P144, A TGF-β1 Antagonist Peptide, Synergizes with Sildenafil and Enhances Erectile Response via Amelioration of Cavernosal Fibrosis in Diabetic Rats

Abstract

Patients with diabetes exhibit more severe erectile dysfunction (ED) and are less responsive to first-line oral phosphodiesterase type 5 inhibitor (PDE5i). It has been suggested that increased collagen deposition and reduced smooth muscle content in the corpus cavernosum are important mechanisms for diabetes-associated ED and that transforming growth factor-β1 (TGF-β1) is a potent fibrotic factor responsible for the structural alterations in the corpus cavernosum. The aims of this study are to determine whether activation of TGF-β1 and its downstream pathways is responsible for the reduced efficacy of the PDE5is in diabetic ED via abnormalities in cavernosal structures and to investigate the synergistic effects of the TGF-β1 antagonist P144 and sildenafil on erectile response. Six weeks after inducting diabetes with streptozotocin in male Sprague-Dawley rats, age-matched control and diabetic rats were treated with vehicle, sildenafil, or P144 alone or in combination for 4 weeks, respectively. Intracavernous pressure, dynamic infusion cavernosometry, and histological and molecular alterations of the corpus cavernosum were analyzed. Diabetic rats exhibited a decreased erectile response, severe corporal veno-occlusive dysfunction (CVOD), and structural alterations including cavernosal fibrosis and decreased smooth muscle content. Expression and activation of TGF-β1 and its downstream Smad and non-Smad pathways increased in diabetic rats. Treatment with sildenafil showed modest effect on erectile response and a less suppressive effect on CVOD, cavernosal fibrosis, and molecular alterations. Treatment with P144 had lower effect on erectile response, even greatly improved the histological and molecular alterations and CVOD than sildenafil. The combined treatment with P144 and sildenafil effectively restored erectile response, CVOD, and histological and molecular alterations. An insufficient suppressive effect of sildenafil on cavernosal fibrosis, severe CVOD, and TGF-β1 pathways was implicated in reduced efficacy of the PDE5i in diabetic ED. Treatment with P144 synergized sildenafil and significantly increased erectile response by the potential antifibrotic activity.