Nitric oxide production is diminished in colonic circular muscle from acquired megacolon

PURPOSE: Nitric oxide modulates human colonic smooth muscle function. To determine whether nitric oxide production is altered in colon from acquired megacolon, we measured cholinergic nerve-mediated contractionsin vitro before and after inhibition of nitric oxide synthase. METHODS: Intramural nerves in circular smooth muscle from histologically normal colon (n=12) and acquired megacolon (n=3) were activated by electrical field stimulation. RESULTS: In controls blockade of nitric oxide synthase by N^G-Nitro-L-Arginine induced increases (P<0.05) in amplitude of contractions; these increases in amplitudes were blocked by L-Arginine (analysis of variance;P<0.05). By contrast, blockade of nitric oxide synthase did not increase amplitudes of contractions with circular smooth muscle from acquired megacolon. An immediate phasic contraction was blocked by atropine sulfate. CONCLUSIONS: The results support the concept that nitric oxide production modulates cholinergic nerve-mediated contractions in normal colonic circular muscle, whereas acquired megacolon is associated with altered release of this inhibitory neurochemical. Potential explanations include depletion of tissue L-Arginine, decreased capacity to recycle citrulline to arginine, or decreased release of vasoactive intestinal peptide from circular smooth muscle in acquired megacolon.Supported by Veterans Administration Medical Research Funds and by West Virginia University.Presented at Digestive Disease Week, Washington, D.C., May 11 to 14, 1997.     

Toxic megacolon: a rare presentation of primary lymphoma of the colon

Primary colonic lymphoma is rare and accounts for less than 1% of colon malignancies. Moreover, diffuse neoplastic invasion of the colon is exceptional. This case describes a patient with primary non-Hodgkin's lymphoma of the colon presenting as toxic megacolon. This unique presentation is the first case reported in the literature of a diffuse colonic lymphoma diagnosed in the setting of a toxic megacolon. Histological confirmation was performed on the piece of colectomy.     

Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon

BACKGROUND: The pathophysiology of constipation is not clearly identified as yet, and the interstital cells of Cajal (ICC), known to generate the slow wave activity and to be involved in intestinal neurotransmission and the enteric nervous system (ENS), are suspected to play an important role. The aims of the present study were to assess the distribution of ICC and neuronal cells of ENS in patients with slow-transit constipation and acquired megacolon. METHODS: Sigmoid colon specimens were obtained from patients who underwent colectomy due to slow-transit constipation (n = 10), acquired megacolon (n = 9) and non-obstructive colon cancer (n = 10) as a control group. The ICC were visualized by c-Kit immunohistochemistry and neuronal cells of the ENS were demonstrated by protein gene product (PGP) 9.5. Density of cells stained by c-Kit and PGP 9.5 was calculated as percent area (area stained/area of X-Y plane) x 100, when images were collected at a magnification of x40 objective, with maximum area examined in the horizontal X-Y plane of 400 microm x 400 microm using an image analyzer. RESULTS: The densities of ICC and PGP 9.5 reactive neuronal structures were significantly decreased in all layers of sigmoid colon specimens in patients with slow-transit constipation and acquired megacolon, compared with that of the control group. However, there was no statistically significant difference in either the density of ICC or that of neuronal structures between the patients with slow-transit constipation and acquired megacolon. CONCLUSIONS: Slow-transit constipation and acquired megacolon were associated with alteration of ICC and neuronal cells of ENS in the sigmoid colon.     

钙离子在大鼠结肠平滑肌运动中作用机制的研究

目的 应用束缚应激大鼠实验模型,研究离体结肠平滑肌的收缩运动及其影响因素,探讨鸟苷素在结肠运动中的作用。方法 建立束缚应激大鼠动物模型,制备离体结肠平滑肌环行肌及纵行肌肌条,应用张力换能器,测定其肌张力。应用放射配基法测定结肠组织及血浆中鸟苷素含量。结果 束缚应激刺激可诱发大鼠排便增加,该动物模型是较好的模拟人ＩＢＳ的实验动物模型。束缚应激大鼠离体结肠平滑肌的张力升高,对Ｋ＾＋、Ｃａ＾２＋、乙酰胆     

