Dietary potassium and laxatives as regulators of colonic potassium secretion in end-stage renal disease
Thiriloganathan Mathialahan and
Geoffrey I. Sandle
Molecular Medicine Unit, St James's University Hospital, Leeds, UK
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Abstract
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Background. In end-stage renal disease (ESRD), colonic potassium (K+) secretion increases as renal K+ excretion declines. The nature of this adaptive process is poorly understood, but post-prandial increases in plasma K+ concentration may be a determining factor. In addition, even though colonic K+ secretion increases in ESRD, interdialytic hyperkalaemia is a serious problem in haemodialysis patients, which might be reduced by stimulating colonic K+ secretion still further using laxatives.
Methods. Plasma K+ concentrations were measured in the fasting state, and for 180 min after the oral administration of 30 mmol of K+ to nine control subjects and 16 normokalaemic patients with ESRD (eight predialysis' patients and eight patients undergoing continuous ambulatory peritoneal dialysis (CAPD)). Plasma K+ concentrations were also monitored for 180 min in fasting controls and ESRD patients who were not given the oral K+ load. To study the effect of laxatives on interdialytic hyperkalaemia, plasma K+ concentrations were measured in eight control subjects and 13 haemodialysis patients before and during 2 weeks treatment with bisacodyl (a cAMP-mediated laxative) and in five haemodialysis patients before and during 2 weeks treatment with lactulose (an osmotic laxative).
Results. Oral K+ loading caused plasma K+ concentration to rise within the normal range (3.55.1 mmol/l) in control subjects, while significantly higher concentrations were achieved in the predialysis' patients and sustained hyperkalaemia developed in the CAPD patients. Bisacodyl treatment had no effect on plasma K+ concentrations in control subjects, but significantly decreased the mean interdialytic plasma K+ concentration (from 5.9±0.2 to 5.5±0.2 mmol/l, P<0.0005) in haemodialysis patients, whereas plasma K+ concentration did not change during lactulose treatment.
Conclusions. Higher plasma K+ concentrations after food may help to maintain K+ homeostasis in ESRD by enhancing colonic K+ secretion. Bisacodyl may be useful for reducing interdialytic hyperkalaemia in patients undergoing haemodialysis.
Keywords: bisacodyl; cAMP; colon; continuous ambulatory peritoneal dialysis; potassium secretion; renal failure
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Introduction
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Rats fed on a K+-enriched diet for 1014 days withstand acute intravenous doses of K+ that are lethal in control animals [1]. The kidney is the main site of this K+ adaptive response, individual nephrons increasing their capacity for K+ secretion [2], although the capacity of the colon for active K+ secretion is also increased [3]. In patients with end-stage renal disease (ESRD), faecal K+ excretion is directly proportional to dietary K+ intake, which raises the possibility that colonic K+ adaptation may occur in this disease [4]. Many of these patients are initially normokalaemic without dietary K+ restriction or dialysis treatment due, at least in part, to enhanced tubular K+ excretion by surviving nephrons [2,5]. Furthermore, rectal K+ secretion is significantly greater in ESRD patients than in normal subjects, and this may reflect an increase in its active (transcellular) component [6,7]. It is therefore conceivable that a pan-colonic increase in K+ secretion becomes critically important in maintaining K+ homeostasis in patients with ESRD [7].
The present study arose from two observations in chronic dietary K+-loaded rats. First, transient increases in post-prandial plasma K+ concentration occur in renal-intact rats fed on a K+-enriched diet [8]. Sustained increases in plasma K+ concentration after food may therefore be a factor in maintaining the colon in its K+ hypersecretory state in ESRD. Secondly, cyclic adenosine monophosphate (cAMP) produces a greater K+ secretory response in the colon of chronic dietary K+-loaded rats compared with controls [9]. Bisacodyl (Dulco-lax®), a cAMP-mediated laxative [10], may therefore stimulate colonic K+ secretion in haemodialysis patients, resulting in a decrease in interdialytic hyperkalaemia.
