstricted rabbit aortic rings (IC50 300 nM). Inhibition of acetylcholine-induced relaxation persisted for at least 2 h after DPI was washed out. In contrast, DPI had no effect on norepinephrine-induced vasoconstriction itself nor on vasorelaxation induced by the NO.-generating agent sodium nitroprusside. These results suggest that NO. synthesis in both macrophages and endothelial cells depends on an NADPH-utilizing flavoprotein. As a new class of NO. synthase inhibitors, DPI and its analogs are likely to prove useful in analyzing the physiologic and pathophysiologic roles of NO(.).
Similar articles
- Inhibitory actions of diphenyleneiodonium on endothelium-dependent vasodilatations in vitro and in vivo.
Wang YX, Poon CI, Poon KS, Pang CC. Wang YX, et al. Br J Pharmacol. 1993 Nov;110(3):1232-8. doi: 10.1111/j.1476-5381.1993.tb13947.x. Br J Pharmacol. 1993. PMID: 7507779 Free PMC article. - Endothelium-independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium.
Dodd-o JM, Zheng G, Silverman HS, Lakatta EG, Ziegelstein RC. Dodd-o JM, et al. Br J Pharmacol. 1997 Mar;120(5):857-64. doi: 10.1038/sj.bjp.0701014. Br J Pharmacol. 1997. PMID: 9138692 Free PMC article. - Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs.
Grimminger F, Weissmann N, Spriestersbach R, Becker E, Rosseau S, Seeger W. Grimminger F, et al. Am J Physiol. 1995 May;268(5 Pt 1):L747-52. doi: 10.1152/ajplung.1995.268.5.L747. Am J Physiol. 1995. PMID: 7762677 - Inhibition of NADPH-cytochrome P450 reductase and glyceryl trinitrate biotransformation by diphenyleneiodonium sulfate.
McGuire JJ, Anderson DJ, McDonald BJ, Narayanasami R, Bennett BM. McGuire JJ, et al. Biochem Pharmacol. 1998 Oct 1;56(7):881-93. doi: 10.1016/s0006-2952(98)00216-0. Biochem Pharmacol. 1998. PMID: 9774150 - Isoforms of nitric oxide synthase. Characterization and purification from different cell types.
Förstermann U, Schmidt HH, Pollock JS, Sheng H, Mitchell JA, Warner TD, Nakane M, Murad F. Förstermann U, et al. Biochem Pharmacol. 1991 Oct 24;42(10):1849-57. doi: 10.1016/0006-2952(91)90581-o. Biochem Pharmacol. 1991. PMID: 1720618 Review. No abstract available.
Cited by
- Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.
Dong T, Hu G, Fan Z, Wang H, Gao Y, Wang S, Xu H, Yaffe MB, Vander Heiden MG, Lv G, Chen J. Dong T, et al. Nat Commun. 2024 Jan 27;15(1):807. doi: 10.1038/s41467-024-45167-5. Nat Commun. 2024. PMID: 38280848 Free PMC article. - In Vitro α-Glucosidase and α-Amylase Inhibition, Cytotoxicity and Free Radical Scavenging Profiling of the 6-Halogeno and Mixed 6,8-Dihalogenated 2-Aryl-4-methyl-1,2-dihydroquinazoline 3-Oxides.
Magwaza NM, More GK, Gildenhuys S, Mphahlele MJ. Magwaza NM, et al. Antioxidants (Basel). 2023 Nov 6;12(11):1971. doi: 10.3390/antiox12111971. Antioxidants (Basel). 2023. PMID: 38001824 Free PMC article. - NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors.
Cipriano A, Viviano M, Feoli A, Milite C, Sarno G, Castellano S, Sbardella G. Cipriano A, et al. J Med Chem. 2023 Sep 14;66(17):11632-11655. doi: 10.1021/acs.jmedchem.3c00770. Epub 2023 Aug 31. J Med Chem. 2023. PMID: 37650225 Free PMC article. Review. - The NADPH Oxidase Inhibitors Apocynin and Diphenyleneiodonium Protect Rats from LPS-Induced Pulmonary Inflammation.
Kouki A, Ferjani W, Ghanem-Boughanmi N, Ben-Attia M, Dang PM, Souli A, El-Benna J. Kouki A, et al. Antioxidants (Basel). 2023 Mar 21;12(3):770. doi: 10.3390/antiox12030770. Antioxidants (Basel). 2023. PMID: 36979018 Free PMC article. - Heterocyclic Diaryliodonium-Based Inhibitors of Carbapenem-Resistant Acinetobacter baumannii.
Kumari P, Kaul G, Kumar TA, Akhir A, Shukla M, Sharma S, Kamat SS, Chopra S, Chakrapani H. Kumari P, et al. Microbiol Spectr. 2023 Mar 28;11(2):e0477322. doi: 10.1128/spectrum.04773-22. Online ahead of print. Microbiol Spectr. 2023. PMID: 36976008 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials