Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis
| Autor: | Kirkby, Nicholas S., Tesfai, Abel, Ahmetaj-Shala, Blerina, Gashaw, Hime H., Sampaio, Walkyria, Etelvino, Gisele, Leão, Nádia Miricéia, Santos, Robson A., Mitchell, Jane A. |
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| Přispěvatelé: | Wellcome Trust, Imperial College London |
| Rok vydání: | 2016 |
| Předmět: |
Male
Biochemistry & Molecular Biology Nitric Oxide Synthase Type III aspirin prostacyclin Research organic chemicals Vioxx 0601 Biochemistry And Cell Biology Ibuprofen Arginine Kidney 0606 Physiology Substrate Specificity Mice Inbred C57BL Drug Combinations Cyclooxygenase 2 nitric oxide 1116 Medical Physiology Animals Humans Endothelium Enzyme Inhibitors methylarginines |
| Zdroj: | The FASEB Journal |
| Popis: | 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 NG-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., AhmetajShala, 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. |
| Databáze: | OpenAIRE |
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