Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis
Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Federation of American Societies for Experimental Biology
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102117/ https://www.ncbi.nlm.nih.gov/pubmed/27601438 http://dx.doi.org/10.1096/fj.201600647R |
_version_ | 1782466398785634304 |
---|---|
author | Kirkby, Nicholas S. Tesfai, Abel Ahmetaj-Shala, Blerina Gashaw, Hime H. Sampaio, Walkyria Etelvino, Gisele Leão, Nádia Miricéia Santos, Robson A. Mitchell, Jane A. |
author_facet | Kirkby, Nicholas S. Tesfai, Abel Ahmetaj-Shala, Blerina Gashaw, Hime H. Sampaio, Walkyria Etelvino, Gisele Leão, Nádia Miricéia Santos, Robson A. Mitchell, Jane A. |
author_sort | Kirkby, Nicholas S. |
collection | PubMed |
description | Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and N(G)-nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.—Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis. |
format | Online Article Text |
id | pubmed-5102117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Federation of American Societies for Experimental Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-51021172016-11-10 Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis Kirkby, Nicholas S. Tesfai, Abel Ahmetaj-Shala, Blerina Gashaw, Hime H. Sampaio, Walkyria Etelvino, Gisele Leão, Nádia Miricéia Santos, Robson A. Mitchell, Jane A. FASEB J Research Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and N(G)-nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.—Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis. Federation of American Societies for Experimental Biology 2016-12 2016-09-06 /pmc/articles/PMC5102117/ /pubmed/27601438 http://dx.doi.org/10.1096/fj.201600647R Text en © The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Kirkby, Nicholas S. Tesfai, Abel Ahmetaj-Shala, Blerina Gashaw, Hime H. Sampaio, Walkyria Etelvino, Gisele Leão, Nádia Miricéia Santos, Robson A. Mitchell, Jane A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title | Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title_full | Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title_fullStr | Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title_full_unstemmed | Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title_short | Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis |
title_sort | ibuprofen arginate retains enos substrate activity and reverses endothelial dysfunction: implications for the cox-2/adma axis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102117/ https://www.ncbi.nlm.nih.gov/pubmed/27601438 http://dx.doi.org/10.1096/fj.201600647R |
work_keys_str_mv | AT kirkbynicholass ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT tesfaiabel ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT ahmetajshalablerina ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT gashawhimeh ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT sampaiowalkyria ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT etelvinogisele ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT leaonadiamiriceia ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT santosrobsona ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis AT mitchelljanea ibuprofenarginateretainsenossubstrateactivityandreversesendothelialdysfunctionimplicationsforthecox2admaaxis |