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Background and Aims: A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design., Methods: Subjects were randomised to receive either 400 microg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention., Results: Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57-104%; p<0.001 v placebo) and 57% (95% CI 40-74%; p<0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4-20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16-47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11-39%; p = 0.09 v placebo) in colonic mucosa., Conclusions: These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid.

Background: Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT(3) receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord., Aims: To examine the effect of the 5-HT(3) receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord., Methods: Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI., Results: CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-effect curves were constructed. Alosetron (1-100 microg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID(50) value of 3.0 microg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 microm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 microg/kg) significantly reduced numbers of Fos-LI neurones to 479.8., Conclusion: The 5-HT(3) receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT(3) receptors are involved in visceral nociceptive transmission, perhaps located on primary afferent or spinal neurones.

Background: Gut mucosal blood flow measurement is used to study a variety of disorders and possibly extrinsic neural function., Aims: To determine optimal measurement criteria and validate this technique as a measure of level of activity of extrinsic autonomic gut innervation., Methods: In 26 healthy volunteers a laser Doppler mucosal probe was applied 10 cm from the anus. Response to inhaled salbutamol 200 microgram and ipratropium 40 microgram, intravenous metoprolol 2.5 mg, and direct sacral nerve electrostimulation (in nine incontinent patients) was also studied., Results: The coefficient of variation for subjects studied under identical conditions on two, three, and four days was 0.06, 0.05, and 0.06, respectively. Mean mucosal blood flow increased after a standard meal. Blood flow decreased for 15 minutes after smoking and returned to baseline at 30 minutes. Fasted measurements at 0900, 1200, 1600, and 2200 were similar. There was a negative correlation between blood flow and body size but not age. Follicular phase mucosal flow was less and more reproducible than luteal. Mucosal blood flow was highest in men and lowest in postmenopausal women. Inhaled salbutamol did not change blood flow; ipratropium significantly reduced, and metoprolol and sacral nerve stimulation increased flow., Conclusions: Measurement of gut mucosal blood flow by laser Doppler flowmetry is highly reproducible. Eating, smoking, body size, sex, ovulatory status, and menstrual phase influence blood flow. Changes in mucosal blood flow induced by autonomically active drugs and nerve stimulation confirm the role of the mucosal microcirculation as a measure of extrinsic nerve activity.

Vitamin D may protect against colorectal cancer by reducing cell proliferation and inducing differentiation. By contrast, epidermal growth factor (EGF) stimulates cell proliferation and may encourage gastrointestinal mucosal healing. This study investigated the effect of a synthetic vitamin D analogue, calcipotriol, and EGF on human rectal epithelial cell proliferation in patients with familial adenomatous polyposis (FAP). In addition, a new technique to measure the cell cycle time is described. Sigmoidoscopic biopsy specimens were obtained from 14 patients with FAP. Tissue was established in organ culture, with or without the addition of EGF (n = 8), or calcipotriol (n = 6). Proliferation was determined using (a) metaphase arrest to measure the crypt cell production rate, (b) native mitotic index, and (c) the growth fraction using PC10 antibody. EGF receptor expression was shown using a polyclonal antibody AP12E. Calcipotriol reduced crypt cell production rate by 52% from mean (SEM) 5.29 (1.18) to 2.56 (0.80) cells/crypt/hour (p < 0.01) and EGF increased crypt cell production rate by 102% from 3.62 (0.59) to 7.33 (0.90) cells/crypt/hour (p < 0.05), and this tissue expressed the EGF receptor. The growth fraction was 48.40 (4.0)%, and the native mitotic index 1.08 (0.14)%. The cell cycle time was estimated as 94.5 hours and the time for mitosis as one hour. Thus, calcipotriol and EGF have divergent effects on human rectal mucosal proliferation.

