A Pilot Study of the Effects of Sildenafil on Stool Characteristics, Colon Transit, Anal Sphincter Function, and Rectal Sensation in Healthy Men

Milone, Mark; DiBaise, John K.

doi:10.1007/s10620-005-2695-5

Cited by 9 publications

(8 citation statements)

References 44 publications

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“…Sildenafil is absorbed systemically and has well-established relaxation effects on smooth muscle that might affect transit. Several studies have reported a reduction in esophageal contractile force by sildenafil treatment, particularly in patients with dysmotility disorders, but this effect is less pronounced in the normal esophagus and in the lower intestine [38,39,40,41,42]. Reduced muscular contractility cannot explain the results reported here because this would be expected to further increase transit time in our disease models, but as shown here, sildenafil reduced transit time.…”

Section: Discussioncontrasting

confidence: 48%

Sildenafil normalizes bowel transit in preclinical models of constipation

et al. 2017

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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.

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Section: Discussioncontrasting

confidence: 48%

Sildenafil normalizes bowel transit in preclinical models of constipation

et al. 2017

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“…In conclusion, ROCK inhibitors like H-1152 and Y-27632 provide selective therapeutic alternatives for anorectal motility disorders characterized with hypertensive IAS (35) over the present options of Ca 2ϩ channel blockers (19), nitric oxide donors (1,17), botulinum toxin (14,23), and specific phosphodiesterase inhibitors (25,45). These approaches are often ineffective because of the side effects or desensitization issues.…”

Section: Discussionmentioning

confidence: 99%

Selectivity of ROCK inhibitors in the spontaneously tonic smooth muscle

Rattan

Patel²

2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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The selectivity of different Rho kinase (ROCK) inhibitors in the spontaneously tonic smooth muscle has not been investigated. We examined this issue using Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarbox anecarboxamide, 2HCl], H-1152 [(S)-(+)-(2-methyl-5-isoquinolinyl) sulfonylhomopiperazine, 2HCl], HA-1077 [(5 isoquinolinesulfonyl) homopiperazine, 2HCl], and ROCK inhibitor II [N-(4-pyridyl)-N'-(2,4,6-trichlorophenyl)urea]. We compared these inhibitors in the spontaneously tonic smooth muscle of the internal anal sphincter (IAS). ROCK, protein kinase C (PKC), and myosin light chain kinase (MLCK) activities were determined in the IAS, before and after different ROCK inhibitors. Y-27632 and H-1152 were approximately 30-fold more potent in the IAS (IC(50): 4.4 x 10(-7) and 7.9 x 10(-8) M, respectively) vs. the phasic rectal smooth muscle (RSM) (IC(50): 1.3 x 10(-5) and 2.5 x 10(-6) M, respectively). HA-1077 and ROCK inhibitor II were equipotent in the IAS vs. RSM. In the IAS, H-1152 was the most potent whereas ROCK inhibitor II is the least. Y-27632 and H-1152 caused concentration-dependent decrease in the IAS tone that correlates directly with the decreases in ROCK activity, without significant effect in the PKC and MLCK activities. This specifically selective correlation between ROCK activity and decrease in the IAS tone was absent in the case of HA-1077 and ROCK inhibitor II, which also inhibited PKC and MLCK. We conclude that the IAS tone is critically dependent on ROCK activity, and H-1152 and Y-27632 are the most selective and potent ROCK inhibitors in the IAS.

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“…NO is an important mediator of gut smooth muscle relaxation and visceral sensation. Milone et al [71] determined the effects of sildenafil daily on colorectal function over 4 weeks. Significant changes in stool frequency, decreased stool consistency, reduced resting anal sphincter pressure were seen after sildenafil.…”

Section: Colorectal Functionmentioning

confidence: 99%

Oral Phosphodiesterase Type 5 Inhibitors: Nonerectogenic Beneficial Uses

Mostafa

2008

The Journal of Sexual Medicine

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Introduction Phosphodiesterase type 5 (PDE5) hydrolyses cyclic guanylate monophosphate (cGMP) specifically to 5′ GMP. PDE5 inhibitors were a breakthrough medication that addressed a previously unfulfilled medical need. They promoted vascular relaxation in the corpora cavernosa and penile erection during sexual stimulation. Sildenafil, vardenafil, and tadalafil were approved then introduced as effective treatments for male erectile dysfunction. This impact has stimulated academic, clinical, and industrial research. Aim To highlight the nonerectogenic beneficial uses of oral PDE5 inhibitors. Method A systematic review of published studies in this affair based on a Pubmed and medical subject heading databases search of all concerned articles. Main Outcome Measures Demonstrated beneficial as well as applicable uses of oral PDE5 inhibitors. Results As chemical molecules, these drugs were shown to exert potential nonerectogenic beneficial effects. They showed efficacy as a useful adjunct in the management of pulmonary hypertension. Additional uses were extended to different utilities: essential hypertension, benign prostatic hyperplasia, gastrointestinal disorders, endothelial dysfunction, female sexual dysfunction, genital blood flow, exercise capacity, Raynaud's phenomenon, sperm motility, etc. Conclusion Exploring PDE5 inhibitors for their possible medical applications in diverse specialties seems to be beneficial in making use of these molecules for the welfare of humanity.

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A Pilot Study of the Effects of Sildenafil on Stool Characteristics, Colon Transit, Anal Sphincter Function, and Rectal Sensation in Healthy Men

Cited by 9 publications

References 44 publications

Sildenafil normalizes bowel transit in preclinical models of constipation

Sildenafil normalizes bowel transit in preclinical models of constipation

Selectivity of ROCK inhibitors in the spontaneously tonic smooth muscle

Oral Phosphodiesterase Type 5 Inhibitors: Nonerectogenic Beneficial Uses

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