Nitric oxide inhibits potassium transport in the rat distal
colon
Roman
Aizman,
Hjalmar
Brismar, and
Gianni
Celsi
Department of Woman and Child Health, Astrid Lindgren Children's
Hospital, Karolinska Institutet, S-17176 Stockholm, Sweden
 |
ABSTRACT |
The effect of the nitric oxide (NO) pathway
on K+ (measured using 86Rb) transport in adult
rat distal colon was investigated in muscle-stripped segments of colons
mounted in Ussing chambers. When added to the mucosal solution, the
endogenous precursor of NO, L-arginine (30 mM), inhibited
both mucosal-to-serosal and serosal-to-mucosal 86Rb fluxes
and caused a prolonged decrease of short-circuit current (Isc). This effect was significantly reduced by
the NO synthase inhibitor
NG-nitro-L-arginine methyl ester
(L-NAME) but not by D-NAME. Mucosal application
of S-nitroso-N-acetyl-penicillamine (SNAP) inhibited mucosal-to-serosal 86Rb flux without affecting
serosal-to-mucosal transport. Serosal addition of two different
exogenous NO donors, sodium nitroprusside (0.1 mM) and SNAP (0.2 mM),
decreased serosal-to-mucosal 86Rb flux, whereas
Isc increased. The SNAP-induced decrease in
86Rb flux was abolished by
1H-(1,2,4)oxodiazolo(4,3-a)quinoxalin-1-one (0.2 mM), a selective
inhibitor of NO-stimulated soluble guanylyl cyclase, and by methylene
blue (0.01 mM). Addition of 8-bromo-cGMP (2 × 10
4 M)
in the presence of an inhibitor of cGMP-specific phosphodiesterase mimicked the effects of NO-donating compounds. This study provides evidence that NO inhibits K+ transport in the rat distal
colon via a cGMP-dependent pathway. The effect on net K+
transport may depend on the side of NO action.
nitric oxide donors; guanosine 3',5'-cyclic monophosphate pathway
 |
INTRODUCTION |
NITRIC OXIDE (NO) is an important mediator
of several physiological processes in the gastrointestinal tract (35).
Endogenous NO is derived from enzymatic conversion of
L-arginine by NO synthase (NOS), a family of isoenzymes
(22). In the gut, NOS is expressed throughout the intestinal wall in
neurons (10), blood vessels (25), and epithelia (40). Because NO breaks
down rapidly under aerobic conditions (11), its effect may be limited
to the local region of production. NO modulates and influences both gut
motility (6) and mucosal blood flow (26). Moreover, elevated levels of
NOS, NO, and products of NO oxidation have been found in patients with
active ulcerative colitis and gastroenteritis (9) and in an
experimental model of hypoxia-induced colonic dysfunction (5),
suggesting a role for NO also in pathological situations.
In addition, it has been suggested that NO directly regulates
intestinal electrolyte and fluid transport, although the effect of NO
on ion and water transport is far from being completely elucidated.
Although some studies have suggested that NO produces a net secretory
effect (18, 24, 39, 42), other studies have shown a net absorptive
effect (15, 29, 33). The conclusions concerning the NO effects on ion
transport are mainly based on electrophysiological recordings of
short-circuit current (Isc) and transmural
potential difference (PD) without direct measurements of unidirectional
ion fluxes (18, 28, 34, 39). There are only a few studies directly
indicating that NO donors stimulate electrogenic Cl
secretion and inhibit Na+ and Cl
absorption
in the intestine (18, 42). Moreover, it has been suggested that the
effect of NO on net water and ion transport in the intestine may depend
on the side of application of the NO-donating compounds (24, 34).
Scanty information is available on the effect of NO on K+
transport in the distal colon. Indeed, the distal part of the
gastrointestinal tract plays an important role in K+
balance by regulating fecal K+ excretion (3). It is well
documented that K+ excretion in the gut is the vectorial
sum of two opposite fluxes, secretion and absorption, which are
mediated by different K+ pumps and transporters, located in
both basolateral and apical membranes of colonocytes (1, 2, 7, 17, 30).
Therefore, the main aim of this study was to determine if NO regulates
K+ transport in the rat distal colon and if the effect on
absorptive or secretory pathways depends on the side of NO application.
 |
METHODS |
Animals.
Adult male Sprague-Dawley rats (65-70 days old, 250-300 g)
fed standard rodent laboratory chow and water ad libitum were used in
all studies. Animals were maintained in a 12:12-h light-dark environment. All experiments were carried out during the light phase.
The protocols used in the present studies were approved by the Swedish
National Board for Animal Research.
Preparation of intestinal tissue.