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Subjects and methods
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Studies were performed in control subjects and patients with ESRD after obtaining informed written consent, the project having been approved by the local ethics committee. Patients with ESRD were taking a variety of drugs (Table 1
), none of which are known to influence colonic K+ secretion.
Plasma K+ concentrations after acute oral K+ loading
At 0900 hours, an intravenous cannula was placed in the antecubital fossa of fasting control subjects (four male, five female; mean age 41±6 years), and patients with ESRD who were either predialysis' (four male, four female; mean age 54±5 years) or undergoing CAPD (five male, three female; mean age 44±3 years). Patients with ESRD omitted their morning medication immediately before the study. We studied these categories of patients to ensure they were normokalaemic and in a steady state of K+ homeostasis. A fasting blood sample was taken, following which each subject drank 200 ml of Ensure Plus (containing 10 mmol of K+) supplemented with 20 mmol of K+ in the form of Kay-Cee-L syrup (Geistlich, Chester, UK). Blood samples were obtained at 20-min intervals for 180 min. Plasma K+ concentrations were also measured at 0900 hours in the fasting state and then at 60-min intervals for 180 min in control subjects (two male, one female; mean age 49±13 years), pre-dialysis' patients (2 male; mean age 51 years) and CAPD patients (2 male, 2 female; mean age 38±2 years), who did not receive the oral K+ load. Plasma K+ concentrations were measured by autoanalyser.
Plasma K+ concentrations during treatment with bisacodyl
Non-fasting plasma K+ concentrations were measured at 0900 hours (1.52 h after a breakfast of cereal, milk, and tea or coffee) two or three times a week for 2 weeks before, and for 2 weeks during, the oral administration of bisacodyl to a group of control subjects (two male, six female; mean age 32±3 years) and a group of haemodialysis patients (10 male, three female; mean age 52±4 years) before starting a dialysis session. In the first week of bisacodyl treatment (the equilibration week), control subjects and patients altered their daily dose to produce an increase in stool frequency which they found acceptable (see Results). Neither the control subjects nor the haemodialysis patients were willing to collect stool samples to evaluate daily stool volume and faecal K+ excretion. Average plasma K+ concentrations were determined in the second week of bisacodyl treatment (the study week), and compared with the average plasma K+ concentrations obtained in the 2 weeks prior to bisacodyl treatment.
Plasma K+ concentrations during treatment with lactulose
Non-fasting plasma K+ concentrations were measured in a similar way before and during the daily administration of 10 ml of lactulose (Duphalac®, an osmotic laxative) to a second group of haemodialysis patients (three male, two female; mean age 44±6 years) in order to increase their stool frequency. These patients were also unwilling to have their daily stool volume and faecal K+ excretion measured.
Statistical analysis
Results are shown as means (±SEM). In the oral K+ loading studies, plasma K+ concentrations at all time points were normally distributed in both groups (one-sample KolmogorovSmirnov test). In the oral K+ loading and laxative studies, comparisons were made using the non-paired or paired two-tailed Student's t-test as appropriate, P<0.05 indicating a significant difference between two means.
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Results
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Plasma K+ concentrations after acute oral K+ loading
Details of the control subjects and the two groups of ESRD patients are shown in Table 2
. Before the study, all groups were taking a normal diet containing 7095 mmol of K+ daily, estimated from their dietary histories. Of the ESRD patients, eight were pre-dialysis' with variable urinary K+ outputs (37128 mmol/24 h, measured in seven patients). The other eight ESRD patients were undergoing CAPD, three of whom were anuric and the remainder had profoundly impaired urinary K+ outputs (1032 mmol/24 h). The three groups were matched for sex, age and weight.
Figure 1
shows that fasting plasma K+ concentrations were within the normal range (3.55.1 mmol/l) in all three groups, although higher in the pre-dialysis' and CAPD patients than in the control subjects (P<0.02). After acute oral K+ loading, plasma K+ concentrations increased but remained within the normal range in the control subjects and in the pre-dialysis' patients, although levels were significantly higher (P<0.05) in the pre-dialysis' patients than in the controls at all time points. In contrast, plasma K+ concentrations increased and remained above the normal range for the final 80 min of the study period in the CAPD patients. It should be emphasized that the overall increases in plasma K+ concentration were similar in the control subjects and the ESRD patients, suggesting comparable rates of K+ absorption in all three groups.