Experimental studies in rats have shown an independent stimulation of rectal cell turnover by either chronic ethanol consumption or age. In this study the combined effect of these two factors on colorectal cell regeneration has been investigated. Ninety male F344 rats aged 2, 12, and 22 months were pair fed nutritionally adequate liquid diets containing 36% of total energy either as ethanol or isoenergetic carbohydrates. After four weeks of feeding, colorectal crypt cell production rates were measured using a stathmokinetic technique with vincristine. While age by itself did not affect colorectal cell renewal, chronic ethanol consumption stimulated rectal, but not colonic crypt cell production rate in an age dependent manner. While no significant effect of ethanol was noted in young animals, cell proliferation was significantly enhanced in middle aged animals by 81% (4.1 (2.7-5.5) v 7.4 (6.0-8.7) cells/crypt/hour, p < 0.001) and in old animals by 138% (4.5 (3.3-5.6) v 10.7 (8.9-12.4) cells/crypt/hour, p < 0.001) after ethanol ingestion. Because acetaldehyde, the first and most toxic metabolite of ethanol, has been detected in the colorectal mucosa and may lead to tissue injury influencing cell regeneration, acetaldehyde concentrations have been measured in the colons of 15 male F344 rats of various ages after an acute intraperitoneal dose of ethanol (2.5 g/kg bodyweight). There was a significant positive correlation between crypt cell production rate and acetaldehyde concentrations measured in the distal and proximal colon after an acute dose of ethanol (r = 0.5955, p < 0.005). These data clearly show that the ethanol mediated stimulation of cell regeneration in the rectum is age dependent. As reported earlier, there was found indirect evidence that acetaldehyde participates in the pathogenesis of rectal hyperregeneration after chronic alcohol consumption. This hyperregeneration of the rectal mucosa after alcohol drinking could by itself favour carcinogenesis, which is especially relevant in old age.

Because ulcerative colitis is largely a disease of non-smokers and nicotine may have a beneficial effect on the disease, the effect of nicotine on rectal mucosa in rabbits was examined. Nicotine was given subcutaneously by an Alzet mini-pump in doses of 0.5, 1.25, and 2 mg/kg/day for 14 days to three groups of eight animals and compared with eight controls. Mean (SD) serum nicotine concentrations (ng/ml) were 3.5 (1.1), 8.8 (2.3), and 16.2 (5.2) respectively in the treated groups. The thickness of adherent mucus on rectal mucosa in controls (median 36 microns) was significantly reduced by low dose (22 microns, p = 0.0011), and increased by high dose nicotine (48 microns, p = 0.035). Incorporation of radioactive glucosamine into papain resistant glycoconjugates was unchanged, indicating that mucin synthesis was unaltered. Prostaglandins (PG) were reduced, in some cases significantly (6-keto PGF1 alpha, PGF2 alpha, and hydroxy-eicosatetraenoic acid), by nicotine, which showed an inverse dose dependence--with greatest inhibition in relation to the lowest dose. Nicotine, and possibly smoking, may affect colitis by an action on mucosal eicosanoids and on adherent surface mucus secretion in the rectum and large bowel.

Morphometric measurements were performed on rectal biopsy specimens from 10 normal control subjects and 33 patients with a relapse of distal ulcerative colitis before and after treatment for four weeks in a double blind controlled trial with oral eudragit S coated 5 amino salicylic acid (n = 12) or rectal prednisolone enemas (n = 15). Measurements were assessed using a computer aided measuring system and a counting technique. When untreated patients were compared with the control group there were significant decreases in the area and height of the surface epithelium, in the area of crypt epithelium, and in the ratios of goblet cells to epithelial cells and of surface epithelium to lamina propria. The vascular and lamina propria areas and the number of intraepithelial polymorphs were increased. Treatment with 5 amino salicylic acid and corticosteroids resulted in similar morphological improvements: there was an increase in the area and height of the surface epithelium and the ratios of surface epithelium to lamina propria and of surface to crypt cell height. The ratio of goblet cells to epithelial cells also increased after treatment, while the numbers of polymorphs in the surface and crypt epithelium and lumen decreased. In conclusion, computerised morphometry is valuable for the assessment of the treatment of patients with ulcerative colitis and that in the doses used both treatments were of similar efficacy.

Ninety nine healthy young volunteers (58 men, 34 women, aged 17-27 years) answered a questionnaire concerning their bowel habit with particular reference to the effects of beverages. Twenty nine per cent (63% women) claimed that coffee induced a desire to defecate. The rectosigmoid motor responses to black, unsweetened coffee were then investigated by multiport manometry in 14 healthy-subjects (12 men, two women, eight of whom claimed coffee caused a desire to defecate (responders). Results revealed an increase in motility index within four minutes after ingestion of both regular and decaffeinated coffee (p less than 0.05) in the eight responders, but not in the six non-responders. The increase in rectosigmoid motility induced by coffee lasted at least 30 minutes. There was no increase in the motility index in any subject after a drink of hot water. These results suggest that drinking coffee can stimulate a motor response of the distal colon in some normal people.

