Evidence That Links Cyclo-oxygenase-2 Inhibition With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-inflammatory Drugs

Abstract

Inhibition of cyclo-oxygenase (COX)-2 by nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective inhibitors such as celecoxib and rofecoxib, is associated with cardiovascular side effects. It was previously thought that the mechanism by which COX-2 inhibitors precipitate this side effect was simply explained; that COX-2 drives the vascular production of the cardio protective hormone, prostacyclin, and that its blockade predisposes to thrombosis and atherosclerosis. However, we have recently shown that vascular prostacyclin is COX-1 driven. We are now left with no clear explanation of how COX-2 inhibitors precipitate cardiovascular side effects. COX-2 is expressed in key anatomical hot spots, including the kidney where its inhibition or genetic deletion results in renal dysfunction. Separate studies have shown that renal dysfunction is associated with a reduction of the enzyme DDAH1, which removes the endogenous inhibitor of NO synthase (NOS), ADMA. We hypothesised that specific loss of COX-2 activity could lead to reduced renal DDAH1 activity and increased plasma levels of ADMA. The resultant reduction in NO release from the endothelium could account for the increased cardiovascular risk associated with clinical use of COX-2 inhibitors. Here we have tested our hypothesis using gene-deleted mice.

Aorta from COX-2 knock-out mice demonstrated normal prostacyclin production but reduced endothelial dependent vasodilator responses, consistent with inhibition of the enzyme eNOS. In line with this, kidneys from COX-2 knock-out mice showed reduced DDAH1 expression and there were elevated levels of ADMA in the kidneys (control, 23±2nM; COX-2 knock-out, 36±5nM) and plasma (control, 0.33±0.02μM; COX-2 knock-out, 4.70±1.81μM); these increases are ‘pathological’ and similar to those associated with cardiovascular dysfunction. Importantly, there was no change in L-arginine levels. These observations provide a novel explanation for how COX-2 selective inhibitors mediate cardiovascular dysfunction and, importantly, one which can be tested in man. If confirmed, supplementation with L-arginine for susceptible patients could be beneficial.