: 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.