Sushil K. Sarna

Physiology and pathophysiology of colonic motor activity

The basic motor function of the colon is to mix and knead its contents, propel them slowly in the caudad direction, hold them in the distal colon until defecation, and provide a strong propulsive force during defecation. Infrequently, it also produces mass movements in the proximal colon. These motor functions are achieved in most species by three different types of contractions: the individual phasic contractions that include the short- and long-duration contractions, organized groups of contractions that include the migrating and nonmigrating motor complexes, and special propulsive contractions (giant migrating contractions). The spatial and temporal patterns of all of these contractions are controlled by myogenic, neural, and chemical control mechanisms. The individual phasic contractions are highly disorganized in time and space in the colon. For this reason, they are effective in mixing and kneading and slow distal propulsion. The underlying cause of the disorganization of short duration contractions is the irregularity in the frequency and waveshape of colonic electrical control activity and its phase unlocking throughout the colon. The individual contractions in many species occur in cyclic bursts called contractile states. At least in some species, these contractile states exhibit mostly caudad and sometimes orad migration. However, there are also nonmigrating or randomly migrating contractile states in the colon. These two patterns of contractile states are called colonic migrating motor complexes and colonic nonmigrating motor complexes, respectively. The giant migrating contractions provide the strong propulsive force for defecation and mass movements. The neural control of colonic contractions is organized at three levels--enteric, autonomic, and central. The enteric nervous system contains cholinergic and peptidergic neurons and plays a major role in the control of colonic contractions. The autonomic nerves, the vagi, pelvic, lumbar colonic, hypogastric, and splanchnic nerves, seem to continuously monitor the state of the colon and provide a modulatory input when necessary. These nerves play a major role in the reflexive control of colonic motor function. The voluntary input from the central nervous system coordinates the motor activity of the colon, rectum, anal canal and sphincters for orderly evacuation of feces during defecation. The role of acetylcholine, nonadrenaline, and the yet to be completely identified nonadrenergic, noncholinergic neurotransmitter, possibly VIP, in the control of contractions is fairly well established. Besides these, there are several other peptides and chemicals that are localized in the colonic wall; their physiological roles remain unknown. Colonic motor activity has been studied in several disease states. The findings have not always been consistent.(ABSTRACT TRUNCATED AT 400 WORDS)

Inflammation modulates in vitro colonic myoelectric and contractile activity and interstitial cells of Cajal

Inflammation suppresses phasic contractile activity in vivo. We investigated whether inflammation also suppresses in vitro phasic contractile activity and, if so, whether this could in part be due to the alteration of specific slow wave characteristics and morphology of the interstitial cells of Cajal (ICC). Circular muscle strips were obtained from normal and inflamed distal canine colon. Inflammation was induced by mucosal exposure to ethanol and acetic acid. The amplitudes of spontaneous, methacholine-induced, substance P-induced, and electrical field stimulation-induced contractions were smaller in inflamed muscle strips than in normal muscle strips. Inflammation reduced the resting membrane potential and the amplitude and duration of slow waves in circular muscle cells. Inflammation did not affect the amplitude of inhibitory junction potentials but did decrease their duration. Ultrastructural studies showed expansion of the extracellular space between circular muscle cells, reduction in the density of ICC and associated neural structures, damage to ICC processes, vacuolization of their cytoplasm, and blebbings of the plasma membrane. We conclude that inflammation-induced alterations of slow wave characteristics contribute to the suppression of phasic contractions. These alterations may, in part, be due to the damage to ICC. Inflammation impairs both the myogenic and neural regulation of phasic contractions.

Physiology and pathophysiology of colonic motor activity: Part one of two

Quantitative measurement of colonic transit has been done by scintigraphy and radiographic visualization of radiopaque markers (340-344). In addition to measuring the total colonic transit time, both methods can quantify transit in specific segments of the colon. The mean transit time measured by the radiopaque markers is about 33 hr in men and 47 hr in women. These data are comparable to that obtained by scintigraphy, which indicated that 71% of the radiolabeled matter introduced into the ascending colon was defecated by 48 hr. Earlier (42, 113, 345) radiological observations in experimental animals and humans indicated that the cecum and the right colon may act as a reservoir. On the basis of these observations, it was postulated that antiperistaltic contractions occur from the transverse to the ascending colon. This has not been demonstrated by in vivo recordings in a normally filled colon. It is possible that the retrograde propulsion observed in radiologic studies was due to the state of the colon at the time of these observations, such as empty colon, anesthesia, severance of the colon from the spinal cord or the presence of barium sulfate or bismuth subnitrate in the colon (42, 113,345). Scintigraphy in a normally filled colon did not demonstrate retrograde propulsion in the ascending colon or the cecum (34). In fact, the colonic content

