The current study sought to clarify the role of phosphodiesterase type 5 inhibitors (PDE-5i) and a vacuum erection device (VED) in penile rehabilitation after laparoscopic nerve-preserving radical proctectomy (LNRP) for rectal cancer. Participants were assigned to one of the following arms-no-intervention, nightly use of sildenafil 25 mg for 3 months after surgery, or concurrent use of nightly sildenafil 25 mg/day for 3 months and a vacuum erection device (VED) 10 to 15 minutes/day for 3 months-in a nonrandomized fashion. All participants had a follow-up of over 12 months prospectively, and patients had baseline, 3-, 6-, and 12-month assessment based on the International Index of Erectile Function-5 (IIEF-5). Seventy-one cases were included in final analyses. In the no-intervention group, the mean baseline IIEF-5 score of 21.9 decreased rapidly to 5.0 at 3 months ( p < .001), 9.2 at 6 months ( p < .001), and stayed at 10.9 at 12 months ( p < .001). In the single therapy group, the mean baseline IIEF-5 score of 22.4 decreased dramatically to 9.0 at 3 months ( p < .001), 14.9 at 6 months ( p = .005), and stayed at 15.1 at 12 months ( p = .005). In the combined therapy group, the mean baseline IIEF-5 score of 23.0 decreased slightly to 15.0 at 3 months ( p = .005), 18.0 at 6 months ( p = .038), and maintained at 18.7 at 12 months ( p = .163). Findings suggested an over 50% decline in the quality of erection function of the patients after LNRP. The early use of PDE-5i alone or combined use of PDE-5i and VED after LNRP maintained erectile function at 12 months.

Erectile dysfunction is the most common complication after pelvic radical surgery. Rehabilitation programs are increasingly being used in clinical practice but there is no high level of evidence supporting its efficacy. The principle of early penile rehabilitation stems from animal studies showing early histological and molecular changes associated with penile corporal hypoxia after cavernous nerve injury. The concept of early penile rehabilitation was developed in late nineties with a subsequent number of clinical studies supporting early pharmacologic penile rehabilitation. These studies included all available phosphodiesterase type 5 inhibitors, intracavernosal injection and intraurethral use of prostaglandin E1 and to lesser extent vacuum erectile devices. However, these studies are of small number, difficult to interpret, and often with no control group. Furthermore, no studies have proven an in vivo derangement of endothelial or smooth muscle cell metabolism secondary to a prolonged flaccid state. The purpose of the present report is a synthetic overview of the literature in order to analyze the concept and the rationale of rehabilitation program of erectile dysfunction following radical pelvic surgery and the evidence of such programs in clinical practice. Emphasis will be placed on penile rehabilitation programs after radical cystoprostatectomy, radical prostatectomy, and rectal cancer treatment. Future perspectives are also analyzed.

Irritable bowel syndrome (IBS) is a prevalent disease characterized by abdominal pain and abnormal bowel habits. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) γ agonist and, although it is mostly used as an antidiabetic agent, it has been reported to have analgesic effects. Nitric oxide (NO), a gaseous molecule that mediates many of the effects of pioglitazone, has been implicated in the pathophysiology of IBS. The aim of the present study was to investigate the effects of pioglitazone on symptoms in a rat model of diarrhoea-predominant IBS (D-IBS).and to determine the role of NO in these effects. Diarrhoea-predominant IBS was induced by intracolonic instillation of acetic acid. Pioglitazone (2 mg/kg, i.p.) was administered on Days 7, 9 and 11 after acetic acid instillation. To investigate the mechanism involved in pioglitazone action, rats were also administered either the PPARγ antagonist GW9662 (3 mg/kg, i.p.), the NO synthase (NOS) inhibitor N(G) -nitro-l-arginine methyl ester (l-NAME; 10 mg/kg, i.p.) or the NO precursor l-arginine (250 mg/kg, i.p.) along with pioglitazone. Visceral hypersensitivity, nociceptive thresholds, defecation frequency, stool form, serum and colon NO production and inducible (i) NOS activity were assessed 1 h after the final injection of pioglitazone or dimethylsulphoxide (used as the vehicle). Pioglitazone reduced visceral hypersensitivity and defecation frequency, increased nociceptive thresholds, NO production and iNOS activity and shifted stool form towards hard stools in D-IBS rats. These effects of pioglitazone were significantly reversed by l-NAME, but not GW9662. l-Arginine augmented the effects of pioglitazone. In conclusion, pioglitazone alleviates symptoms in a rat model of D-IBS through an NO-dependent mechanism.