Peptidergic nerves in the colon of patients with ulcerative colitis

BACKGROUND/AIMS: The cause of impaired motility, such as diarrhea and toxic megacolon, in patients with ulcerative colitis is unknown. Neuropeptides have recently been shown to be a neurotransmitter in the non-adrenergic non-cholinergic inhibitory and excitatory nerves in the human gut. To clarify the physiological significance of vasoactive intestinal polypeptide, substance P and neurotensin in the colon of patients with ulcerative colitis, we investigated the enteric nerve responses on lesional and normal bowel segments derived from patients with ulcerative colitis and patients who underwent colon resection for colonic cancers. METHODOLOGY: Twenty-four specimens were obtained from the lesional colon of 6 patients with ulcerative colitis (4 male, 2 female; ages 14-51 years, mean: 40.3 years). The patients with ulcerative colitis had chronic disease (4 with moderate disease, 2 with severe disease). Seventy-two specimens were obtained from the normal colon of 10 patients with colonic cancer (8 men and 2 women; ages 40-56 years, mean: 51.2 years). A mechanographic technique was used to evaluate in vitro muscle responses to these peptides of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers. RESULTS: (1) Peptidergic nerves such as vasoactive intestinal polypeptide, substance P, and neurotensin nerves were found to act on both normal colon and ulcerative colitis colon; (2) the colon with ulcerative colitis was more strongly innervated by vasoactive intestinal polypeptide nerves than the normal colon; (3) Substance P and neurotensin nerves act more weakly in the UC colon that the normal colon. CONCLUSIONS: These findings suggest that peptidergic nerves play an important role in the impaired motility observed in patients with UC.     

Reduced Expression of Serotonin Receptor(s) in the Left Colon of Patients With Colonic Inertia

PURPOSE: Serotonin regulates colonic motility via receptors expressed on neural fibers and smooth muscle. Colonic inertia is characterized by delayed colonic transit. Abnormalities in serotonin receptor protein, as judged by immunoreactivity levels, could contribute to the origin of colonic inertia. The aim of this study was to investigate the expression of serotonin receptor(s) immunoreactivity in the left colon of patients with colonic inertia compared with controls. METHODS: Sixteen patients who underwent subtotal colectomy for colonic inertia were assessed. Colonic transit time was measured with the radiopaque marker technique and presented as the number of retained markers in the colon on Day 5. The control group consisted of 18 patients who underwent left hemicolectomy for colonic carcinoma; histologically normal tissues from the left colon were used. Immunohistochemical staining for serotonin receptor was performed with a rabbit anti-idiotypic antibody. The average positive area (square pixels) in the mucosa, muscularis mucosa, submucosa, and circular and longitudinal muscles per microscopic field (63×) was calculated based on measurement of the positively stained area in 20 randomly chosen microscopic fields in each related structure. The Scion Image computer analysis system was used. RESULTS: Serotonin receptor(s) immunoreactivity was mainly detected in the muscular mucosa, circular muscles, and longitudinal muscles and rarely in the mucosa and submucosa. In muscularis mucosa and circular muscle, the positive areas were significantly less in the colonic inertia group than in controls (muscularis mucosa: 29.1 ± 10.8 vs. 109.7 ± 28.2, P < 0.05; circular muscle: 25.6 ± 6.2 vs.90.2 ± 19.1, P < 0.01). There were significantly positive correlations in the control group in serotonin receptor(s) immunoreactivity levels between circular muscle and longitudinal muscle (r = 0.54, P < 0.05) and between muscular mucosa and longitudinal muscle (r = 0.57, P < 0.05) but not in colonic inertia patients. In addition, the positive areas in the circular muscle were positively correlated to the colonic transit time (Spearmans rank correlation, 0.83; P < 0.01). CONCLUSION: In colonic inertia patients, the serotonin receptor(s) immunoreactivity level is lower in muscular mucosa and circular muscle. The absence of a correlation of serotonin receptor(s) immunoreactivity in the muscular mucosa and muscularis propria in the patient group implies that an uncoordinated expression of serotonin receptors may also contribute to colonic inertia. However, the positive correlation between serotonin receptor(s) immunoreactivity levels in the circular muscle and the transit time observed in colonic inertia patients suggests a decrease in stimulatory subtypes and at the same time an increase in inhibitory subtypes of serotonin receptors in this tissue.     

