Assessing the therapeutic potential of PDE-5 inhibitors in adults: Insights from a multi-omics study.

Abstract

Phosphodiesterase-5 inhibitors have beneficial pleiotropic effects and hold promise as adjuvant treatments for cancer, dementia, and other disorders. Sixteen men and women aged 50-60 were administered daily sildenafil/tadalafil for 1 month. We characterized molecular signatures of sildenafil/tadalafil treatment via analyses and multi-omics integration of the serum metabolome and skeletal muscle proteome and transcriptome. In serum, eicosanoids decreased and arginine biosynthesis pathway components increased following sildenafil/tadalafil. In skeletal muscle following sildenafil, blood vessel development and immune response genes increased, indicating augmented angiogenesis and possible inflammation at proximate biopsy sites. Proteins related to telomere maintenance and protein folding increased, suggesting reduced cellular senescence and cellular stress or functional adaptations. In skeletal muscle following tadalafil, there were no differentially expressed genes, and despite reduction of many proteins there were no enriched biological processes. Notably, sildenafil resulted in a more cohesive and substantial molecular signal in skeletal muscle. Multi-omics integration for both treatments revealed significant coexpression patterns. Phosphodiesterase-5 inhibitors showed systemic anti-inflammatory effects, as indicated by reduced serum levels of pro-inflammatory eicosanoids. However, this did not translate to immunohistochemical changes. Additional research is warranted to investigate PDE-5 inhibitor effects on various tissues, which can inform prospective applications for drug repurposing.