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, 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., 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.
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and n.kirkby@imperial.ac.uk.
Nicholas S
NS
Kirkby
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
Abel
A
Tesfai
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
Blerina
B
Ahmetaj-Shala
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
Hime H
HH
Gashaw
Department of Physiology and Biophysics, National Institute in Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Walkyria
W
Sampaio
Department of Physiology and Biophysics, National Institute in Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Gisele
G
Etelvino
Department of Physiology and Biophysics, National Institute in Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Nádia Miricéia
NM
Leão
Department of Physiology and Biophysics, National Institute in Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Robson A
RA
Santos
Vascular Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and j.a.mitchell@ic.ac.uk.
Jane A
JA
Mitchell
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004338:Drug Combinations; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D013379:Substrate Specificity
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D007052:Ibuprofen; C106674:ibuprofen arginine
Vioxx; aspirin; methylarginines; nitric oxide; prostacyclin