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
Medical Research: What should clinicians and patients take away from your report?
Dr. Mitchell: This work is experimental, but shows a potential marker of NSAID cardiovascular risk and, if ADMA does prove to predict risk, there is the potential to reduce this risk by taking arginine supplements. These ideas MUST be tested with organized clinical trials before patients or clinicians do anything. There are potential dangers of taking arginine so the benefits and risks of this will need to carefully determined.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Mitchell: We need to take a two pronged approach:
Firstly we need to conduct a clinical study where patients taking NSAIDs donate regular blood samples and where heart attacks and stokes are monitored. Then their blood samples can be analyzed for ADMA levels. Correlations can then be made to see if ADMA is a good biomarker. If it proves to be, then its use could be implemented as a clinical screen for those taking NSAIDs regularly, such as study might take 5-10 years.
Secondaly, in parallel and while the clinical study is being conducted we need to perform basic experiments using laboratory animals and cells in culture to establish presence how NSAIDs affect ADMA levels, how these might interact with other drug therapies, such as PPI, and most importantly, investigate the functional effects of increased ADMA on cardiovascular inflammation and blood vessel function. This will allow us to accurately predict during the course of the clinical study, if arginine therapy will protect.
Blerina Ahmetaj-Shala, Nicholas S. Kirkby, Rebecca Knowles, Malak Al’Yamani, Sara Mazi, Zhen Wang, Arthur T. Tucker, Louise Mackenzie, Paul C. J. Armstrong, Rolf M. Nüsing, James A. P. Tomlinson, Timothy D. Warner, James Lieper, and Jane A. Mitchell