The aims of the study were to determine the extent of male sexual dysfunction after surgical treatment of rectal cancer and to examine the outcome of postoperative treatment with sildenafil.

A prospective study was performed in patients who underwent attempted curative total mesorectal excision (TME) for low rectal cancers. Sexual function scores were determined by questionnaire preoperatively and at 3 and 12 months postoperatively. Outcomes were examined in patients who were sexually active preoperatively.

From 2000 to 2007, 207 patients underwent TME at our institution, of whom 49 (24%) were sexually active preoperatively. Erectile dysfunction and ejaculatory problems were present in 80% and 82%, respectively of the 49 patients at 3 months postoperatively, and in 76% and 67%, respectively at 12 months. Lateral lymph node dissection was a strong risk factor for postoperative sexual dysfunction. The impotency rate was 37% and 47% of patients were unable to ejaculate. Sildenafil was administered to 16 patients who requested the drug during follow-up, and sexual dysfunction was improved in 11 of these patients (69%).

Sexual dysfunction occurs frequently after rectal cancer treatment and is mainly caused by surgical damage in lateral lymph node dissection. Sildenafil may be effective for the treatment of sexual dysfunction.

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by visceral hypersensitivity and altered bowel function. There are increasing evidences suggested that VSL#3 probiotics therapy has been recognized as an effective method to relieve IBS-induced symptoms. The aim of this study was to examine the effects of VSL#3 probiotics on visceral hypersensitivity (VH), nitric oxide (NO), fecal character, colonic epithelium permeability, and tight junction protein expression. IBS model was induced by intracolonic instillation of 4% acetic acid and restraint stress in rats. After subsidence of inflammation on the seventh experimental day, the rats were subjected to rectal distension, and then the abdominal withdrawal reflex and the number of fecal output were measured, respectively. Also, colonic permeability to Evans blue was measured in vivo, and tight junction protein expression was studied by immunohistochemistry and immunoblotting method. Rats had been pretreated with VSL#3 or aminoguanidine (NOS inhibitor) or VSL#3+ aminoguanidine before measurements. The rats at placebo group showed hypersensitive response to rectal distension (P < 0.05) and defecated more stools than control rats (P < 0.05), whereas VSL#3 treatment significantly attenuated VH and effectively reduced defecation. Aminoguanidine reduced the protective effects of VSL#3 on VH. A pronounced increase in epithelial permeability and decreased expression of tight junction proteins (occludin, ZO-1) in placebo group were prevented by VSL#3, but not aminoguanidine. VSL#3 treatment reduce the hypersensitivity, defecation, colonic permeability and increase the expression of tight junction proteins (occludin, ZO-1). As the part of this effect was lowered by NOS inhibitor, NO might play a role in the protective effect of VSL#3 to some extent.

Lithium, a widely used drug in bipolar-affective disorders, plays gastro-protective roles. The effects of lithium on several tissues are mediated through nitric oxide (NO), which regulates gastrointestinal motility and mucosal integrity. The aim of this study was to investigate the protective effect of chronic lithium administration on visceral hypersensitivity and to investigate the role of NO as a potential mechanism of lithium in a rat model of irritable bowel syndrome.