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Fig. 1. Plasma K+ concentrations (mean±SEM) in nine normal subjects (open bars), eight pre-dialysis' patients (stippled bars) and eight CAPD patients (solid bars) after the oral administration of 30 mmol K+. At each time point, values for pre-dialysis' and CAPD patients were significantly greater (P<0.02) compared with controls.
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Previous studies in normal subjects have demonstrated that plasma K+ concentrations and urinary K+ excretion exhibit diurnal variation, being highest around noon and lowest in the evening and early morning [1113]. A similar but blunted pattern has been reported in patients with chronic renal insufficiency [13]. Figure 2
shows that in the present study, plasma K+ concentrations did not vary significantly over 180 min in groups of control subjects, pre-dialysis' patients or CAPD patients, not receiving the oral K+ load. It should be noted that although the mean fasting plasma K+ concentration in the controls shown in Figure 1
was 0.6 mmol/l lower than the mean value in the smaller group of controls shown in Figure 2
, in the former group individual values were 3.5 mmol/l in three subjects and the other values ranged between 3.6 and 3.9 mmol/l. Nevertheless, taken together, the data in Figures 1
and 2
, which depict plasma K+ concentrations as a function of time, indicate that the prompt (within 20 min) increases in plasma K+ concentration after oral K+ loading reflect rapid K+ absorption rather than diurnal variation.

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Fig. 2. Plasma K+ concentrations (mean±SEM) in three normal subjects (open bars), two pre-dialysis' patients (stippled bars) and four CAPD patients (solid bars), who did not receive the oral K+ load.
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Plasma K+ concentrations during administration of bisacodyl
Of the control subjects, five took 5 mg bisacodyl daily and three took 10 mg bisacodyl daily, and in each case the number of stools increased from one to two (n=5) or three (n=3) a day. Of the haemodialysis patients, eight took 5 mg bisacodyl daily, two took 10 mg bisacodyl daily, and three required only 5 mg bisacodyl on alternate days to increase the number of stools from one to two (n=6), three (n=5) or four (n=2) a day. Bisacodyl has a duration of action of 1012 h, and was taken in the evening. In each case, the increase in stool frequency was associated with stool softening, but there was no diarrhoea. There was no evidence that bisacodyl treatment resulted in hypovolaemia in the haemodialysis patients, in whom body weight and blood pressure were essentially unchanged (Table 3
).
During the 2 weeks before and after bisacodyl treatment, non-fasting plasma K+ concentration was measured four times in each control subject and six times in each haemodialysis patient. Figure 3
shows average plasma K+ concentrations before and during the second (study) week of bisacodyl treatment in individual control subjects and haemodialysis patients. As shown in Table 3
, the mean plasma K+ concentration was significantly higher in the haemodialysis patients (5.9±0.2 mmol/l) than in the control subjects (4.04±0.1 mmol/l, P<0.0001). In five of the eight control subjects, plasma K+ concentration decreased slightly during the second week on bisacodyl, but overall there was no significant change in this group (4.04±0.1 mmol/l pre-bisacodyl vs 3.9±0.1 mmol/l on bisacodyl). By contrast, bisacodyl treatment was associated with generally more pronounced decreases in plasma K+ concentration in 12 of the 13 haemodialysis patients, with an overall decrease from 5.9±0.2 to 5.5±0.2 mmol/l (P<0.0005). The bisacodyl-induced decrease in plasma K+ concentration in the haemodialysis patients (0.4±0.1 mmol/l) was significantly greater than that in the control subjects (0.14±0.1 mmol/l, P<0.05). This suggests that bisacodyl may have stimulated K+ secretion in the K+-adapted colon of haemodialysis patients, but not in the control subjects. Data from individual haemodialysis patients (Figure 3
) indicate that the size of the decrease in plasma K+ concentration was not related to the initial (-Bis) value.