The rats were anesthetized intraperitoneally with thiobutabarbital (6 mg/100 g body wt). Thereafter, the distal colon (one-third from the
colorectal junction) was quickly removed, cut open, emptied of feces,
and bathed in ice-cold physiological saline solution (PSS; in mM: 118 NaCl, 4.5 KCl, 0.54 MgCl2, 2.5 CaCl2, 1.2 NaH2PO4, 25 NaHCO3, and 10 D-glucose, pH 7.4) constantly gassed with 95% O2 and 5% CO2. The tissue was stretched and
carefully stripped of its serosal and muscular layers by blunt
dissection. Colonic sheets (0.725-cm2 exposed surface area)
were mounted into Ussing chambers (WPI, New Haven, CT) and bathed on
both sides with 10 ml of PSS, which was circulated by a peristaltic
pump. The solution was constantly gassed (95% O2-5%
CO2) and maintained at 37°C by a water-jacketed bath.
Bioelectrical and unidirectional flux measurements.
Transmural PD (mV) and Isc (µA/cm2)
were measured with the aid of an automatic voltage clamp (EVC-1000
voltage/current clamp; WPI) using Ag-AgCl electrodes connected to the
bathing solution via agar bridges. The tissues were continuously
short-circuited to zero PD except for brief intervals of 4 s every 1 min, at which time the open-circuit PD was read. Tissue conductance
(Gt, in mS/cm2) was calculated using
the formula Isc/PD. Tissue PD,
Isc, and Gt were continuously
monitored with the help of a personal computer equipped with a digital
input/output and analog-digital converter card (Advantech PCL-711B).
After tissues were mounted, they were allowed to equilibrate for at
least 30 min to achieve stable PD and Isc before
any drug addition and unidirectional flux measurements. Tissues with
baseline Gt higher than 25 mS/cm2 were
excluded from the study, since higher conductances might be related to
tissue damage or transepithelial leakage (8, 27, 30). For the same
reason, tissues having Gt values that significantly
changed during the study were excluded from unidirectional K+ flux determinations.
Unidirectional K+ fluxes were measured by a
sample-and-replace protocol (12) across short-circuited colonic mucosa
using 86Rb as a marker of K+ (43). After
equilibration, 1 µCi/ml 86Rb was added to the serosal or
mucosal "hot" side. Samples (1 ml) were collected from the
corresponding "cold" bathing solution at 10-min intervals and
counted in a liquid scintillation counter (LKB). Immediately after
collection, 1 ml of prewarmed bathing solution was replaced on the
"cold" side.
After four control periods, the mean of which was calculated and used
as the baseline, drugs were added in small volumes from concentrated
stocks to solutions bathing either the serosal or the mucosal side, and
drug-induced fluxes were measured during five additional periods. In
all studies in which the drug was added to the "cold" side, the
replacement buffer contained the same drug to maintain the appropriate
concentration in the bathing solution during the whole experiment.
Mucosal-to-serosal (Jm
s) and serosal-to-mucosal
(Js
m) fluxes were measured in different tissues.
To calculate net 86Rb flux
(Jnet = Jm
s
Js
m),
tissues were paired on the basis of a conductance difference of <20%
(24, 42, 43). A positive Jnet indicated
86Rb absorption, and a negative Jnet
represented 86Rb secretion.
Materials.
S-nitroso-N-acetyl-penicillamine (SNAP), sodium
nitroprusside (SNP), L-arginine,
N G-nitro-L-arginine methyl ester
(L-NAME), D-NAME, 8-bromo-cGMP, and methylene
blue were obtained from Sigma Chemical; the specific inhibitor of cGMP
phosphodiesterase,
4-{[3',4'-(methylenedioxy)benzyl]amino}-6-methoxyquinazoline, was
obtained from Calbiochem; 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) was purchased from Tocris Cookson; and 86Rb was from Amersham.
Statistics.
Data are presented as means ± SE, with n indicating the
number of rats. The paired Student's t-test and
the two-way ANOVA (when indicated) were used to determine statistical
difference. A P value of <0.05 was considered significant.
 |
RESULTS |
To evaluate if colonic K+ transport is regulated by NO
production, segments of the rat distal colon were incubated with the natural precursor of NO, i.e., L-arginine. Addition of
L-arginine (30 mM) to the mucosal bathing solution produced
a sustained decrease in Isc and PD without
significant changes in Gt (Table
1). A statistical difference in
Isc and PD was observed after 20 min. To study the
effect of L-arginine on K+ transport, we
measured the unidirectional K+ fluxes using
86Rb as a marker for K+. Unidirectional
K+ fluxes were rapidly affected by L-arginine
(Fig. 1). In basal conditions, there was a
negative Jnet, i.e., a 86Rb flux from
the serosal to mucosal side representing secretion. Both
Jm
s and Js
m were
inhibited by L-arginine, although the time of onset was
different. The Js
m was inhibited at 10 min,
whereas the effect on Jm
s was observed after 20 min. Thereafter, the fluxes were inhibited almost to the same extent. Therefore, during the first 10 min, we observed a net K+ absorption, whereas after 20 min the net K+
transport did not differ from basal values. At lower concentrations (20 mM) L-arginine did not affect fluxes, whereas at higher
concentrations (40-50 mM) it produced marked changes in tissue
electrical parameters (>2- to 3-fold elevation in
Gt), most likely reflecting changes in
transepithelial permeability and/or tissue damage (data not shown). Serosal application of L-arginine (30 mM) did not
alter Js
m or Jm
s (Table
2).

