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...

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Autores principales: Kirkby, Nicholas S., Tesfai, Abel, Ahmetaj-Shala, Blerina, Gashaw, Hime H., Sampaio, Walkyria, Etelvino, Gisele, Leão, Nádia Miricéia, Santos, Robson A., Mitchell, Jane A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Federation of American Societies for Experimental Biology 2016
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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
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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.
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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
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