Abstract
Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation. Oral administration of sildenafil caused increased cGMP levels in mouse intestinal epithelium demonstrating that blocking cGMP-breakdown is an alternative approach to increase cGMP in the gut. Both linaclotide and sildenafil reduced proliferation and increased differentiation in colon mucosa, indicating common target pathways. The homeostatic effects of cGMP required gut turnover since maximal effects were observed after 3 days of treatment. Neither linaclotide nor sildenafil treatment affected intestinal transit or water content of fecal pellets in healthy mice. To test the effectiveness of cGMP elevation in a functional motility disorder model, mice were treated with dextran sulfate sodium (DSS) to induce colitis and were allowed to recover for several weeks. The recovered animals exhibited slower transit, but increased fecal water content. An acute dose of sildenafil was able to normalize transit and fecal water content in the DSS-recovery animal model, and also in loperamide-induced constipation. The higher fecal water content in the recovered animals was due to a compromised epithelial barrier, which was normalized by sildenafil treatment. Taken together our results show that sildenafil can have similar effects as linaclotide on the intestine, and may have therapeutic benefit to patients with CIC, IBS-C, and post-infectious IBS.
Highlights
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by altered bowel habits and abdominal pain that adversely affect quality of life
It was recently reported that increasing cyclic guanosine monophosphate (cGMP) levels by intraperitoneal (IP) injection of the phosphodiesterase 5 (PDE-5) inhibitor vardenafil had profound effects on homeostasis in the colon epithelium [23]
The clinical success of the Guanylyl cyclase-C (GC-C) agonist linaclotide demonstrates the utility of cGMP elevation in the intestinal epithelium for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) patients
Summary
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by altered bowel habits and abdominal pain that adversely affect quality of life. IBS is sub-classified as constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), or mixed symptom. There is no cure for IBS, and current treatment strategies often require patients to take multiple medications to control their symptoms [1]. Laxatives, and antidiarrheals are prescribed to help normalize alterations in bowel habits, while tricyclic antidepressants and antispasmodics aim to minimize visceral pain associated with the disease [2]. The variable effectiveness of this symptom-targeted approach to IBS treatment underscores the need for alternatives
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