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Fig. 3. Effect of bisacodyl on plasma K+ concentrations in individual control subjects (open circles) and haemodialysis patients (closed circles). -Bis' data points represent the average of four plasma K+ measurements in the control subjects, and six plasma K+ measurements in the haemodialysis patients, during the 2 weeks preceding bisacodyl treatment. +Bis' data points represent the average of two plasma K+ measurements in the control subjects, and three plasma K+ measurements in the haemodialysis patients, during the second (study) week of bisacodyl treatment.
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Because of recruitment difficulties, it was not possible to match individuals in the two groups exactly according to sex and age (Table 3
). However, it seems highly unlikely that the effect of bisacodyl would be gender-related in individuals of either group. As a group, the haemodialysis patients were older than the control subjects. Nevertheless, the ability of bisacodyl to reduce interdialytic hyperkalaemia was not age-dependent, because in seven of the haemodialysis patients aged 2258 years (similar to the age range of the control subjects), bisacodyl treatment decreased plasma K+ concentration (from 5.94±0.3 to 5.4±0.3 mmol/l, P<0.01) to the same extent as in the entire group.
Plasma K+ concentrations during administration of lactulose
Five haemodialysis patients were treated with 10 ml of lactulose daily, which increased the number of softened stools from one to two (n=4) or three (n=1) a day, without producing diarrhoea or evidence of hypovolaemia. In contrast to bisacodyl, lactulose had no effect on interdialytic hyperkalaemia (Table 3
).
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Discussion
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Several studies suggest that rectal, and perhaps colonic, K+ secretion increases in patients with ESRD [4,6,7]. Enhanced K+ secretion, reflecting stimulation of an active K+ secretory process, certainly occurs throughout the colon in rats maintained on a K+-enriched diet [3]. Increased net K+ secretion has been demonstrated in the rectum of ESRD patients using an initial intraluminal K+ concentration of 45 mmol/l [6], and net K+ secretion may be even greater in the ascending colon where the K+ concentration of ileal effluent is
14 mmol/l. In patients with ESRD, the factors responsible for maintaining the colonic epithelium in its K+ hypersecretory state are unclear. Distal colonic expression of the mRNA encoding CHIF (channel-inducing factor, a K+-channel regulatory protein) and plasma aldosterone concentrations are both significantly enhanced at 48 h in a rat model of acute renal failure [14], and similar changes may contribute to increased distal colonic K+ secretion in patients with ESRD. Nevertheless, increased rectal K+ secretion has been demonstrated in ESRD patients without secondary hyperaldosteronism [6,7]. Colonic K+ secretory capacity may therefore adapt to the dietary K+ load independently of aldosterone when renal K+ excretion is severely restricted.
In the present study, acute oral K+ loading caused a modest increase in plasma K+ concentration to the mid-normal range in control subjects, sustained increases to within the upper normal range in pre-dialysis' patients, and hyperkalaemia in CAPD patients. Increases in plasma K+ concentration after food have been previously reported in normal rats maintained on a K+-enriched diet [8], and in human subjects with normal renal function ingesting a diet heavily supplemented with K+ [15]. Increases in plasma K+ concentration, such as those seen in the present study, certainly influence renal K+ excretion, and it is conceivable that colonic K+ secretion responds in a similar way. For example, in intact rats, raising plasma K+ concentration from 4 to 6 mmol/l stimulates a prompt increase in renal distal tubular K+ secretion [16], while increasing peritubular K+ concentration stimulates K+ secretion in isolated perfused rabbit cortical collecting ducts [17,18]. This response reflects, at least in part, increases in apical and basolateral membrane K+ conductances and activation of the Na+,K+-ATPase pump [18]. Chronically dietary K+-loaded but renal-intact rats, and rats with chronic renal insufficiency and minimal dietary K+ supplementation, exhibit increased colonic K+ secretion and mucosal Na+,K+-ATPase activity compared with controls [19,20]. A similar increase in colonic Na+,K+-ATPase activity in ESRD patients would therefore provide a mechanism for enhanced basolateral cellular K+ uptake. Furthermore, high conductance apical K+ channels have been identified in surface epithelial cells in human colon [21] which, like apical K+ (ROMK) channels in principal cells of the collecting duct [22], form the rate-limiting step of K+ secretion, and may be activated by increases in plasma K+ concentration. Thus, significant increases in plasma K+ concentration in response to food may constitute a repetitive signal for the up-regulation/activation of components of the colonic K+ secretory process in patients with ESRD. This idea is also supported by studies in haemodialysis patients, in whom rectal K+ secretion was significantly greater before dialysis (when they were hyperkalaemic) than after dialysis (when they were normokalaemic) [7].
