Exploring the application of sildenafil for high-fat diet-induced erectile dysfunction based on interleukin-18-mediated NLRP3/Caspase-1 signaling pathway

Abstract

Background Inflammation is a key risk factor for heart disease and has also been linked to erectile dysfunction (ED). Sildenafil is a phosphodiesterase type 5 inhibitor with a strong antioxidant effect. Interleukin (IL)-18 is a proinflammatory factor. Excessive production and release of IL-18 disrupt the balance between IL-18 and IL-18 binding proteins in certain inflammatory diseases, leading to the occurrence of pathological inflammation. Aim We evaluated the effects of sildenafil on erectile function in a rat model of high-fat diet–induced ED. Methods Male Sprague Dawley rats (6 weeks old) were divided into 5 groups: control, ED, sildenafil, IL-18, and IL-18 + sildenafil. Subsequently, intracavernous pressure and mean arterial pressure were used to assess the erectile function of these rats. The expression of endothelial nitric oxide synthase, pyroptosis factors, and the ratio of smooth muscle cells and collagen fibers were evaluated in the serum and corpora tissue. Outcomes Exploring the role and mechanism of sildenafil in ED through NLRP3-mediated pyroptosis pathway. Results In comparison to the ED and IL-18 groups, there were statistically significant increases in the ratio of intracavernous pressure to mean arterial pressure, endothelial nitric oxide synthase expression, and the ratio of smooth muscle cells to collagen fibers following sildenafil intervention (P < .05). The sildenafil group and IL-18 + sildenafil group also showed statistically significant decreases the expression of NLRP3, caspase-1, and gasdermin D (P < .05). Clinical Implications Sildenafil can improve erectile dysfunction by inhibiting inflammation. Strengths and Limitations Strengths are that the relationship between pyroptosis and ED has been verified through in vitro and in vivo experiments. The limitation is that the conclusions drawn from animal and cells experiments need to be confirmed in clinical research. Conclusion Sildenafil may reduce the effect of IL-18–induced inflammation in high-fat diet–induced ED rats through NLRP3/caspase-1 pyroptosis pathway.

Neutrophil extracellular traps promote erectile dysfunction in rats with diabetes mellitus by enhancing NLRP3-mediated pyroptosis

“…GSDMD-N facilitates cell membrane pore formation, leading to distinct morphological alterations, such as cytoplasm swelling, membrane fracture, and inflammatory factor release, which promotes inflammatory responses 18 , 19 . Despite that pyroptosis is reportedly the key pathogenic mechanisms of ED under different pathological conditions 15 , 20 , 21 , little is known about its molecular mechanisms in this disorder, especially in the context of DM, and further investigation is warranted.…”