Abstract
Staurosporine (3-100 nM), frequently used as a protein kinase C (PKC) inhibitor, increased accumulation of nitrite in the culture medium of rat peritoneal macrophages up to 6 times above the control level. Moreover, when used in combination with the stable analogue of cyclic AMP, dibutyrylcyclic AMP (db cyclic AMP; 0.1 mM), and/or a cytokine, tumour necrosis factor-alpha (TNF alpha; 100 u ml-1), staurosporine synergistically potentiated, up to 30 times, nitrite accumulation. On the other hand, the other PKC inhibitors, calphostin C and H-7 (10 nM-10 microM) were not effective under the same conditions. The staurosporine-induced nitrite accumulation, in both the presence and the absence of TNF alpha and/or db cyclic AMP was effectively inhibited by the protein synthesis inhibitor, cycloheximide, or by the nitric oxide (NO) synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA). Thus our data suggest that staurosporine may enhance NO production in macrophages via intracellular mechanisms unrelated to the PKC inhibition.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ignarro L. J., Fukuto J. M., Griscavage J. M., Rogers N. E., Byrns R. E. Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8103–8107. doi: 10.1073/pnas.90.17.8103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
- Omura S., Iwai Y., Hirano A., Nakagawa A., Awaya J., Tsuchya H., Takahashi Y., Masuma R. A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J Antibiot (Tokyo) 1977 Apr;30(4):275–282. doi: 10.7164/antibiotics.30.275. [DOI] [PubMed] [Google Scholar]
- Sowa G., Przewłocki R. cAMP analogues and cholera toxin stimulate the accumulation of nitrite in rat peritoneal macrophage cultures. Eur J Pharmacol. 1994 Jan 15;266(2):125–129. doi: 10.1016/0922-4106(94)90101-5. [DOI] [PubMed] [Google Scholar]
- Tamaoki T. Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol. 1991;201:340–347. doi: 10.1016/0076-6879(91)01030-6. [DOI] [PubMed] [Google Scholar]