An organ culture method for the maintenance of rectal biopsies over a period of 24 hours is described. Good preservation of histological architecture and continued crypt cell proliferation were shown over the culture period. The colonic enzyme alkaline phosphatase was found to rise over the period of culture. This rise was dependent upon continued protein synthesis by the cell. Changes in alkaline phosphatase activity during culture in biopsies from patients with ulcerative colitis and Crohn's disease are reported. This organ culture system and the measurement of alkaline phosphatase activity during culture provides a new approach to the assessment of luminal antigens as possible effectors of colonic epithelial cell damage.

Dietary calcium may inhibit colonic carcinogenesis promoted by high fat, phosphate, and low fibre diets. In persons at risk for colon cancer oral calcium supplements significantly suppress increased rectal epithelial proliferation. This was studied in a cohort of 35 volunteers: 26 first degree relatives of colorectal cancer patients and nine who had had colonic adenomas (mean age 51.6 years, 17 (49%) men, all negative for large bowel neoplasia). 1.25-1.5 g elemental calcium was given in divided daily doses for three months. Rectal pinch biopsies were taken without bowel preparation, before and mean 8.4 weeks during and 7.2 weeks after treatment and incubated with tritiated thymidine. The mean number of labelled cells, as a ratio of the total number of crypt cells (labelling index-LI), and their crypt position, were determined. The mean number of labelled cells decreased during treatment by 29%, especially in the basal three-fifths of crypts. There was also a significant 10% increase in mean number of crypt cells during treatment. [Mean LI decreased by 36% (p less than 0.001) during calcium treatment and almost returned to basal values after cessation.] If a raised LI is a marker of potential malignancy and a randomised clinical trial confirms that calcium suppresses it, dietary intervention studies in high risk persons are indicated.

The acute effects of single pharmacological doses of glucocorticoid hormones on net electrolyte and water transport and electrical potential difference (pd) in the rectum was studied in control subjects and in patients with either active or inactive ulcerative colitis, using a dialysis technique. Compared with 17 control subjects, nine patients with active ulcerative colitis exhibited marked decreases in net sodium absorption and rectal pd, while these transport parameters were normal in six patients with inactive ulcerative colitis. Intravenous administration of hydrocortisone hemisuccinate (100 mg) resulted five hours later in significant and quantitatively similar increases in net sodium and water absorption and pd in nine control subjects, seven patients with active ulcerative colitis, and six patients with inactive ulcerative colitis. Intravenous administration of methylprednisolone phosphate (40 mg) to eight control subjects produced increases in net sodium and water absorption and pd five hours later, which did not differ significantly from those produced by hydrocortisone; methylprednisolone induced similar changes in two patients with active ulcerative colitis. These results indicate that single pharmacological doses of glucocorticoids stimulate acute increases in rectal sodium and water absorption in control subjects and in patients with acute ulcerative colitis. The ability of systemically administered glucocorticoids to reduce diarrhoea in ulcerative colitis may therefore be related to direct effects on distal colonic sodium and water transport, as well as to their better known anti-inflammatory action.

The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as determined by stathmokinetic techniques), and preneoplastic morphological changes was studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or high dose, had no effect on crypt cell production rate (CCPR) at any time interval whereas tumour incidence in both low dose warfarin and high dose warfarin groups was significantly reduced. Morphological changes were observed using scanning electron microscopy, which by conventional histology were shown to be adenoma precursors. In the control group the number of microadenomas increased with time after starting azoxymethane. In warfarin treated animals, the number of microadenomas also increased with time, but the actual incidence was reduced when compared with controls. These results suggest that the effects of warfarin on tumour development is unrelated to its anticoagulant effect, because increased dose did not result in greater tumour reduction. Furthermore, there was no overall change in CCPR when warfarin was administered. Warfarin may exert a specific effect, by preventing neoplastic change in cells which have undergone morphologically undetectable changes associated with early carcinogenesis.

The transmucosal electrical potential difference (pd) and the sodium and potassium net fluxes were measured in the rectum of subjects taking carbenoxolone. There was a rise in transmucosal pd persisting throughout treatment in all subjects which was accompanied by an increase in sodium absorption and potassium secretion. Comparison of the pd changes produced by carbenoxolone with those due to the mineralocorticoid 9-alpha-fluorocortisol showed that carbenoxolone had about 1/1000th the potency on a weight basis and the two drugs appeared to be additive in their effects. Topical instillation of carbenoxolone into the rectum produced an elevation of pd which persisted for three days. Amiloride and bendrofluazide did not interfere with these actions of carbenoxolone but spironolactone abolished them. One patient who developed fluid retention and hypokalaemia had a rectal pd similar to that of the other patients who had no side effects.

