Nephrol Dial Transplant (2003) 18: 341–347
Original Article
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
Abstract Background. In end-stage renal disease (ESRD), colonic potassium (Kq) secretion increases as renal Kq excretion declines. The nature of this adaptive process is poorly understood, but post-prandial increases in plasma Kq concentration may be a determining factor. In addition, even though colonic Kq secretion increases in ESRD, interdialytic hyperkalaemia is a serious problem in haemodialysis patients, which might be reduced by stimulating colonic Kq secretion still further using laxatives. Methods. Plasma Kq concentrations were measured in the fasting state, and for 180 min after the oral administration of 30 mmol of Kq to nine control subjects and 16 normokalaemic patients with ESRD (eight ‘predialysis’ patients and eight patients undergoing continuous ambulatory peritoneal dialysis (CAPD)). Plasma Kq concentrations were also monitored for 180 min in fasting controls and ESRD patients who were not given the oral Kq load. To study the effect of laxatives on interdialytic hyperkalaemia, plasma Kq 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 Kq loading caused plasma Kq concentration to rise within the normal range (3.5–5.1 mmolul) 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 Kq concentrations in control subjects, but significantly decreased the mean interdialytic plasma Kq concentration (from 5.9"0.2 to 5.5"0.2 mmolul, P - 0.0005) in haemodialysis patients, whereas plasma Kq concentration did not change during lactulose treatment. Correspondence and offprint requests to: Professor G. I. Sandle, Molecular Medicine Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK. Email:
[email protected] #
Conclusions. Higher plasma Kq concentrations after food may help to maintain Kq homeostasis in ESRD by enhancing colonic Kq 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
Introduction Rats fed on a Kq-enriched diet for 10–14 days withstand acute intravenous doses of Kq that are lethal in control animals [1]. The kidney is the main site of this ‘Kq adaptive’ response, individual nephrons increasing their capacity for Kq secretion [2], although the capacity of the colon for active Kq secretion is also increased [3]. In patients with end-stage renal disease (ESRD), faecal Kq excretion is directly proportional to dietary Kq intake, which raises the possibility that colonic ‘Kq adaptation’ may occur in this disease [4]. Many of these patients are initially normokalaemic without dietary Kq restriction or dialysis treatment due, at least in part, to enhanced tubular Kq excretion by surviving nephrons [2,5]. Furthermore, rectal Kq 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 Kq secretion becomes critically important in maintaining Kq homeostasis in patients with ESRD [7]. The present study arose from two observations in chronic dietary Kq-loaded rats. First, transient increases in post-prandial plasma Kq concentration occur in renal-intact rats fed on a Kq-enriched diet [8]. Sustained increases in plasma Kq concentration after food may therefore be a factor in maintaining the colon in its Kq hypersecretory state in ESRD. Secondly, cyclic adenosine monophosphate (cAMP) produces a greater Kq secretory response in the colon
2003 European Renal Association–European Dialysis and Transplant Association
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T. Mathialahan and G. I. Sandle
Table 1. Medication of patients with ESRD Drug
Oral Kq load (ns16)
Bisacodyl (ns13)
Lactulose (ns5)
ACE inhibitor Ca2q channel blocker Beta-blocker H2-antagonist Proton pump inhibitor Nitrate Aspirin Metoclopramide Erythropoietin Vitamin B complex Folic acid Calcichew Alpha-calcidol
5 8 5 1 6 1 2 3 12 12 13 11 9
1 4 2 – 2 – 2 3 6 9 9 5 3
– 2 – – 1 – – 1 2 3 3 1 1
of chronic dietary Kq-loaded rats compared with controls [9]. Bisacodyl (Dulco-lax1), a cAMP-mediated laxative [10], may therefore stimulate colonic Kq secretion in haemodialysis patients, resulting in a decrease in interdialytic hyperkalaemia.
Subjects and methods 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 Kq secretion.
Plasma Kq concentrations after acute oral Kq 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 Kq homeostasis. A fasting blood sample was taken, following which each subject drank 200 ml of Ensure Plus (containing 10 mmol of Kq) supplemented with 20 mmol of Kq in the form of Kay-Cee-L syrup (Geistlich, Chester, UK). Blood samples were obtained at 20-min intervals for 180 min. Plasma Kq 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 Kq load. Plasma Kq concentrations were measured by autoanalyser.
