Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation–predominant irritable bowel syndrome
Graphical abstract
Introduction
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a global prevalence around 11% [1]. It is characterized by intestinal dysmotility with altered defecation pattern together with recurrent abdominal pain due to visceral hypersensitivity [2]. 80% of IBS patients experience depressive behavior, that has been implicated in IBS pathophysiology [3].
The intestinal GC-C/extracellular cGMP pathway has recently been recognized as a novel pathway that is involved in chronic visceral hypersensitivity and fluid secretion [4]. The guanyl cyclase C agonist linaclotide has recently gained FDA approval for therapy of IBS- constipation [5].However, linaclotide is contraindicated in pediatric patients as it may lead to severe diarrhea and dehydration [6]. In contrast, drugs such as tadalafil, that increase cGMP by inhibiting phosphodiesterase 5 (PDE-5), are well tolerated when used for management of pediatric patients with pulmonary hypertension [7]. Accordingly, in the present study, the effects of tadalafil versus those of linaclotide were investigated in an IBS- constipation model induced by cold (0 to 4 °C) intragastric saline administration. The study aimed to determine whether the beneficial effects observed with linaclotide in IBS- constipation, might also be shared by tadalafil without inducing the severe diarrhea reported for linaclotide. The study also investigated the effects of the drugs on the behavioral changes associated with the IBS model. An attempt was made to determine whether the ability of tadalafil to be systemically absorbed and to cross the blood brain barrier might impact its beneficial effects on the gastrointestinal dysfunction and depressive behavior in IBS, compared to linaclotide which is a locally acting drug.
Section snippets
Material and methods
72 male Wistar rats (200–250 g) were kept in 6 groups, 12 rats each (control naïve, control tadalafil treated, control linaclotide treated, IBS untreated, IBS tadalafil treated group, IBS linaclotide treated group). Rats were given food at specific hours and water freely for a one week period before tests.
Cold intragastric saline (0 to 4 °C), for 14 consecutive days [8], was administered for induction of an IBS predominant constipation model. Rats in the control group were given isotonic saline
Number of fecal pellets
Fig. 1 showed that induction of IBS- predominant constipation model significantly (P < .001) decreased number of fecal pellets compared to control group. Simultaneous treatment with tadalafil or linaclotide significantly increased number of fecal pellets (P < .05, P < .001), respectively, relative to IBS untreated group. A greater improvement was seen with linaclotide compared to tadalafil, (P < .05).
Fecal water content
Fig. 2 showed that induction of IBS- predominant constipation model significantly (P < .001)
Discussion
In the present work gastric instillation of cold saline (0 to 4 °C) for 14 days, in rats, resulted in development of an IBS model with predominant constipation (IBS-C). This model was characterized by increased intestinal transit time, with reduced fecal pellets and fecal water content. An increase in visceral hypersensitivity was also noted as evidenced by an increase in abdominal withdrawal reflex following colorectal distention and increase in colonic C fos, a marker of neuronal activation
Author contributions
Amina Sedky and Yosra Magdy conceived the idea, designed the study, performed the rat experiments, analyzed the data and prepared the manuscript.
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