Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system.

The aim of this study was to investigate the ability of sildenafil to regulate osteopontin (OPN) gene and protein in peripheral blood mononuclear cells (PBMCs) from healthy blood donors. OPN is expressed by a wide variety of cell types, including immune cells. OPN functions are linked to various physiological and pathological conditions. Sildenafil is a selective inhibitor of type 5 phosphodiesterase. Sildenafil has recently been found to have immunomodulatory effects in animal models and in studies performed in humans. PMA-stimulated and unstimulated PBMCs from 16 healthy blood donors (men) were cultured with sildenafil (at concentrations of 400 ng/ml and 4 µg/ml). OPN level in culture supernatants was measured by enzyme-linked immunosorbent assay. The analysis of OPN gene expression was performed by real-time PCR. Cell viability was assessed by trypan blue staining. PMA plus ionomycin stimulation of PBMCs resulted in a significant increase of OPN production and gene expression (p < 0.001). Sildenafil significantly decreased OPN secretion (p < 0.05) and gene expression (p < 0.05) in stimulated PBMCs; however, had no effect on OPN in unstimulated PBMCs. Sildenafil did not affect PBMCs viability. Sildenafil downregulates OPN in PBMCs from healthy men. Despite accumulating evidence for the immunomodulatory effects of sildenafil on human immune system cells, further studies are needed to determine if this drug affects the level of cGMP and NF-κB in PBMCs. In addition, it is needed to evaluate sildenafil’s activity in PBMCs from patients with elevated OPN levels.

Sildenafil is a selective type 5 phosphodiesterase (PDE5) inhibitor, commonly used in the treatment of erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). The results of recent studies suggest that this drug modulates function of the immune system. However, only few studies were performed in humans. Therefore, the aim of this study was to investigate the ability of sildenafil to regulate the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β and IL-6 in peripheral blood mononuclear cells (PBMCs) from healthy men. Phorbol myristate acetate (PMA) ñ stimulated and unstimulated PBMCs from 16 participants were cultured in the absence or presence of sildenafil (400 ng/mL and 4 µg/mL). TNF-α, IL-1β and IL-6 concentrations in culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Cell viability was assessed by trypan blue staining. Sildenafil at a concentration of 400 ng/mL significantly increased TNF-α production in stimulated PBMCs (p < 0.05) but had no effects on IL-1β and IL-6. The drug did not affect PBMCs viability. This is the first report describing such effects of sildenafil in humans.

Sildenafil is used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Numerous studies revealed beneficial effects of its use in renal, liver, heart and bone marrow transplant recipients. Some reports suggested that the drug modulates the function of the immune system, however, its influence on antigen-induced proliferation of lymphocytes remains unknown. Thus, the aim of the study was to investigate the effects of sildenafil on human peripheral blood mononuclear cells (PBMCs) proliferation in a mixed lymphocyte reaction. It was demonstrated that the drug did not affect auto-and alloantigen-induced proliferation of PBMCs and showed no cytotoxic effect.