The myoelectrical activity of the rectosigmoid has been studied in 66 subjects at rest and after stimulation with either pentagastrin 6.0 mug/kg hr intravenously in 21 cases, neostigmine 0.5 mg intramuscularly in 20 cases, or two bisacodyl suppositories in 19 cases. Two electrical rhythms were present at rest. A faster rhythm (frequency 6-9 cycles/min) predominated and its incidence was significantly increased by neostigmine at all levels in the rectosigmoid and by bisacodyl in the rectum only. The incidence of the slower rhythm (frequency 2.5-4.0 cycles/min) was significantly increased by pentagastrin which had no effect on the faster rhythm. The amplitude of each basic electrical rhythm rose when its incidence was increased. Motor waves were augmented corresponding to which of the two electrical rhythms was increased after stimulation.

To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.

The rectal potential difference (PD) was measured in 27 patients with Crohn's disease, and in 16 subjects without gastrointestinal disease to establish a normal range. Sigmoidoscopic assessment and rectal biopsy were performed in all patients with Crohn's disease, and the mean resting rectal PD was significantly reduced in patients with sigmoidoscopically active disease and in those with abnormalities of the superficial epithelium on rectal biopsy. Patients with diarrhoea had a significantly lower mean resting PD than those with normal bowel habit, suggesting that an abnormality of rectal sodium transport may be contributing to the diarrhoea in these patients. The response of rectal PD to mineralocorticoid stimulation with oral fludrocortisone was measured in 13 patients. The PD failed to rise only with patients with sigmoidoscopically active disease, and the test proved to be a less sensitive indication of minor mucosal abnormalities than sigmoidoscopy of biopsy.

The effect of glucagon on human colonic myoelectrical activity is described. By means of intraluminal, serosal, and surface electrodes, recordings from all areas of the large bowel have been obtained. Glucagon inhibited both electrical and pressure rhythms in all subjects tested. Evidence is produced to suggest a direct action on colonic smooth muscle. A controlled trial using glucagon during routine barium enema examinations suggests that it may prove to be useful for hypotonic examinations of the colon where painful spasm is present.

The effect of two concentrations of prednisolone on synthesis of prostaglandin E2 (PGE2) by 40 rectal biopsies in organ culture was investigated using both laminar flow bioassay and radioimmunoassay (RIA). Prednisolone (concentration 8.33 x 10(-7)M) reduced mean synthesis of PGE2 to 36.4% of control values (measured by bioassay) or 26.2% of control values (measured by RIA). With prednisolone (concentration 5.66 X 10(-4) M) synthesis of PGE2 was 7.7% of control values (RIA). The two concentrations are similar respectively to those achieved in plasma after oral prednisolone and delivered topically by prednisolone enemata. Inhibition of PG synthesis may thus explain prednisolone's anti-inflammatory action in the treatment of ulcerative colitis.

Using a pH-sensitive radiotelemetering device the effect of lactulose on luminal pH in the ileum, colon, and rectum has been compared with that of two other laxative agents. Lactulose produced marked acidification of proximal colonic contents but this effect was not consistently maintained into the distal colon. Sodium sulphate acidified distal rather than proximal colonic contents. However, for a similar degree of laxation it was not possible to produce a significantly more uniform reduction of pH along the length of the colon by combining these laxatives compared with lactulose alone. Magnesium sulphate had little effect upon luminal pH except in the rectum where a significant rise occurred. These results are discussed in relation to both normal colonic physiology and to their possible relevance to the treatment of chronic hepatic encephalopathy by colonic acidification.

The effects of rectal infusions (500 ml) of deoxycholic acid (1 mmol/l, 3 mmol/l) or normal saline on basal anorectal motility and responses to rectal distension were studied in 11 normal volunteers. Deoxycholic acid (1 mmol/l) did not alter anorectal motor patterns under basal conditions but reduced the rectal volumes required to induce a desire to defecate (deoxycholic acid 76 (12) ml v saline 123 (12) ml; mean (SEM) p less than 0.01), and to produce anal relaxation (deoxycholic acid 83 (14) ml v saline 152 (24) ml; p less than 0.05) and perception of the rectal balloon (deoxycholic acid 56 (10) ml v saline 104 (17) ml; p less than 0.01) that were sustained for the period of distension (1 min). Seven of 10 subjects could not tolerate an infusion of 3 mmol/l deoxycholic acid. Between two and 30 minutes after the start of the infusion they experienced an extreme urge to defecate which was associated with large amplitude pressure waves in the rectal channels (amplitude 30 (5) mmHg, duration 0.7 (0.1) min, frequency 1.7 (0.4)/min). Such contractions were never seen during saline infusion. Thus, rectal infusion of deoxycholic acid at physiological concentrations increases the sensitivity of the rectum to distension, and promotes an urgent desire to defecate in normal subjects.