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Fig. 1.
Unidirectional [mucosal-to-serosal (Jm s) and
serosal-to-mucosal (Js m)] and net
(Jnet) 86Rb fluxes (in
µM · cm 2 · h 1)
in rat distal colon following mucosal addition of
L-arginine (30 mM). Here and in Figs. 2-7, arrows
indicate addition of drugs. *Significantly different from baseline;
n (no. of rats) = 4 in each group.
|
|
To evaluate if the effect of L-arginine on K+
transport is mimicked by NO, we studied the effect of mucosal SNAP, an
exogenous NO donor. Mucosal SNAP (0.2 mM) evoked a rapid and prolonged
increase of Isc and PD without affecting
Gt (Fig. 2A).
Mucosal SNAP did not affect Js
m but
significantly decreased Jm
s after 20 min, thus
resulting in increased K+ secretion compared with baseline
(Fig. 3A).

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Fig. 2.
Time course of short-circuit current (Isc),
potential difference (PD), and tissue conductance
(Gt) responses to mucosal (A) or serosal
(B) addition of 0.2 mM
S-nitroso-N-acetylpenicillamine (SNAP) in rat distal
colon. Isc and PD are presented as difference from
baseline; Gt is presented in absolute values.
*Significantly different from baseline; n = 4 in each group.
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Fig. 3.
Unidirectional and net K+ (86Rb) fluxes in rat
distal colon following mucosal (A) or serosal (B)
addition of 0.2 mM SNAP. Data are presented in absolute values, in
µM · cm 2 · h 1.
*Significantly different from baseline; n = 4 for each group.
|
|
To estimate if the NO-induced alteration in K+ transport
depended on the side of application, the effect of SNAP added from the
mucosal side was compared with the response from the serosal side.
Serosal addition of SNAP (0.2 mM) rapidly increased
Isc and PD (Fig. 2B) without affecting
Gt. In contrast to mucosal addition, serosal SNAP
did not alter Jm
s but significantly decreased
Js
m after 20 min, thus resulting in increased K+ absorption compared with baseline (Fig. 3B).
The effect of serosal SNAP was determined also at different
concentrations (Table 3). At lower doses
(0.04 mM), the effect of SNAP on Js
m was relatively small and therefore the mean Jnet did
not differ from basal values. At higher concentrations (1.0 mM),
Js
m was affected approximately to the same
extent as with 0.2 mM SNAP; therefore, the mean
Jnet reversed from secretion to absorption. However, we observed that 1.0 mM SNAP affected baseline
Gt (the mean value increased from 13.2 ± 2.0 to
17.2 ± 2.5 mS/cm2; n = 4).
To evaluate if the effect of SNAP is due to the release of NO, we also
determined the response to another NO donor, SNP, which is structurally
unrelated to SNAP. Serosal addition of SNP (0.1 mM) produced a rapid
and transient increase in Isc and PD without affecting Gt (Fig.
4A). SNP also significantly
decreased Js
m (Fig. 4B) but did not
alter Jm
s. Therefore, Jnet
was reversed from secretion to absorption within 30 min after exposure
to serosal SNP.

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Fig. 4.
Time course of Isc, PD, and Gt
(A) and unidirectional and net K+
(86Rb) fluxes (in
µM · cm 2 · h 1)
(B) in rat distal colon following serosal addition of 0.1 mM
sodium nitroprusside (SNP). *Significantly different from baseline;
n = 4 in each group.
|
|
In the following protocols, we further characterized the NO-dependent
intracellular pathway inhibiting K+ fluxes in rat distal colon.
The inhibitory effects of L-arginine on
Jm
s were significantly abolished by the mucosal
addition of the NOS inhibitor, L-NAME (7 mM), 5 min before
L-ar-ginine, whereas the inactive compound,
D-NAME (7 mM), did not alter the
L-arginine-induced decrease in Jm
s
(Fig. 5). L-NAME alone did not
significantly change Jm
s (basal value of
0.52 ± 0.01, 0.49 ± 0.02 after 10 min, 0.53 ± 0.03 after 20 min, and 0.48 ± 0.04
µM · cm
2 · h
1
after 30 min; n = 4 at each time point).