Plasma Kq concentrations during treatment with bisacodyl Non-fasting plasma Kq concentrations were measured at 0900 hours (1.5–2 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 Kq excretion. Average plasma Kq concentrations were determined in the second week of bisacodyl treatment (the ‘study’ week), and compared with the average plasma Kq concentrations obtained in the 2 weeks prior to bisacodyl treatment.
Plasma Kq concentrations during treatment with lactulose Non-fasting plasma Kq concentrations were measured in a similar way before and during the daily administration of 10 ml of lactulose (Duphalac1, 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 Kq excretion measured.
Statistical analysis Results are shown as means ("SEM). In the oral Kq loading studies, plasma Kq concentrations at all time points were normally distributed in both groups (onesample Kolmogorov–Smirnov test). In the oral Kq loading and laxative studies, comparisons were made using the nonpaired or paired two-tailed Student’s t-test as appropriate, P - 0.05 indicating a significant difference between two means.
Results Plasma Kq concentrations after acute oral Kq 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 70–95 mmol of Kq daily, estimated from their dietary histories. Of the ESRD patients, eight were ‘pre-dialysis’ with variable urinary Kq outputs (37– 128 mmolu24 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 Kq outputs (10–32 mmolu 24 h). The three groups were matched for sex, age and weight. Figure 1 shows that fasting plasma Kq concentrations were within the normal range (3.5–5.1 mmolul) in all three groups, although higher in the ‘pre-dialysis’ and CAPD patients than in the control subjects (P - 0.02). After acute oral Kq loading, plasma Kq concentrations increased but remained within the
Colonic Kq secretion in renal failure
343 q
Table 2. Clinical details of volunteers receiving acute oral K
load
Subject
Group
Sex
Age (years)
Weight (kg)
Urine output (mlu24 h)
Urinary Kq output (mmolu24 h)
1 2 3 4 5 6 7 8 9 Mean"SEM 10 11 12 13 14 15 16 17 Mean"SEM 18 19 20 21 22 23 24 25 Mean"SEM
Control Control Control Control Control Control Control Control Control
M M M M F F F F F
– – – – – – – – –
M M M M F F F F
1550 1760 2260 3440 – 3020 2870 2760
71 128 36 62 – 79 37 55
CAPD CAPD CAPD CAPD CAPD CAPD CAPD CAPD
M M M M M F F F
85 76 81 97 84 56 56 65 60 73"5 109 99 78 86 62 109 49 56 81"8* 123 68 63 87 67 69 54 76 76"8*
– – – – – – – – –
Pre-dialysis Pre-dialysis Pre-dialysis Pre-dialysis Pre-dialysis Pre-dialysis Pre-dialysis Pre-dialysis
29 31 68 58 40 38 62 27 28 41"6 64 63 53 58 47 63 25 55 54"5* 50 55 51 53 41 33 31 38 44"3*
0 720 700 580 0 0 3160 150
0 20 15 10 0 0 32 11
*Not significantly different from control group value.
normal range in the control subjects and in the ‘pre- depict plasma Kq concentrations as a function of time, dialysis’ patients, although levels were significantly indicate that the prompt (within 20 min) increases in higher (P - 0.05) in the ‘pre-dialysis’ patients than plasma Kq concentration after oral Kq loading reflect in the controls at all time points. In contrast, plasma rapid Kq absorption rather than diurnal variation. Kq concentrations increased and remained above the normal range for the final 80 min of the study period Plasma Kq concentrations during administration in the CAPD patients. It should be emphasized that of bisacodyl the overall increases in plasma Kq concentration were similar in the control subjects and the ESRD patients, Of the control subjects, five took 5 mg bisacodyl daily suggesting comparable rates of Kq absorption in all and three took 10 mg bisacodyl daily, and in each case three groups. the number of stools increased from one to two (ns5) Previous studies in normal subjects have demon- or three (ns3) a day. Of the haemodialysis patients, strated that plasma Kq concentrations and urinary eight took 5 mg bisacodyl daily, two took 10 mg Kq excretion exhibit diurnal variation, being highest bisacodyl daily, and three required only 5 mg bisacoaround noon and lowest in the evening and early dyl on alternate days to increase the number of stools morning [11–13]. A similar but blunted pattern has from one to two (ns6), three (ns5) or four (ns2) a been reported in patients with chronic renal insuffi- day. Bisacodyl has a duration of action of 10–12 h, ciency [13]. Figure 2 shows that in the present study, and was taken in the evening. In each case, the plasma Kq concentrations did not vary significantly increase in stool frequency was associated with stool over 180 min in groups of control subjects, ‘pre- softening, but there was no diarrhoea. There was no dialysis’ patients or CAPD patients, not receiving the evidence that bisacodyl treatment resulted in hypovooral Kq load. It should be noted that although the laemia in the haemodialysis patients, in whom body mean fasting plasma Kq concentration in the controls weight and blood pressure were essentially unchanged shown in Figure 1 was 0.6 mmolul lower than the (Table 3). mean value in the smaller group of controls shown During the 2 weeks before and after bisacodyl in Figure 2, in the former group individual values treatment, non-fasting plasma Kq concentration was were 3.5 mmolul in three subjects and the other values measured four times in each control subject and six ranged between 3.6 and 3.9 mmolul. Nevertheless, times in each haemodialysis patient. Figure 3 shows taken together, the data in Figures 1 and 2, which average plasma Kq concentrations before and during
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Fig. 1. Plasma Kq 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 Kq. At each time point, values for ‘pre-dialysis’ and CAPD patients were significantly greater (P - 0.02) compared with controls.