Substantial interdialytic hyperkalaemia affects many patients undergoing long-term haemodialysis, despite restriction of dietary K+ intake. We therefore investigated whether laxatives might stimulate colonic K+ secretion sufficiently in haemodialysis patients to reduce interdialytic hyperkalaemia. We chose bisacodyl because this cAMP-mediated laxative stimulates apical K+ efflux in rabbit distal colon, apparently via K+ channels in the apical membrane [23]. In addition, we have recently identified apical K+ channels in the surface epithelial cells of human and rat colon that are activated by cAMP [21,24]. Furthermore, studies in vitro have shown that cAMP stimulates a greater colonic K+ secretory response in dietary K+-loaded rats than in control animals [9]. In the present study, bisacodyl was administered to increase stool frequency to acceptable levels, which produced a significant fall in interdialytic hyperkalaemia in one group of haemodialysis patients, but had no effect on plasma K+ concentration in control subjects. However, in a second group of haemodialysis patients treated with lactulose to produce a comparable increase in stool frequency, there was no change in interdialytic hyperkalaemia. The ability of bisacodyl (but not lactulose) to significantly decrease plasma K+ concentration in haemodialysis patients suggests that this cAMP-mediated laxative has a specific stimulatory effect on K+ movement into the lumen of the colon, which is already adapted to deal with the dietary K+ load. It seems much less likely that the proposed increase in colonic K+ secretion occurred by solvent drag, because (i) the osmotic laxative lactulose had no effect on plasma K+ concentration in these patients, (ii) bisacodyl was used at doses which avoided diarrhoea, and (iii) diarrhoea per se does not cause significant faecal K+ losses by washout alone [25].
In summary, this study demonstrates that periods of sustained increases in plasma K+ concentration, sometimes to hyperkalaemic levels, occur after an acute oral K+ load in predialysis' and CAPD patients who are normokalaemic in the fasting state. These changes in plasma K+ concentration may enhance colonic K+ secretion and help to maintain K+ homeostasis in ESRD. In addition, treatment with bisacodyl may provide a simple means of reducing interdialytic hyperkalaemia, while at the same time relieving constipation, a common symptom in haemodialysis patients. Additional studies are required to determine whether long-term bisacodyl treatment leads to even greater decreases in plasma K+ concentration than those reported here.
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Acknowledgments
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We are grateful to Professor A. M. Davison, Dr E. Will and Dr C. Newstead for allowing us to study their patients and to the Wellcome Trust for financial support.
