Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA319

Poster Communications

The effect of phosphodiesterase-5 inhibitor tadalafil on the severity of joint injury in rats with adjuvant arthritis

E. F. Bahadir1, M. Koroglu2, M. Yuksel3, F. Ercan2, I. Alican1

1. Physiology, Marmara University School of Medicine, Istanbul, Turkey. 2. Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey. 3. Medical Laboratory Techniques, Marmara University Vocational School of Health Services, Istanbul, Turkey.

Rheumatoid arthritis (RA) is an inflammatory systemic and autoimmune disease, characterized by chronic, symmetric and erosive synovitis, mainly of peripheral joints. Although etiology of RA isn't clearly described, recent research efforts have been focused on oxidative stress. Tadalafil is a selective and potent inhibitor of phosphodiesterase (PDE)-5 for the cure of sexual dysfunction. PDE-5 inhibitors have been proved to reduce oxidative stress to decrease inflammatory events in various experimental models. This study aimed to investigate whether tadalafil has a protective effect on the severity of joint damage using an experimental RA model. Male Sprague-Dawley rats (300-450 g; n=8 per group) were inoculated intradermally into the plantar surface of right hand paw with 0.1 ml of complete Freund's adjuvant (CFA) containing 10 mg/ml of heat-killed Mycobacterium tuberculosis. Control group received the vehicle (0.1 ml paraffin oil). After being injected with CFA on day-0, tadalafil (10 mg/kg; per oral) was given between days 5-15. Other groups received the guanyly cyclase inhibitor ODQ (10 mg/kg; intraperitoneally), the non-selective nitric oxide synthase inhibitor L-NAME (25 mg/kg; subcutaneously) or the non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg; intraperitoneally) on day-15 prior to tadalafil. All rats were decapitated after stunning on day-16 and metatarsophalangeal joints, gastrocnemius muscle and trunk blood were sampled. Joints were stained with hematoxylin & eosin and Masson's trichrome for histopathological evaluation. Muscle samples and blood were used for biochemical assays. The study protocol was approved by Marmara University, Animal Care and Use Committee. Values are means ± S.E.M., compared by ANOVA and Student's t-tests. Arthritis group revealed markedly increased paw edema (34.76±0.93 mm2, p<0.01), increased muscle lipid peroxidation (6.60±1.26 nmol/g, p<0.01) and glutathione levels (0.75±0.08 mmol/g; p<0.001) in comparison to control. Tadalafil did not show a beneficial effect on these parameters. High microscopic score showing joint injury and increased muscle luminol- and lucigenin-enhanced chemiluminesce levels showing oxidant production in the arthritis group (4.00±0.69; 13.17±2.47 rlu/mg and 10.69±1.43 rlu/mg, respectively) were attenuated by tadalafil (1.17±0.31, p<0.01; 4.48 ±1.12, p<0.01 rlu/mg and 3.04±0.33 rlu/mg, p<0.001, respectively); however, other treatments did not change the effects of tadalafil on these parameters. These results suggest that inhibition of PDE-5 enzyme by tadalafil decreases the extent of the histopathological damage in joints and generation of reactive oxygen metabolites in the muscle in a rat model of experimental RA via mechanisms that do not seem to interfere with guanlyl cyclase, nitric oxide or cyclooxygenase.

Where applicable, experiments conform with Society ethical requirements