Decreased interstitial cell of cajal volume in patients with slow-transit constipation

BACKGROUND & AIMS: The cause of slow-transit constipation is incompletely understood. Recent observations suggest a central role for interstitial cells of Cajal in the control of intestinal motility. The aim of this study was to determine the volume of interstitial cells of Cajal in the normal sigmoid colon and in the sigmoid colon from patients with slow transit constipation. METHODS: Sigmoid colonic samples were stained with antibodies to protein gene product 9.5, c-Kit, and alpha-smooth muscle actin. Three-dimensional reconstruction of regions of interest was performed using consecutive images collected on a laser scanning confocal microscope and ANALYZE software. RESULTS: Volume of interstitial cells of Cajal was significantly decreased in all layers of sigmoid colonic specimens from patients with slow-transit constipation compared with normal controls. Neuronal structures within the colonic circular smooth muscle layer were also decreased. CONCLUSIONS: A decrease in the volume of interstitial cells of Cajal may play an important role in the pathophysiology of slow-transit constipation.     

Electron microscopy of the intestine and rectum in acquired immunodeficiency syndrome

To provide a better understanding of the morphologic changes that take place in the intestine and colon in acquired immunodeficiency syndrome (AIDS), electron microscopy was performed on intestinal or colonic biopsy specimens obtained from 6 patients with AIDS and from 2 patients with AIDS-related lymphadenopathy syndrome. Cryptosporidia were attached to the plasma membrane of epithelial cells in 2 patients and were noninvasive. An invasive protozoan organism identified as Microsporidia was found in 1 patient. Evidence for epithelial cell injury was limited. Unusually prominent secretory granules in colonic epithelial cells (a morphologic counterpart of secretion) was found in 2 patients. Tubuloreticular structures were observed in 7 patients. The structures were found in endothelial cells, lymphocytes, monocytes, intraepithelial lymphocytes, and free in the capillary lumen. Tube- and ring-shaped forms were observed in 2 patients, prominent intraepithelial mast cells in 4 patients, rectal spirochetosis in 1 patient, and pseudomembranous colitis in 1 patient with intestinal and systemic shigellosis. Vesicular rosettes, retroviruses, other viruses, and Mycobacterium avium-intracellulare were not observed. These observations expand our knowledge of morphologic changes in the colonic and intestinal mucosa in patients with AIDS. Tubuloreticular structures are so prominent, in contrast to our previous electron-microscopic observations in other disease and normal states of the intestine and colon, that their finding (though clearly nonspecific) may be a clue to the diagnosis of AIDS in an otherwise equivocal situation.     

成人特发性巨结肠一例并文献复习

特发性巨结肠是一种发病机制不明的后天获得性疾病,特点是部分结肠或全部结肠扩张,通常表现为排便异常、腹胀及腹痛。本文报告了成人特发性巨结肠并肠梗阻一例,予结肠次全切除术＋末端回肠造口术治疗,并对成人特发性巨结肠的诊断、鉴别诊断及治疗进行讨论。     

Decreased vasoactive intestinal peptide levels and glutathione depletion in acquired megacolon

We reported decreased vasoactive intestinal peptide levels in acquired megacolon. The origin of altered neuropeptide levels is unknown, but recent work suggested that tissue antioxidants may function as neuroprotectants. Our hypothesis was that altered levels of inhibitory neurotransmitters in human colon are associated with depletion of the tripeptide thiol, glutathione. Normal colon samples (N=10; from patients 41–80 years old) and acquired megacolon samples (N=10; from patients 31–98 years old) were obtained at surgery. Vasoactive intestinal peptide levels were decreased in muscularis externa from acquired megacolon (P=0.01), while there was a modest increase in NADPH diaphorase activity in muscularis externa from megacolon (P=0.10). Glutathione in acquired megacolon was detectable in muscularis externa from only five specimens (P<0.05), but was not significantly different (P>0.05) in the mucosal-submucosal layer. The results supported the presence of vasoactive intestinal peptide and NADPH diaphorase in distinct subpopulations of nerves in human colon. The results also supported the hypothesis that glutathione functions as a neuroprotectant in a subset of patients with acquired megacolon.Supported by VA Medical Research Funds.     