Giant Migrating Contractions During Defecation in the Dog Colon

The colonic motor correlates of defecation were studied in 5 conscious dogs. A set of six strain-gauge transducers were implanted on the colon of each dog. An implanted cannula gave access to the terminal ileum. During a total control recording period of 230 h we observed 12 large-amplitude contractions that occurred spontaneously in the proximal colon and migrated caudad. We called them giant migrating contractions. The mean amplitude of these contractions was 2.8 times larger than the mean peak amplitude of phasic contractions during colonic motor complexes. The following stimuli were applied to induce defecation: 2 mg/kg guanethidine (i.v.), 30 micrograms/kg neostigmine (i.v.), 1-4 ml/kg castor oil (p.o.), 200 ml of 25% glucose (into ileum), and rectal distention by a balloon (120 ml). In 85% of experiments with guanethidine, neostigmine, glucose, and castor oil, giant migrating contractions occurred before defecation. The giant migrating contractions migrated over the entire colon or a part of its length. The migration velocity varied from 0.2 to 3.2 cm/s (mean +/- SE, 0.82 +/- 0.1 cm/s). In 11% of the experiments, giant contractions occurred almost simultaneously at different recording sites at the time of defecation. In 4% of the experiments giant contractions occurred only at a single site. Balloon expulsion was only rarely accompanied by giant contractions in the colon, and then occurred only at a distal site and did not migrate. We conclude that the colon has spontaneous but infrequent large-amplitude caudad-migrating contractions. These contractions may be the motor equivalent of mass movements. Defecation is usually preceded by colonic giant migrating contractions. The giant migrating contractions may provide a major force for defecation and be partially responsible for the evacuation of the colon during defecation. However, evacuation of contents such as a balloon seems to be possible without giant migrating contractions.

Resolution of postoperative ileus in humans

Bipolar electrodes were placed in the ascending and descending colon of 13 patients during laparotomy. The magnitude of their operations varied from exploratory laparotomy to total gastrectomy. The magnitude and length of the operations performed did not correlate positively with the duration of postoperative ileus. Signals were recorded for up to 4 hours daily for up to 8 days after operation during periods of rest and, in some patients, after administration of epidural or parenteral morphine sulfate. Power spectrum analyses of electrical control activity (ECA) showed dominant frequencies in both lower (2–9 cpm) and higher (9–14 cpm) ranges. During postoperative recovery, the mean ECA frequencies in right and left colon were relatively constant, but a variety of dominant ECA frequency relationships were observed. The modal pattern in the right colon was a shift in the dominant frequency from the higher to the lower range as recovery progressed, while the modal pattern in the left colon was persistent dominance of ECA in the higher frequency range. Electrical response activity (ERA) initially was comprised of only random, disorganized single bursts but became progressively more complex through the initial 3 postoperative days with the appearance of more organized bursts and clusters, some of which propagated very slowly (about 5 cm/min) both orad and aborad. ERA recovery culminated, typically on the third or fourth postoperative day, with the return of long bursts of continuous ERA, some of which propagated at a higher velocity (about 80 cm/ min) and exclusively in the aborad direction and which were accompanied by passage of flatus or by defecation.

Motor function of the opossum sphincter of Oddi.

We studied the opossum sphincter of Oddi (SO) because in this species the SO is approximately 3 cm in length and its extraduodenal location permits recording of motor activity with negligible interference from duodenal motor activity. The SO segment of 120 animals was evaluated by one or more of the following: (a) intraluminal manometry; (b) electromyography; (c) common bile duct (CBD) flow monitored by a drop counter; (d) cineradiography of intraductal contrast medium; and (e) histologic examination. SO pull-throughs using an infused catheter of 0.6-mm o.d. invariably showed a high pressure zone (HPZ) of 18 +/- 3 SE mm Hg in the terminal 4-5 mm of the SO segment. This HPZ had a narrow lumen, 0.5-0.7 mm in diam, and prominent circular muscle. The HPZ in the terminal SO had both active and passive components. HPZ with minimal amplitude and a paucity of underlying smooth muscle were present inconstantly at the junction of the SO segment with the CBD and pancreatic duct, respectively. The dominant feature of the SO segment was rhythmic peristaltic contractions that originated in the proximal SO and propagated toward the duodenum. These contractions occurred spontaneously at a rate of 2-8/min, ranged up to 200 mm Hg in magnitude, had a duration of approximately 5 s and were not abolished by tetrodotoxin. Concurrent myoelectric and manometric recordings showed that each phasic contraction was immediately preceded by an electrical spike burst. Simultaneous recordings of cineradiography, CBD inflow of contrast medium, SO manometry, and SO electromyography indicated that rhythmic peristaltic contractions stripped contrast medium from the SO into the duodenum. During SO systole, CBD emptying was transiently interrupted, whereas SO filling occurred during the diastolic interval between SO peristaltic contractions. SO distention increased the frequency of SO peristalsis. We conclude that (a) the dominant feature of the opossum SO is rhythmic peristaltic contractions that originate in the proximal SO and propagate toward the duodenum; (b) these forceful SO peristaltic contractions are myogenic in origin and serve as a peristaltic pump that actively empties the SO segment; (c) CBD outflow occurs passively during SO diastole, but is interrupted transiently during each SO peristaltic contraction; and (d) a short HPZ with active as well as passive components exists in the distal SO segment and acts as a variable resistor to SO outflow.