The effect of intravenous infusion of gastrin II on gastric and colonic motor activity was studied in 12 patients; gastric acid output was also measured. Administration of gastrin at near-maximal dose levels stimulates the motor activity of the antrum but has no measurable effect on the activity of the proximal colon, sigmoid, or rectum. The results suggest that gastrin plays a part in the regulation of gastric motility but that it is not a mediator of the gastro-colic reflex.

Spontaneous basal rectal activity, recorded after resection of the sigmoid colon for diverticular disease, was more than twice the normal. The rectum of post-resection cases yielded a markedly exaggerated overall response to prostigmine, in addition to producing abundant fast wave patterns. The response to stretch of the apparently normal colonic muscle remaining after resection of the sigmoid for diverticular disease resembled unresected diverticular segments, though less in degree, suggesting that a fundamental disorder of colonic muscle may be involved in the aetiology of colonic diverticula.

THE SMOOTH MUSCLE SPHINCTERIC ACTIVITY OF THE ANUS IN CATS IS BASED ON TWO DISTINCT MECHANISMS: a typical anal component, characterized by anal slow pressure waves not related to spike potentials in the internal anal sphincter, and an intestinal-like pressure component related to spiking activity in the internal sphincter. Anal slow pressure waves are influenced by the activity of alpha excitatory receptors within the internal sphincter, whereas no conclusive data are available concerning the action of adrenergic beta receptors on this pressure component. Intestinal-like pressure waves and the correlated spiking activity in the internal anal sphincter are influenced by alpha and beta inhibitory adrenergic receptors. The rectal wall of the cat contains alpha and beta adrenergic receptors producing relaxation.

The isolated internal anal sphincter from cats shows a myogenic spontaneous rhythmic activity. Basal tension and frequency of contraction waves from internal anal sphincter strips are inhibited by muscarinic and beta-adrenergic receptors and excited by alpha-adrenergic receptors. Isoprenaline in high doses had an alpha-adrenoceptor-stimulating activity in strips from the internal sphincter. The inhibitory muscarinic receptors may be the final effectors in the anorectal reflex. The relaxing effect of acetylcholine on the internal sphincter was sometimes preceded by a temporary contraction due to the interaction of intermingled longitudinal muscle fibres. Rectal circular muscle strips contain excitatory muscarinic receptors and inhibitory alpha- and beta-adrenergic receptors. The same can be said of the strips from the longitudinal muscle layer at the anal canal and at the rectum.

The direct action of intraluminal senna and related compounds on the human colon and rectum has been investigated. Motility was recorded by balloon kymography with recording units inserted into well established transverse colostomies or into the rectum. The motility of the colon was not changed by intraluminal senna glycosides but the introduction of senna previously incubated with faeces or Esch. coli stimulated the colon to peristalt. The peristalsis was similar to that stimulated by rheinanthrone, an oxanthrone produced by chemical hydrolysis and reduction of senna. Both activated senna and rheinanthrone appeared to act in the colon by contact stimulation. No peristaltic response was stimulated in the rectum, either with activated senna or with rheinanthrone.

A method is described which allows rapid measurement of the electrical potential difference across colonic mucosal epithelium to be carried out during routine sigmoidoscopy. The potential differences measured had a mean value of 25 mV (range 4 to 51 mV) in 27 subjects with normal bowel. Six hours after two intravenous injections of 0.5 mg aldosterone the potential difference had risen to 60 mV (range 37 to 101 mV). The time course of responses studied after a single injection of aldosterone showed that the potential allowance rose within four hours and had fallen again after 18 hours. Urinary sodium concentrations and sodium/potassium ratios fell after aldosterone injections, the time course of the changes being similar to that of the potential differences of the colon. Sodium concentration of stool fluid also fell. The concentration of chloride in the stool fluid was consistent with a passive distribution of chloride according to the electrochemical gradient, but that of potassium was considerably greater than expected from a passive distribution, suggesting that potassium is actively secreted into the lumen of the colon.