Motor responsiveness of proximal and distal human colonic muscle layers to acetylcholine,noradrenaline, and vasoactive intestinal peptide

There is an increasing body of evidence suggesting regional heterogeneity in human colonic function. Using circular and longitudinal muscle strips from proximal and distal human colon, the present study sought to determine whether such regional differences were apparent in smooth muscle responsiveness to neurohumoral agents. Both proximal and distal muscle gave quantitatively similar responses to acetylcholine, as they did for noradrenaline. However, the circular muscle of the distal colon was more sensitive to vasoactive intestinal peptide than was the circular muscle of the proximal colon. Longitudinal muscle from both regions was comparatively insensitive to VIP.     

Idiopathic chronic constipation is associated with decreased colonic vasoactive intestinal peptide

To investigate the reported association between idiopathic chronic constipation and morphologic abnormalities of enteric nerves, we measured the concentrations of six neuropeptides, vasoactive intestinal peptide, peptide histidine-methionine, substance P, methionine5-enkephalin, neuropeptide Y, and the bombesinlike intestinal peptides, in descending colon from 4 patients with idiopathic chronic constipation. Decreased concentrations of vasoactive intestinal peptide (707 +/- 112 ng/g wet tissue) and peptide histidine-methionine (543 +/- 58 ng/g) were found in the muscularis externa obtained from constipated patients compared with normal concentrations (40 patients) of vasoactive intestinal peptide (1199 +/- 47 ng/g) and peptide histidine-methionine (815 +/- 45 ng/g). Vasoactive intestinal peptide was identified by immunocytochemistry in nerve fibers within the circular smooth muscle layer of descending colon obtained from 6 control patients, but not in nerve fibers within the circular smooth muscle of descending colon obtained from 3 patients with idiopathic chronic constipation. By contrast, the distribution of immunoreactive met5-enkephalin was similar in normal descending colon and in descending colon obtained from patients with idiopathic chronic constipation. Decreased colonic concentrations of vasoactive intestinal peptide (a candidate nonadrenergic, noncholinergic inhibitory neurotransmitter) may be associated with diminution of inhibitory innervation of colonic circular smooth muscle in some patients with idiopathic chronic constipation.     

Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease.

The distribution in the bowel wall of vasoactive intestinal polypeptide-, neuropeptide Y-, and substance P-containing nerve cell bodies and nerve fibers has been described in human sigmoid colon by immunohistochemical examination. In patients with chronic idiopathic constipation, diverticular disease, and in controls (of tissue taken from patients with carcinoma, from a site distant from the tumor that appeared macroscopically normal), the concentrations of vasoactive intestinal polypeptide, neuropeptide Y, and substance P have been measured by immunoassay in the following preparations of sigmoid colon: mucosa, whole colonic wall with mucosa dissected away, circular muscle, and taenia coli. In idiopathic constipation, the vasoactive intestinal polypeptide content of the whole wall minus mucosa was reduced when compared with controls (P less than 0.05) but was unaltered in the mucosa, circular muscle, and taenia coli. In diverticular disease, the vasoactive intestinal polypeptide content of the mucosa and whole wall minus the mucosal layer was increased when compared with control tissue (P less than 0.05 and P less than 0.02, respectively) but was unaltered in the circular muscle and taenia coli. Substance P and neuropeptide Y levels in all layers of colonic wall were unaltered in these two diseases. The disturbances in the normal neural content of vasoactive intestinal polypeptide in the bowel wall in idiopathic constipation and diverticular disease may initiate or contribute to the functional changes seen in these disorders.     

Acute dilatation of the colon]

Dilated colon is provoked by obstructing lesions, toxic megacolon or colonic pseudoobstruction. The obstructing lesions of the colon are colonic volvulus, inflammatory bowel disease with stenosis or colonic cancer. Toxic megacolon is more often caused by I.B.D. and rarely by infectious diseases. Etiological diagnosis is possible after clinical and radiological evaluation. Colonoscopy is always indicated, except in toxic megacolon. Balloon dilatation of strictures, palliative treatment of colonic carcinoma by Laser procedures, reduction of colonic volvulus and aspiration of colonic pseudoobstruction are the principal indications of therapeutic colonoscopy in the non surgical treatment of dilated colon.     

