Background/Purpose: Rheumatoid Arthritis (RA) is associated with an increase in cardiovascular (CV) risk explained in part by an accelerated atherosclerosis as a consequence of endothelial dysfunction. Non-steroidal anti-inflammatory drugs (NSAID) are widely prescribed in RA patients in case of acute pain. Surprisingly, despite the commonly held belief that NSAID worsen CV risk, data concerning their impact on endothelial function in RA are lacking. The present study investigated the effect of naproxene (COX non-selective inhibitor), diclofenac (COX-1 preferential inhibitor) and celecoxib (COX-2 selective 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 naproxene (10 mg/kg/d), or diclofenac (5mg/kg twice a day), or celecoxib (3 mg/kg/d) or saline (Vehicle) for 21 days. Arthritis score and tarsus diameter were daily monitored. At the end of treatment, thoracic aortas were harvested to measure the relaxation to acetylcholine 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 relaxing effect of a NO donor (sodium nitroprussiate, SNP) was studied on endothelium-denuded aortic rings. Blood pressure and heart rate were also assessed.

Results: Compared to “Vehicle”, AIA “Naproxene”, AIA “Diclofenac” and “AIA Celecoxib” exhibited reduced (p<0.05) arthritic score and paw diameters. Diclofenac was responsible for an elevation of the blood pressure. Naproxene and diclofenac significantly (p<0.05) improved Ach-induced relaxation through distinct mechanisms. Naproxene increased NO synthase activity and EDHF production (p<0.05), decreased arginase activity (p<0.05) and decreased superoxide anions production (p<0.05). Diclofenac increased EDHF production (p<0.05), decreased arginase activity (p<0.05) and decreased superoxide anions production (p<0.05) but had no effect on NO synthase activity. By contrast, celecoxib did not modify Ach-induced relaxation but only increased NO synthase activity and EDHF production (p<0.05). The response of rings to the NO donor was unchanged after treatment whatever the treatment.

Conclusion: Our study demonstrates for the first time that naproxene and diclofenac are beneficial for endothelial function in case of arthritis, even though diclofenac enhanced blood pressure. Conversely, despite the same effect on the inflammatory symptoms, the COX-2 selective NSAID (celecoxib) did not improve endothelial function. From a clinical perspective, these results raise the question of the restriction of the use of COX-2 selective inhibitors in patients with inflammatory rheumatisms. In case of arthritis, the use of a non-selective COX inhibitor could be a preferential choice due to beneficial effects for the vascular function without changes in blood pressure.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/conventional-non-steroidal-anti-inflammatory-drugs-but-not-cox2-selective-inhibitors-are-beneficial-on-vascular-function-in-arthritis-a-study-in-adjuvant-induced-arthritis/