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Notes
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Correspondence and offprint requests to: Professor G. I. Sandle, Molecular Medicine Unit, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Email: g.i.sandle{at}leeds.ac.uk 
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References
|
---|
- Thatcher JC, Radike AW. Tolerance to potassium intoxication in the albino rat. Am J Physiol1947; 151:138146[Free Full Text]
- Hayslett JP, Binder HJ. Mechanism of potassium adaptation. Am J Physiol1982; 243:F103F112[ISI][Medline]
- Kliger AS, Binder HJ, Bastl C, Hayslett JP. Demonstration of active potassium transport in the mammalian colon. J Clin Invest1981; 67:11891196[ISI][Medline]
- Hayes CP, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic renal failure. Trans Assoc Am Phys1967; 80:207216[Medline]
- Schon DA, Silva P, Hayslett JP. Mechanism of potassium excretion in renal insufficiency. Am J Physiol1974; 227:13231330[Free Full Text]
- Sandle GI, Gaiger E, Tapster S, Goodship THJ. Enhanced rectal potassium secretion in chronic renal insufficiency: evidence for large intestinal potassium adaptation in man. Clin Sci1986; 71:393401[ISI][Medline]
- Sandle GI, Gaiger E, Tapster S, Goodship THJ. Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long-term dialysis. Clin Sci1987; 73:247252[ISI][Medline]
- Boyd JE, Mulrow PJ. Further studies of the influence of potassium upon aldosterone production in the rat. Endocrinology1972; 90:299301[ISI][Medline]
- Foster ES, Sandle GI, Hayslett JP, Binder HJ. Cyclic adenosine monophosphate stimulates active potassium secretion in the rat colon. Gastroenterology1983; 84:324330[ISI][Medline]
- Beubler E, Juan H. Is the effect of diphenolic laxatives mediated via a release of prostaglandin E? Experientia1978; 14:386387
- Solomon R, Weinberg MS, Dubey A. The diurnal rhythm of plasma potassium: relationship to diuretic therapy. J Cardiovasc Pharmacol1991; 17:854859[ISI][Medline]
- Steele A, deVeber H, Quaggin SE, Scheich A, Ethier J, Halperin ML. What is responsible for the diurnal variation in potassium excretion? Am J Physiol1994; 267:R554R560[Abstract/Free Full Text]
- Hishida A, Honda N, Kumagai H, Sudo M, Nagase M. Diurnal variation of urinary potassium excretion in chronic renal insufficiency. Miner Electrolyte Metab1982; 7:2027[ISI][Medline]
- Rabb H, Wang Z, Postler G, Soleimani M. Possible molecular basis for changes in potassium handling in acute renal failure. Am J Kidney Dis2000; 35:871877[ISI][Medline]
- Gennari FJ, Segal AS. Hyperkalemia: An adaptive response in chronic renal insufficiency. Kidney Int2002; 62:19[ISI][Medline]
- Stanton BA, Giebisch GH. Potassium transport by the renal distal tubule: Effects of potassium loading. Am J Physiol1982; 243:F487F493[ISI][Medline]
- Muto S, Giebisch G, Sansom S. An acute increase of peritubular K stimulates K transport through cell pathways of CCT. Am J Physiol1988; 255:F108F144[Abstract/Free Full Text]
- Muto S, Asano Y, Seldin D, Giebisch G. Basolateral Na+ pump modulates apical Na+ and K+ conductances in rabbit cortical collecting ducts. Am J Physiol1999; 276:F143F158[Abstract/Free Full Text]
- Bastl C, Hayslett JP, Binder HJ. Increased large intestinal secretion of potassium in renal insufficiency. Kidney Int1977; 12:916[ISI][Medline]
- Kashgarian M, Taylor CR, Binder HJ, Hayslett JP. Amplification of cell membrane surface in potassium adaptation. Lab Invest1980; 42:581588[ISI][Medline]
- Mathialahan T, Perry M, Sandle GI. Does bisacodyl decrease hyperkalaemia in end-stage renal failure by stimulating colonic apical K+ channels? Gastroenterology2000; 118:A607.
- Giebisch G. Renal potassium transport: Mechanisms and regulation. Am J Physiol1998; 274:F817F833[ISI][Medline]
- Moreto M, Planas JM, Naftalin RJ. Effects of secretagogues on the K+ permeability of mucosal and serosal borders of rabbit colonic mucosa. Biochim Biophys Acta1981; 648:215224[ISI][Medline]
- Perry MD, Sandle GI. Protein kinase A but not protein kinase C regulates high conductance apical potassium channels in rat distal colon. J Physiol2000; 527:39P[CrossRef][ISI]
- Hammer HF, Santa Ana CA, Schiller LR, Fordtran FS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest1989; 84:10561062[ISI][Medline]
Received for publication: 7.12.01
Accepted in revised form: 4. 9.02