Background Rheumatoid Arthritis (RA) is associated with increased cardiovascular risk (CVR) explained in part by accelerated atherosclerosis as a consequence of endothelial dysfunction. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed in RA patients in case of acute pain. Surprisingly, despite the commonly-held belief that NSAIDs worsen CVR, data regarding their effect on endothelial function in RA are lacking.
Objectives The present study investigated the effect of naproxen (a non-selective COX inhibitor), diclofenac (a preferential COX-2 inhibitor) and celecoxib (a selective COX-2 inhibitor) on vascular function in arthritic rats and identified the underlying mechanisms.
Methods Adjuvant-induced arthritis (AIA) was induced in 6 weeks-old male Lewis rats by injection of Mycobacterium butyricum in adjuvant at the basis of the tail. At the onset of arthritis, rats were daily treated (i.p.) with naproxen (10 mg/kg/d), diclofenac (5mg/kg twice a day), celecoxib (3 mg/kg/d) or saline (Vehicle) for 21 days. Arthritis scores were daily monitored. At the end of treatment, thoracic aortas were harvested to measure the relaxation to acetylcholine (Ach) on pre-constricted aortic rings in the presence or not of inhibitor of nitric oxide (NO) synthase (L-NAME), arginase (nor-NOHA), EDHF (Apamin/Charybdotoxin), or a superoxide dismutase analog (Tempol). The effects of a NO donor (sodium nitroprussiate, SNP) and norepinephrine (NE) were studied on endothelium-denuded aortic rings.
Results All NSAIDs significantly reduced to the same extent arthritis score in AIA (p<0.05). By contrast, differences exist between NSAIDs regarding endothelial function. Both naproxen and diclofenac significantly (p<0.05) improved Ach-induced relaxation whereas celecoxib did not change the response to Ach. These differences on endothelial function were not explained by differences in the response of vascular smooth muscle to NE or SNP which remained unchanged after the 3 treatments. Of interest, the positive effects of naproxen and diclofenac likely relied on different mechanisms. Whilst naproxen tends to improve NOS activity and decrease superoxide anion production, diclofenac decreased arginase activity, superoxide anion production and improved EDHF production.
Conclusions Our study demonstrates for the first time that naproxen and diclofenac have positive effects on endothelial function in case of arthritis whereas celecoxib had no effect, despite a similar reduction of inflammatory symptoms. From a clinical perspective, these data highlight the heterogeneity of effects of NSAIDs as regards CVR in RA and encourage designing clinical trials to confirm our experimental data and help guiding the better choice of NSAIDs for the global management of RA patients.
Disclosure of Interest None declared