Colitis was induced by the intracolonic administration of acetic acid. After subsidence of inflammation on the seventh experimental day, nociception and defecation parameters were measured. A subgroup of animals had been pretreated with lithium carbonate (600 mg/L) for 35 days. Thereafter, either a non-selective NO synthase (NOS) inhibitor (N-nitro-L-arginine methyl ester [L-NAME], 10 mg/kg), a selective NOS inhibitor (aminoguanidine, 100 mg/kg), or saline were administered intraperitoneally 1 h before measurements.

Chronic lithium attenuated the visceral hypersensitivity, increased the nociceptive threshold, and decreased stool frequency. L-NAME and aminoguanidine decreased the nociceptive threshold and reduced the protective effects of lithium on visceral hypersensitivity. Stool frequency was increased in both the lithium-treated and water-treated groups by L-NAME administration, but not aminoguanidine. The form of defecation in the lithium-treated rats shifted toward hard stools rather than being soft and formless, but NOS inhibitors did not change the stool consistency pattern.

The results indicate the antinociceptive property of chronic lithium on visceral hypersensitivity. As this effect was lowered by NOS inhibitors, NO might play a role in the protective effect of lithium to some extent.

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.

To highlight the nonerectogenic beneficial uses of oral PDE5 inhibitors.

A systematic review of published studies in this affair based on a Pubmed and medical subject heading databases search of all concerned articles.

Demonstrated beneficial as well as applicable uses of oral PDE5 inhibitors.

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.

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.

This study was designed to evaluate the effect of vaginal electrical stimulation on rectal tone and compliance and anal sphincter pressure and to explore possible mechanisms involved in the effects of vaginal electrical stimulation on rectal tone in conscious dogs.

Seven dogs inserted with a probe with two ring electrodes were studied. The study included two experiments. The first experiment was composed of two series of sessions rectal tone and compliance; and anal sphincter pressure. Each series included three sessions: vaginal electrical stimulation with long pulses, vaginal electrical stimulation with trains of long pulses, and vaginal electrical stimulation with trains of short pulses. The second experiment was performed in two sessions: vaginal electrical stimulation with long pulses plus guanethidine, and vaginal electrical stimulation with trains of long pulses plus guanethidine. In each session, rectal tone was recorded.

1) Vaginal electrical stimulation with long pulses or trains of long pulses but not trains of short pulses significantly decreased rectal tone and increased anal sphincter pressure. 2) None of the vaginal electrical stimulation methods altered rectal compliance. 3) The inhibitory effect of vaginal electrical stimulation on rectal tone was abolished by guanethidine.

Vaginal electrical stimulation with long pulses or trains of long pulses but not trains of short pulses reduces rectal tone and increases anal sphincter pressure. The inhibitory effect of vaginal electrical stimulation on rectal tone is mediated by the sympathetic pathway. These findings suggest that vaginal electrical stimulation may be a potential therapy for fecal incontinence.

Colonic electric stimulation has been shown to alter motor functions of the colon; however, its effects on other organs of the gut have been investigated rarely.

This study was performed in 12 dogs implanted with one pair of colonic serosal electrodes and a gastric cannula. Experiments were performed to study: 1) the effect of colonic electric stimulation on proximal gastric tone and compliance; 2) the effect of colonic electric stimulation on rectal tone and compliance; 3) the sympathetic mechanism involved in the effects of colonic electric stimulation on gastric/rectal tone. A computerized barostat was used to assess gastric/rectal tone and compliance.

Colonic electric stimulation inhibited both gastric and rectal tone with a higher potency in gastric tone. Colonic electric stimulation reduced gastric but not rectal compliance. The inhibitory effect of colonic electric stimulation on gastric tone but not rectal tone was abolished by an adrenergic blockade, guanethidine.

Colonic electric stimulation inhibits both gastric and rectal tone with a higher potency in inhibiting gastric tone. Colonic electric stimulation reduces gastric but not rectal compliance. The inhibitory effect of colonic electric stimulation on gastric tone seems to be mediated by the sympathetic pathway.