Ultrastructural abnormalities in endoscopically and histologically normal and involved colon in ulcerative colitis

Twenty colonoscopies (eight complete or almost complete; 12 short) were carried out on 15 patients with ulcerative colitis with the aim of comparing the endoscopic aspects with the light and electron microscopic features in biopsies taken from multiple sites. Patients with severe attacks were examined without prior preparation (two examinations). When the attack was mild to moderate (11 examinations), or the patient was in remission (seven examinations), two saline enemas were given up to 1 h before examination. There was a favorable correlation between the endoscopic and light microscopic features in 94.7% of the biopsies (total number of biopsies, 76). The electron microscope findings greatly exceeded those observed by light microscope and indicated that the major abnormality resides within the colonic epithelial cells. Distinctive ultrastructural changes were present both in apparently uninvolved (endoscopically and histologically) parts of colon and in inactive stages of ulcerative colitis. These findings suggest that colonic mucosal involvement may be universal, persist during clinical remission, and precede the light microscopic findings. They also support the importance of maintenance therapy.     

Das neurogene Megakolon: Liegt immer ein Morbus Hirschsprung zugrunde?

The development of megacolon in adults is attributed to malformations of the enteric nervous system apart from mechanic, metabolic, endocrinologic, pharmacologic, neurologic, infectious or systemic causes. Hirschsprung’s disease is considered to represent the most acknowledged form of intestinal innervation disorders underlying the formation of megacolon. In order to evaluate this association, morphologic alterations of the enteric nervous system were examined in patients (age: 19 to 67 years) with megacolon. From the resected colonic segments conventional serial sections and whole-mount preparations were obtained and submitted to immunohistochemical procedures for Protein Gene Product 9.5 as a neuronal marker allowing the 2-dimensional assessment of the architecture of the intramural nervous plexus layers. Whereas complete aganglionosis was diagnosed in only 25% of the cases examined, thus resembling classic Hirschsprung’s disease, the remaining colonic segments showed other forms of intestinal neuronal malformations: 1. Hypoganglionosis of varying severity, 2. intestinal neuronal dysplasia characterised by submucosal giant ganglia and concomitant hypertrophy of nerve fibers, 3. heterotopic ganglia located ectopically within the longitudinal muscle layer as well as within the lamina propria mucosae. In contrast to conventional histologic sections, whole-mount preparations allowed a more subtle assessment of the morphologic alterations of intramural nervous plexus from the normal to the pathologic area and, therefore, a more precise diagnostic classification of intestinal innervation disorders. It could be shown that neurogenic megacolon in adults is not only caused by aganglionosis but also by non-aganglionic innervation disorders. The findings implicate that in adolescent and adult patients suffering from intestinal motility disorders and a concomitant development of megacolon hypoganglionic conditions and intestinal neuronal dysplasia have to be taken into consideration in regards to the diagnostic and therapeutic approach.     

Impaired capsaicin and neurokinin-evoked colonic motility in inflammatory bowel disease

BACKGROUND: Inflammatory bowel disease (IBD) is associated with altered sensory and motor function in the human colon. The aim of the present study was to compare neuromuscular function in normal and IBD-affected colon in vitro, with emphasis on inhibitory enteric nerves, sensory neuropeptides and stimulation of axon collaterals. METHODS: Strips of longitudinal and circular muscle were prepared following colectomy from six patients with intestinal carcinoma (mean age 64.2 +/- 4.8 years) and six patients with IBD (Crohn's disease, n = 3; ulcerative colitis, n = 3: mean age 35.8 +/- 5.7 years). Responses were measured to electrical field stimulation, potassium chloride, 1,1-dimethyl-4-phenylpiperazinium iodide, isoprenaline, calcitonin gene-related peptide (CGRP), capsaicin and neurokinin (NK)-1 and -2 receptor subtype-specific agonists, alone or after muscle precontraction. RESULTS: The NK-1 and CGRP receptor-mediated relaxation was reduced in the circular (by 44%, P < 0.05) and longitudinal (by 61%, P < 0.05) muscle from IBD-affected colon, respectively. Maximal NK-2 receptor-mediated contraction was also significantly decreased in both longitudinal (71%, P < 0.001) and circular (51%, P < 0.01) muscle. Capsaicin evoked relaxation in precontracted colonic longitudinal and circular muscle; this was significantly diminished in the IBD-affected colon (by 63%, P < 0.001 and 76%, P < 0.01, respectively). Responses evoked by stimulation of enteric inhibitory nerves were not significantly altered. CONCLUSIONS: Colonic muscle strips from patients with IBD exhibited impaired CGRP and NK-1 receptor-mediated relaxation and NK-2 receptor-mediated contraction. Capsaicin-activated relaxation of colonic smooth muscle is deficient in IBD-affected colon. These results suggest a discrete effect of IBD on sensory-motor coupling and tachykinin-mediated effects on colonic motility.     

