To investigated whether the PDE5 inhibitor vardenafil ameliorates erectile dysfunction (ED) and corporal fibrosis in spontaneously hypertensive rats by regulating the HMGB1/RAGE/NF-κB pathway.

Spontaneously hypertensive rats were treated with vardenafil. Erectile function was evaluated by electrical stimulation, while the levels of cyclic guanosine monophosphate (cGMP) and NO in corpus cavernosum tissues were quantified using assay kits. Fibrosis was assessed via Masson and immunohistochemistry staining. The HMGB1/RAGE/NF-κB pathway and fibrosis markers were analyzed by Western blot. In vitro , a cellular hypertension model with HMGB1 overexpression was constructed. Cell proliferation and apoptosis were detected via EdU staining and flow cytometry. The levels of cGMP and NO in the cell supernatant were measured, the expression of α-SMA was examined by immunofluorescence, and pathway and fibrosis-related proteins were analyzed by Western blot.

In vivo , vardenafil significantly increased intracranial pressure maximum/mean arterial pressure and AUC/mean arterial pressure ratios, elevated the levels of cGMP, NO, and p-eNOS/eNOS, reduced collagen deposition and restored α-SMA expression in rat corpus cavernosum tissue. It also downregulated the levels of HMGB1, RAGE, p-NF-κB, TGF-β1, and collagen. In vitro, vardenafil promoted proliferation, inhibited apoptosis, raised cGMP and NO, and enhanced α-SMA expression of rat vascular endothelial cells. Western blot results aligned with in vivo data, showing upregulation of p-eNOS/eNOS and suppression of the HMGB1/RAGE/NF-κB pathway and fibrotic proteins by vardenafil. However, HMGB1 overexpression partially inverted the effects of vardenafil, confirming pathway dependence.

Vardenafil has the potential to alleviate cavernosal fibrosis by inhibiting the HMGB1/RAGE/NF-κB pathway, thereby improving hypertension-associated ED.