Cyclooxygenase-2, Asymmetric Dimethylarginine and the Cardiovascular Hazard from NSAIDs

Background —Large scale, placebo controlled trials established that nonsteroidal anti-inflammatory drugs (NSAIDs) confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin (PGI 2 ). An alternative mechanism by which NSAIDs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide (NO) throughout the vasculature. Methods —Targeted and untargeted metabolomics were employed to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis (OA) patients exposed to NSAIDs on the L-arginine/NO pathway. Results —Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen inducible Cox-2 (iCox-2) KO mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared to their wild-type (WT) controls. Moreover, the expression of genes in the L-arginine/NO pathway was not alterated in the renal medulla or cortex of iCox-2 KO mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in OA patients with confirmed exposure to NSAIDs that inhibit COX-1 and COX-2. By contrast, plasma asymmetric dimethylarginine (ADMA) was increased in mice infused with angiotensin II (Ang II) sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine and ADMA were restored to normal levels. The increase in ADMA in response to infusion with Ang II in celecoxib treated mice was also related to transient impairment of renal function. Conclusions —Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.