Laparoscopic-Assisted Rectosigmoidectomy with Ileal Loop Interposition. Surgical Treatment of Chagasic Megacolon

Background  Chagas disease is a frequent cause of acquired megacolon in several countries of Latin America. Several procedures have been described to treat this condition. Recently a report of 147 patients treated with an open rectosigmoidectomy with an ileal loop interposition showed a low rate of complications (8.5 percent) and recurrence (3.1 percent).1 Technique  We present the video of a 42-year-old Latin American man who had a diagnosis of chagasic megacolon and was treated with the technique described by Netinho et al. 1 but with the use of laparoscopy. The patient was placed in a supine modified lithotomy position in Allen stirrups; the monitor was placed near the left leg of the patient, and both the surgeon and the assistant stood at the right side of the patient. Four trocars were used. Exploratory laparoscopy was performed. The proximal third of the rectum, sigmoid, and left colon were fully mobilized. Vascular pedicles were sectioned. The rectum was divided by using a linear laparoscopic cutter. A Pfannensteil incision was made and the colon was proximally divided. An ileal loop was interposed isoperistaltically between the descending colon and the rectum. Both the ileoileal and the ileocolic anastomoses were handsewn, and the distal ileorectal anastomoses were performed with a circular stapler under laparoscopic control. The patient is without symptoms or recurrence one year after the surgery. Conclusions  Laparoscopic approach allows the easy and correct dissection of the lateral attachments and offers the advantages of a more cosmetic and less painful procedure. Laparoscopic rectosigmoidectomy with ileal loop interposition is a technique that can be performed by laparoscopy with good results and should be an option in the treatment of chagasic megacolon. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Video presentation at the 2nd International Congress of Colorectal Surgery, Florida, February 13 to 14, 2007. An erratum to this article can be found at     

Spontaneous contractions and some electrophysiologic properties of circular muscle from normal sigmoid colon and ulcerative colitis

Spontaneous contractions, inhibitory responses produced by electrical field stimulation, and some electrophysiologic properties of circular smooth muscle from normal sigmoid colon and from sigmoid colon of ulcerative colitis patients were compared in vitro using simultaneous recordings of mechanical and intracellular electrical activity. In normal colonic circular muscle obtained from 21 patients, the frequency of spontaneous summation contractions ranged from 3 to 7 per 4 min, whereas in circular muscle from 13 patients with ulcerative colitis, the frequency of these contractions ranged from 1 to 9 per 4 min. Nonadrenergic, noncholinergic relaxation produced by electrical field stimulation was recorded in the majority of circular smooth muscle strips from both normal colon and colon from patients with ulcerative colitis. There were no significant differences in mean resting membrane potential, mean slow-wave frequency, mean maximum slow-wave amplitude, or inhibitory-junction potential amplitudes recorded using circular smooth muscle from both normal colon and colon from patients with ulcerative colitis. There appeared to be a weak association in patients with ulcerative colitis between increasing duration of symptoms and decreasing frequency of spontaneous summation contractions, but there were no associations between the frequency of these contractions and the severity of colonic inflammation, patient age, or the frequency of stools. The mechanism accounting for a wider range in the frequency of summation contractions recorded from colonic circular smooth muscle in ulcerative colitis remains to be determined.