Adrenergic Stimulation Mediates Visceral Hypersensitivity to Colorectal Distension Following Heterotypic Chronic Stress

BACKGROUND & AIMS Chronic stress exacerbates or causes relapse of symptoms such as abdominal pain and cramping in patients with irritable bowel syndrome. We investigated whether chronic stress increases plasma norepinephrine and sensitizes colon-specific dorsal root ganglion (DRG) neurons by increasing expression of nerve growth factor (NGF) in the colon wall. METHODS Heterotypic chronic stress (HeCS) was applied to male Wistar rats and neurologic and molecular responses were analyzed. Tissues were analyzed for NGF expression. RESULTS HeCS significantly increased visceromoter response to colorectal distension; expression of NGF increased in colonic muscularis externa and mucosa/submucosa. Rheobase decreased, resting membrane potential was depolarized, and electrogenesis of action potentials increased in colon-specific thoracolumbar DRG neurons. Luminal administration of resiniferatoxin in distal colon, systemic administration of anti-NGF antibody, or inhibition of the NGF receptor trkA by k252a or antisense oligonucleotides in thoracolumbar DRG blocked the chronic stress-induced visceral hypersensitivity to colorectal distension. Blockade of alpha1/alpha2- and beta1/beta2-adrenergic receptors prevented the stress-induced visceral hypersensitivity and increased expression of NGF in the colon wall. HeCS did not induce any inflammatory response in the colon wall. CONCLUSIONS The peripheral stress mediator norepinephrine induces visceral hypersensitivity to colorectal distension in response to HeCS by increasing the expression of NGF in the colon wall, which sensitizes primary afferents in the absence of an inflammatory response.

NF-κB activation by oxidative stress and inflammation suppresses contractility in colonic circular smooth muscle cells

Abstract Background & Aims: Transcription factor nuclear factor κB (NF-κB) plays a critical role in transcriptional changes in several diseases, including inflammation. The aim of this study was to investigate whether NF-κB is activated by inflammation and oxidative stress in colonic circular smooth muscle cells and whether that leads to suppression of their contractility. Methods: The experiments were performed on freshly dissociated single cells using electrophoretic mobility shift assay, Western immunoblotting, and immunofluorescence imaging. Results: The NF-κB DNA binding was ∼6-fold greater in cells from the inflamed colon vs. those from the normal colon. Supershift assay indicated that the antibodies to p65, p50, and c-Rel, but not that to p52, shifted the NF-κB band. Western immunoblotting and immunofluorescence imaging also demonstrated the presence of p65, p50, and c-Rel proteins in the cytoplasm and their translocation to the nucleus by H 2 O 2 -induced oxidative stress. H 2 O 2 treatment degraded IκB β , but not IκB α , to translocate NF-κB to the nucleus. Hydrogen peroxide concentration and time dependently activated NF-κB DNA binding and suppressed cell contraction to acetylcholine. NF-κB inhibitors significantly inhibited these effects. Inhibition of NF-κB prior to and during inflammation in intact dogs also reversed the suppression of contractility. Conclusions: Transcription factor NF-κB is activated in colonic circular muscle cells by inflammation and oxidative stress. This activation of NF-κB mediates the suppression of cell contractility.

Electrical and contractile activities of the human rectosigmoid.

Electrical and mechanical activities were recorded from the rectosigmoid of normal subjects using an intraluminal recording tube with two sets of bipolar electrodes and strain gauges. Four distinct types of electrical activities were recorded. (1) Electrical control activity (ECA). This activity varied in amplitude and frequency over time and the control waves were not phase-locked. The means of dominant frequency components in the lower and higher frequency ranges were 3.86 +/- 0.18 SD and 10.41 +/- 0.46 SD c/min, respectively. The overall dominant frequency component was mostly in the lower frequency range of 2.0-9.0 c/min. (2) Discrete electrical response activity (DERA). This activity appeared as short duration bursts (less than 10 s) of response potentials whose repetition rate was in the total colonic electrical control activity frequency range of 2.0-13.0 c/min. The mean duration of this activity was 2.24 +/- 1.30 SD s. (3) Continuous electrical response activity (CERA). This activity appeared as long duration bursts (greater than 10 s) of response potentials which were not related to electrical control activity. Its mean duration was 14.78 +/- 3.68 SD s. This activity generally did not propagate. (4) Contractile electrical complex (CEC). This activity appeared as oscillations in the frequency range of 25-40 c/min and was also not related to electrical control activity. This activity propagated, sometimes proximally and sometimes distally. Its mean duration was 18.87 +/- 9.22 SD s. The latter three types of electrical activities were all associated with different types of contractions. These contractions, however, did not always occlude the lumen. Colonic electrical control activity controls the appearance of discrete electrical response activity in time and space. The mechanism of generation of continuous electrical response activity and contractile electrical complex is not yet known.

Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis.

Crohns disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohns disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Gα(q) protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the α(1C)1b subunit of Ca(v)1.2b channels, CPI-17 and Gα(q). TNBS inflammation increased IGF-1 and TGF-β time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-β induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of immune cells does not correlate directly with the intensity of generation of inflammatory mediators. The inflammatory mediators in TNBS and DSS inflammations target different genes to impair smooth muscle function.