Previous studies have shown that sildenafil inhibits the esophageal motility in both humans and animals. The aim of this study was to investigate the effects of sildenafil on intestinal myoelectrical activity and motility. The study was composed of 2 experiments and performed in 7 healthy female dogs with a duodenal cannula 20 cm beyond pylorus (19-26 kg). The first experiment was designed to study the effects of sildenafil on intestinal myoelectrical activity and it included 2 sessions each consisting of 30-minute baseline, 15-minute posttreatment (placebo or 100 mg sildenafil) and 90 minutes after a liquid meal. Intestinal myoelectrical activity was recorded during the entire experiment period. The second experiment was aimed to investigate the effect of sildenafil on intestinal motility and was performed immediately after a solid meal. Intestinal motility was measured by a manometric catheter inserted into the small intestine via the duodenum cannula for 30 minutes at baseline and 60 minutes after sildenafil. Sildenafil significantly reduced the amplitude but had no effect on the frequency and regularity of the intestinal myoelectrical activity. Sildenafil significantly inhibited postprandial intestinal contractions. Although the frequency of the contractions was not altered, the mean area under the curve was significantly reduced during the first 30 minutes (P < .03) and second 30 minutes after sildenafil (P < .03); the power of intestinal contractile activities was also significantly reduced during the first 30 minutes (P < .0004) and second 30 minutes after sildenafil (P < .0003) in comparison with baseline. In conclusion, sildenafil inhibits the amplitude of both intestinal contractile activity and intestinal slow waves.

Sildenafil stimulates the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway through inhibition of type 5 phosphodiesterase. NO-cGMP pathway causes smooth muscle relaxation. The aim of this study is to evaluate the effects of sildenafil on gallbladder motility.

Twenty healthy male volunteers (21-35 years old) participated in this randomized, double blind, crossover, and placebo-controlled study. Oral sildenafil (50 mg) or placebo was randomly dispensed to each volunteer on two consecutive days. After the sildenafil or placebo, a special meal with a high fat content was administered. Gallbladder volume was measured using sonography preprandially and at 5, 15, 30, 60, 120 and 180 minutes postprandially.

Sildenafil showed an inhibitory effect on gallbladder contraction in healthy volunteers that began at 30 minutes. Gallbladder volumes showed significant differences at 30 minutes following the test meal (approximately 50-60 min after the sildenafil intake), between placebo (15.4 +/- 5.1 mL) and the sildenafil groups (19.3 +/- 6.1 mL) (P < 0.05). In addition, gallbladder volume was significantly higher during the refilling phase in the sildenafil group (P < 0.05 at 180 min). Maximal contraction was achieved at 60 minutes in each group.

Sildenafil constituted a significant inhibitory effect on gallbladder discharge in healthy individuals when compared with placebo group. Because of this inhibitory effect, sildenafil consumption for long periods may potentiate risks of gallbladder disorders and gallstone formation resulting from disturbed gallbladder motility.

Visceral hypersensitivity is a consistent finding in a considerable proportion of patients with irritable bowel syndrome (IBS), and may provide a physiological basis for the development of IBS symptoms. In this study, we aimed to confirm the hypothesis that nitric oxide (NO) is involved in maintaining visceral hypersensitivity in IBS. Ten healthy volunteers (HV) and 12 IBS patients with documented hypersensitivity to rectal distension underwent a rectal barostat study. The effect of placebo and the specific NO synthase inhibitor NG -monomethyl-L-arginine (L-NMMA) on resting volume, rectal sensitivity to distension and rectal compliance was evaluated in a double-blind, randomized, cross-over fashion. NG -monomethyl-L-arginine did not alter resting volumes in HV or IBS patients. In HV, l-NMMA did not alter rectal sensory thresholds compared to placebo (45 +/- 3 and 46 +/- 3 mmHg, respectively). In contrast, L-NMMA significantly increased the threshold for discomfort/pain in IBS patients (placebo: 18 +/- 2, l-NMMA: 21 +/- 3 mmHg, P < 0.05). Rectal compliance was not affected by L-NMMA. Although NO does not seem to play a major role in normal rectal sensation or tone, we provide evidence that NO may be involved in the pathophysiology of visceral hypersensitivity in IBS.

