Sildenafil normalizes bowel transit in preclinical models of constipation

Area of Science:

• Gastroenterology
• Pharmacology

Background:

• Guanylyl cyclase-C (GC-C) agonists like linaclotide treat constipation by increasing intestinal cGMP.
• Limited use of GC-C agonists in pediatric patients necessitates alternative cGMP-elevating strategies.

Purpose of the Study:

• To investigate if the PDE-5 inhibitor sildenafil can increase intestinal cGMP and mimic linaclotide's therapeutic effects in preclinical constipation models.

Main Methods:

• Oral administration of sildenafil and linaclotide in mouse models.
• Assessment of intestinal cGMP levels, colon mucosa proliferation and differentiation.
• Evaluation of intestinal transit and fecal water content in healthy and induced colitis/constipation models.

Main Results:

• Sildenafil increased intestinal cGMP, reduced colon cell proliferation, and increased differentiation, similar to linaclotide.
• Sildenafil normalized intestinal transit and fecal water content in dextran sulfate sodium-induced colitis recovery and loperamide-induced constipation models.
• Sildenafil improved compromised epithelial barrier function in a colitis recovery model.

Conclusions:

• Sildenafil effectively increases intestinal cGMP and exhibits therapeutic effects comparable to linaclotide in preclinical models.
• Sildenafil demonstrates potential as an alternative therapeutic agent for chronic constipation, IBS-C, and post-infectious IBS.