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. 2025 Apr 30:19:3351-3361.
doi: 10.2147/DDDT.S514209. eCollection 2025.

Procyanidin Improves Erectile Function in Rats by Inhibiting PDE5A Activity

Yudong Su #  1   2 , Jinman Shui #  1 , Danshi Qi  1 , Jie Bai  1 , Xiaoxia Xu  2 , Yongchun Huang  1 , Ruilian Li  1 , Qiong Wu  2 , Haiyan Wang  2 , Chengzhu Cao  2 , Zhanhai Su  2 , Shoude Zhang  1   3
Affiliations

Procyanidin Improves Erectile Function in Rats by Inhibiting PDE5A Activity

Yudong Su et al. Drug Des Devel Ther. .

Abstract

Purpose: Erectile dysfunction (ED), a prevalent form of male sexual dysfunction, is predominantly treated with Phosphodiesterase type 5 inhibitors (PDE5Is). Our previous research highlighted procyanidin, a natural compound, as a notably effective PDE5I. In the current study, we intend to further validate the inhibitory activity of procyanidin on PDE5A through in vitro and in vivo assessments. This study aims to validate the efficacy of procyanidin as a treatment for ED.

Methods: The binding affinity of procyanidin for PDE5A was assessed by molecular docking, molecular dynamics (MD) simulations, and microscale thermophoresis (MST) assay. The toxicity of procyanidin on penile corpus cavernosum smooth muscle (CCSM) cells (n=5) was evaluated. Additionally, its effects on intracellular cyclic guanosine monophosphate (cGMP) levels in CCSM cells (n=5) were evaluated. The absorption of procyanidin was evaluated by measuring plasma levels at various times after oral gavage to Sprague-Dawley (SD) rats (n=6). Subsequently, the effects of procyanidin on intracavernous pressure (ICP) and cGMP levels in penile cavernous tissue were evaluated in SD rats (n=6).

Results: Procyanidin forms three hydrogen bonds with PDE5A and stabilizes the complex structure, exhibiting equilibrium dissociation constants (KD) value of 7.77 ± 2.39 µmol/L. Additionally, procyanidin exhibits minimal cytotoxicity toward CCSM cells and significantly elevates intracellular cGMP levels compared to the control group. In vivo studies demonstrate that procyanidin is rapidly absorbed, achieving peak blood concentrations within one hour. Simultaneously, procyanidin significantly increases ICP and cGMP levels in rats compared to the control group.

Conclusion: These findings indicate that procyanidin sustains elevated cGMP levels within cells by targeting PDE5A, thereby exhibiting therapeutic efficacy in improving ICP. Procyanidin emerges as a promising PDE5I for treating ED and potentially other related conditions.

Keywords: cavernosum smooth muscle cells; cyclic guanosine monophosphate; erectile dysfunction; microscale thermophoresis; sexual dysfunctions.

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Conflict of interest statement

The authors declare that they have no competing financial interests or personal relationships that may have influenced the research reported in this study.

Figures

None
Graphical abstract
Figure 1
Figure 1
Determination of procyanidin affinity for PDE5A. (A) Molecular structure of procyanidin. (B) MST test of procyanidin and PDE5A, the data are presented as the mean ± SD, 95% confidence intervals: top (970.4, 976.0), bottom (912.1, 920.8). (C) Molecular docking of procyanidin with PDE5A. (D) RMSD values obtained from the MD simulation system for the interactions between procyanidin and PDE5A.
Figure 2
Figure 2
Effects of procyanidin on CCSM cells. (A) Effect of procyanidin on the Toxicity of CCSM cell (n=5). (B) Effect of procyanidin on cGMP levels in CCSM cells (n=5). The data are presented as the mean ± SD. ns Mean no significance, vs control group; *Mean P < 0.05, vs control group; **Mean P < 0.01, vs control group; ***Mean P < 0.001, vs control group; ****Mean P < 0.0001, vs control group.
Figure 3
Figure 3
Absorption of procyanidin in rats. (A) LC-MS/MS determination of procyanidin in rat blood at different time points. (B) Absorption curve of procyanidin in rat plasma. The data are presented as the mean ± SD (n=6).
Figure 4
Figure 4
Effect of procyanidin on erectile function in rats. (A) Intracavernous pressure (ICP) and mean arterial pressure (MAP) in control rats (n=6). (B) Intracavernous pressure (ICP) and mean arterial pressure (MAP) in the sildenafil-treated rats (n=6). (C) Intracavernous pressure (ICP) and mean arterial pressure (MAP) in the procyanidin-treated rats (n=6). (D) Differential statistics of the ratio of maximal intracavernous pressure to mean arterial pressure (ICPMax/MAP) in control, sildenafil, and procyanidin groups of rats, 95% confidence intervals: control vs sildenafil (−0.2049, −0.03253), control vs procyanidin (−0.1751, −0.002719). (E) Differential statistics of cGMP levels in corpus cavernosum in control, sildenafil, and procyanidin groups of rats, 95% confidence intervals: control vs sildenafil (−7.616, −0.6818), control vs procyanidin (−7.308, −0.3738). The data are presented as the mean ± SD (n=6). *Mean P < 0.05, vs control group; **Mean P < 0.01, vs control group.
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