Elsevier

Life Sciences

Volume 256, 1 September 2020, 117960
Life Sciences

Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation–predominant irritable bowel syndrome

https://doi.org/10.1016/j.lfs.2020.117960Get rights and content

Abstract

Background

Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated.

Methods

72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days.

Results

Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide).

Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide).

Conclusion

Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.

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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      Three rats of each group were separated for measurement of the intestinal transit and cGMP level. According to the literature the intestinal transit was measured by administration of powdered charcoal via gastric gavage (Sagar et al. 2005; Sedky and Magdy, 2020; Sharman et al. 2017). After one hour; they were sacrificed and the small and large intestines were isolated.

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