The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction.

Abstract

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg-1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg-1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg-1 LIMK2i and 20.0 mg kg-1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

• Authors: Min Chul Cho, Junghoon Lee, Juhyun Park, Sohee Oh, Ji Sun Chai, Hwancheol Son, Jae-Seung Paick, Soo Woong Kim
• Journal: Asian journal of andrology (Asian J Androl) 2019 Sep-Oct Vol. 21 Issue 5 Pg. 493-500 ISSN: 1745-7262 [Electronic] China
• PMID: 30829289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase 5 Inhibitors
• Pyrimidines
• Sulfonamides
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• Lim Kinases
• Limk2 protein, rat
• udenafil

Topics

• Animals
• Apoptosis (drug effects)
• Arterial Pressure
• Electric Stimulation
• Erectile Dysfunction (drug therapy, etiology, pathology)
• Lim Kinases (antagonists & inhibitors)
• Male
• Nerve Crush
• Nitric Oxide Synthase Type III (metabolism)
• Penis (drug effects, pathology)
• Peripheral Nerve Injuries (complications, pathology)
• Phosphodiesterase 5 Inhibitors (therapeutic use)
• Phosphorylation
• Pyrimidines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides (therapeutic use)