Fig. 2. Plasma Kq 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 Kq load.
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345
Table 3. Clinical details of volunteers receiving bisacodyl or lactulose Group (M:F)
Age (years)
Control (2:6) Bisacodyl q Bisacodyl P HD (9:4) Bisacodyl q Bisacodyl P HD (3:2) Lactulose q Lactulose P
32"3
Weight (kg)
Plasma Kq (mmolul)
Syst BP (mmHg)
Diast BP (mmHg)
– –
4.04"0.1 3.9"0.1 NS
– –
– –
73.1"3.4 72.8"3.6 NS
5.9"0.2 5.5"0.2 - 0.0005
139"4 136"5 NS
77"2 74"2 - 0.05
80.8"9.9 81.1"9.8 NS
5.7"0.3" 5.64"0.2 NS
143"5 149"5 - 0.02
87"2 89"3 NS
52"4*
44"6
Mean"SEM; HD, haemodialysis group; *P - 0.02 compared with control group. "P - 0.0001 compared with pre-laxative value in control group.
the second (‘study’) week of bisacodyl treatment in individual control subjects and haemodialysis patients. As shown in Table 3, the mean plasma Kq concentration was significantly higher in the haemodialysis patients (5.9"0.2 mmolul) than in the control subjects (4.04"0.1 mmolul, P - 0.0001). In five of the eight control subjects, plasma Kq concentration decreased slightly during the second week on bisacodyl, but overall there was no significant change in this group (4.04"0.1 mmolul pre-bisacodyl vs 3.9" 0.1 mmolul on bisacodyl). By contrast, bisacodyl treatment was associated with generally more pronounced decreases in plasma Kq concentration in 12 of the
13 haemodialysis patients, with an overall decrease from 5.9"0.2 to 5.5"0.2 mmolul (P - 0.0005). The bisacodyl-induced decrease in plasma Kq concentration in the haemodialysis patients (0.4"0.1 mmolul) was significantly greater than that in the control subjects (0.14"0.1 mmolul, P - 0.05). This suggests that bisacodyl may have stimulated Kq secretion in the Kq-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 Kq concentration was not related to the initial (‘ Bis’) value. 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 agedependent, because in seven of the haemodialysis patients aged 22–58 years (similar to the age range of the control subjects), bisacodyl treatment decreased plasma Kq concentration (from 5.94"0.3 to 5.4" 0.3 mmolul, P - 0.01) to the same extent as in the entire group. Plasma Kq concentrations during administration of lactulose
Fig. 3. Effect of bisacodyl on plasma Kq concentrations in individual control subjects (open circles) and haemodialysis patients (closed circles). ‘ Bis’ data points represent the average of four plasma Kq measurements in the control subjects, and six plasma Kq measurements in the haemodialysis patients, during the 2 weeks preceding bisacodyl treatment. ‘qBis’ data points represent the average of two plasma Kq measurements in the control subjects, and three plasma Kq measurements in the haemodialysis patients, during the second (‘study’) week of bisacodyl treatment.
Five haemodialysis patients were treated with 10 ml of lactulose daily, which increased the number of softened stools from one to two (ns4) or three (ns1) a day, without producing diarrhoea or evidence of hypovolaemia. In contrast to bisacodyl, lactulose had no effect on interdialytic hyperkalaemia (Table 3).
