MedicalResearch.com Interview with:
Dr. Jane A. Mitchell
National Heart and Lung Institute
Imperial College, London, UK
Medical Research: What is the background for this study? What are the main findings?
Dr. Mitchell: Anti-inflammatory drugs (NSAIDs) work by inhibiting the enzyme COX-2. COX-2 selective anti-inflammatory drugs, like Vioxx, were introduced to reduce gastrointestinal side effects associated with these drugs. However, COX-2 inhibitors as well as most older NSAIDs are associated with increased risk of heart attacks although the precise mechanisms underlying these side effects are not completely understood.
The main findings of this study are:
1) COX-2 is highly expressed in the kidney where its genetic deletion leads to changes in more than 1000 genes.
2) Analysis of these genes revealed changes in 2-3 specific genes that regulate levels of ADMA, an endogenous inhibitor of the nitric oxide released by vessels, that can be reversed by giving more of the substrate for NO, L-arginine.
3) Further studies showed that ADMA was indeed increased in the plasma of mice where COX-2 gene was knocked out or in normal mice given a COX-2 inhibitor.
4) In mice where COX-2 was knocked out the release of nitric oxide from vessels was reduced and this could be reversed by supply L-arginine.
5) ADMA was also increased in human volunteers taking a COX-2 inhibitor