Propagating sequences (PS) are important in colonic propulsion and defecation, yet the triggers of these motor patterns are not understood. Nonadrenergic noncholinergic neurones are believed to modulate smooth muscle in the gastrointestinal tract via the ubiquitous inhibitory neurotransmitter nitric oxide (NO). In the mouse colon periods of quiescence correlate with an increase in the release of NO. We investigated the colonic response to NO synthase inhibition in the conscious human subject. Intravenous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA; 3 or 6 mg kg(-1) h(-1)) occurred in random order in six healthy volunteers in whom a 5 m long nasocolonic manometry catheter was positioned such that 16 recording sites, at 7.5-cm intervals, spanned the terminal ileum and colon. L-NMMA infusion at 3 mg kg(-1) h(-1), but not 6 mg kg(-1) h(-1) significantly (P = 0.02) increased proximal colonic PS frequency (2.0 +/- 1.9 vs 11.7 +/- 7.0 PS h(-1)) and non-propagating motor activity (5,296 +/- 2,750 vs 6,362 +/- 1,275 mmHg s). We conclude that blockade of NO synthesis has a stimulatory effect on the frequency of proximal colonic PS. This suggests removal of tonic nitrergic inhibition of the colon might be a physiological stimulus for propagating activity.

Gastrointestinal (GI) smooth muscle responses to stimulation of the nonadrenergic noncholinergic inhibitory nerves have been suggested to be mediated by polypeptides, ATP, or another unidentified neurotransmitter. The discovery of nitric-oxide (NO) synthase inhibitors greatly contributed to our understanding of mechanisms involved in these responses, leading to the novel hypothesis that NO, an inorganic, gaseous molecule, acts as an inhibitory neurotransmitter. The nerves whose transmitter function depends on the NO release are called "nitrergic", and such nerves are recognized to play major roles in the control of smooth muscle tone and motility and of fluid secretion in the GI tract. Endothelium-derived relaxing factor, discovered by Furchgott and Zawadzki, has been identified to be NO that is biosynthesized from l-arginine by the constitutive NO synthase in endothelial cells and neurons. NO as a mediator or transmitter activates soluble guanylyl cyclase and produces cyclic GMP in smooth muscle cells, resulting in relaxation of the vasculature. On the other hand, NO-induced GI smooth muscle relaxation is mediated, not only by cyclic GMP directly or indirectly via hyperpolarization, but also by cyclic GMP-independent mechanisms. Numerous cotransmitters and cross talk of autonomic efferent nerves make the neural control of GI functions complicated. However, the findingsrelated to the nitrergic innervation may provide us a new way of understanding GI tract physiology and pathophysiology and might result in the development of new therapies of GI diseases. This review article covers the discovery of nitrergic nerves, their functional roles, and pathological implications in the GI tract.

Nitric oxide is an important mediator of gut smooth muscle relaxation and visceral sensation. Sildenafil results in stimulation of the nitric oxide-cyclic GMP pathway. We sought to determine the effects of daily sildenafil administration on colorectal function. Over a 4-week period, sildenafil was administered during weeks 2 and 3. Stool frequency and consistency were assessed daily. Anorectal manometry, rectal sensation, and colon transit testing were performed at the end of weeks 1 and 3. Ten healthy men were studied. No significant differences in segmental or total colon transit time were noted; however, significant changes in stool frequency and trends toward decreased stool consistency were noted during sildenafil use. A trend toward reduced resting anal sphincter pressure was seen after sildenafil. Rectal volumes to first sensation and desire to defecate were significantly increased after sildenafil on test day 2 only. Additionally, volumes to desire to defecate and maximal tolerable volume were significantly increased before sildenafil on test day 2 compared to before sildenafil on test day 1. We conclude that daily administration of sildenafil is well tolerated and results in alterations in colorectal function.