Discussion Several studies suggest that rectal, and perhaps colonic, Kq secretion increases in patients with ESRD [4,6,7]. Enhanced Kq secretion, reflecting stimulation of an
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T. Mathialahan and G. I. Sandle q
active K secretory process, certainly occurs throughout the colon in rats maintained on a Kq-enriched diet [3]. Increased net Kq secretion has been demonstrated in the rectum of ESRD patients using an initial intraluminal Kq concentration of 45 mmolul [6], and net Kq secretion may be even greater in the ascending colon where the Kq concentration of ileal effluent is ;14 mmolul. In patients with ESRD, the factors responsible for maintaining the colonic epithelium in its Kq hypersecretory state are unclear. Distal colonic expression of the mRNA encoding CHIF (channel-inducing factor, a Kq-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 Kq secretion in patients with ESRD. Nevertheless, increased rectal Kq secretion has been demonstrated in ESRD patients without secondary hyperaldosteronism [6,7]. Colonic Kq secretory capacity may therefore adapt to the dietary Kq load independently of aldosterone when renal Kq excretion is severely restricted. In the present study, acute oral Kq loading caused a modest increase in plasma Kq concentration to the mid-normal range in control subjects, sustained increases to within the upper normal range in ‘predialysis’ patients, and hyperkalaemia in CAPD patients. Increases in plasma Kq concentration after food have been previously reported in normal rats maintained on a Kq-enriched diet [8], and in human subjects with normal renal function ingesting a diet heavily supplemented with Kq [15]. Increases in plasma Kq concentration, such as those seen in the present study, certainly influence renal Kq excretion, and it is conceivable that colonic Kq secretion responds in a similar way. For example, in intact rats, raising plasma Kq concentration from 4 to 6 mmolul stimulates a prompt increase in renal distal tubular Kq secretion [16], while increasing peritubular Kq concentration stimulates Kq secretion in isolated perfused rabbit cortical collecting ducts [17,18]. This response reflects, at least in part, increases in apical and basolateral membrane Kq conductances and activation of the Naq,Kq-ATPase pump [18]. Chronically dietary Kq-loaded but renal-intact rats, and rats with chronic renal insufficiency and minimal dietary Kq supplementation, exhibit increased colonic Kq secretion and mucosal Naq,Kq-ATPase activity compared with controls [19,20]. A similar increase in colonic Naq,Kq-ATPase activity in ESRD patients would therefore provide a mechanism for enhanced basolateral cellular Kq uptake. Furthermore, high conductance apical Kq channels have been identified in surface epithelial cells in human colon [21] which, like apical Kq (ROMK) channels in principal cells of the collecting duct [22], form the rate-limiting step of Kq secretion, and may be activated by increases in plasma Kq concentration. Thus, significant increases in plasma Kq concentration in response to food may constitute a repetitive signal for the up-regulationuactivation of components of the colonic Kq secretory process
in patients with ESRD. This idea is also supported by studies in haemodialysis patients, in whom rectal Kq 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 Kq intake. We therefore investigated whether laxatives might stimulate colonic Kq secretion sufficiently in haemodialysis patients to reduce interdialytic hyperkalaemia. We chose bisacodyl because this cAMP-mediated laxative stimulates apical Kq efflux in rabbit distal colon, apparently via Kq channels in the apical membrane [23]. In addition, we have recently identified apical Kq 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 Kq secretory response in dietary Kq-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 Kq 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 Kq concentration in haemodialysis patients suggests that this cAMPmediated laxative has a specific stimulatory effect on Kq movement into the lumen of the colon, which is already adapted to deal with the dietary Kq load. It seems much less likely that the proposed increase in colonic Kq secretion occurred by ‘solvent drag’, because (i) the osmotic laxative lactulose had no effect on plasma Kq concentration in these patients, (ii) bisacodyl was used at doses which avoided diarrhoea, and (iii) diarrhoea per se does not cause significant faecal Kq losses by ‘washout’ alone [25]. In summary, this study demonstrates that periods of sustained increases in plasma Kq concentration, sometimes to hyperkalaemic levels, occur after an acute oral Kq load in ‘predialysis’ and CAPD patients who are normokalaemic in the fasting state. These changes in plasma Kq concentration may enhance colonic Kq secretion and help to maintain Kq 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 Kq concentration than those reported here.
Acknowledgements. 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.
Colonic Kq secretion in renal failure
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