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Fig. 5.
86Rb Jm s in rat distal colon after
mucosal addition of L-arginine (30 mM) + N G-nitro-L-arginine methyl ester
(L-NAME; 7 mM) or L-arginine + D-NAME (7 mM). Statistical changes in
Jm s following mucosal addition of
L-arginine (30 mM) alone are presented in Fig. 1 and are
indicated here only for comparison. +Significantly different from
L-arginine alone (2-way ANOVA); n = 4-5 for
each group.
|
|
To evaluate if the NO-induced inhibition of K+ transport is
mediated by the cGMP pathway, the colonic mucosa was incubated with
SNAP in the presence of guanylyl cyclase inhibitors. The selective
inhibitor of NO-stimulated soluble guanylyl cyclase, ODQ (0.2 mM),
added to the mucosal (Fig. 6A) or
serosal (Fig. 6B) side, blocked the SNAP-induced inhibition
of unidirectional 86Rb fluxes and significantly reduced the
SNAP-mediated elevation of Isc and PD (data not
shown). Methylene blue (10 µM), a less selective inhibitor of
guanylyl cyclase, was also used. As expected, methylene blue, added to
the serosal side, prevented the decrease of K+ flux
(Js
m) caused by SNAP alone (Fig.
7).

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Fig. 6.
Unidirectional K+ fluxes in rat distal colon after mucosal
(A) or serosal (B) addition of SNAP (0.2 mM) and
1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) (0.2 mM). Data are
presented in absolute values, in
µM · cm 2 · h 1.
*Significantly different from baseline; +significantly different from
SNAP alone (2-way ANOVA); n = 4-5 for each group.
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Fig. 7.
Effect of serosal methylene blue (10 µM) on serosal SNAP (0.2 mM)-induced inhibition of 86Rb Js m.
Data are presented in absolute values, in
µM · cm 2 · h 1.
*Significantly different from baseline; +significantly different from
SNAP alone (2-way ANOVA); n = 3-4 for each group.
|
|
In the last protocol, the colon was treated with exogenous 8-bromo-cGMP
(2 × 10
4 M) in the presence of the cGMP-specific
phosphodiesterase inhibitor, methoxyquinazoline
(5 × 10
7 M) (38). Both drugs were added to the
mucosal side. Application of these drugs produced a sustained increase
in Isc and PD without affecting
Gt. Moreover, these drugs caused a significant
decline in Jm
s, similar to the response induced
by mucosal SNAP or L-arginine (Table
4).
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Table 4.
Effect of 8-bromo-cGMP in presence of cGMP-specific phosphodiesterase
inhibitor on 86Rb Jm s and on electrical
parameters of rat distal colon
|
|
 |
DISCUSSION |
The present study demonstrates that K+ transport in the rat
distal colon is regulated by an NO-dependent pathway and suggests that
this regulation may be of physiological relevance. These conclusions
are based on the following results.
The natural precursor of NO, i.e., L-arginine, affected
K+ transport, and this effect was abolished by the
inhibitor of NOS, L-NAME, but not by the inactive compound
D-NAME. It is therefore likely that the effect of
L-arginine is mediated by an NOS-dependent production of
NO. Indeed, both the constitutive and the inducible isoforms of NOS are
expressed in the rat colon and may therefore convert
L-arginine to NO (14).
Two different NO donors (SNP and SNAP) added to the serosal side
induced similar effects on K+ transport. It has been
suggested that the action of NO donors may be partially explained by
the release of other substances unrelated to NO (13, 36). The finding
that SNP and SNAP had similar effects on 86Rb fluxes tends
to exclude this possibility. In this regard, SNAP, a nitrosothiol that
is structurally unrelated to SNP, produces fewer byproducts (13) and
may be more identical to NO in its actions than SNP (34).
Furthermore, the dose-dependent response to SNAP suggests that toxicity
does not contribute to the NO donor response. In this study, the effect
of NO donors on K+ transport was observed at doses that did
not cause epithelial leakage, as determined by a stable electrical
conductance (Gt). Higher doses of
L-arginine (40-50 mM) and SNAP (1 mM)
increased electrical conductance, indicating that cell damage
and/or increased epithelial permeability may occur (4, 16).
The intracellular pathway mediating the intestinal effects of NO is
still disputed. Most studies found that NO stimulates intestinal cGMP
production (18, 22, 39, 41). However, some studies deny or question the
role of cGMP in intestinal NO action (32, 33). The results of the
present study strongly indicate that cGMP mediates the effect of NO on
colonic K+ transport (Fig. 8).
ODQ, a specific inhibitor of NO-activated soluble guanylyl cyclase,
which does not affect NOS or NO (23), completely prevented the effect
of SNAP on K+ fluxes. Moreover, a general inhibitor of
guanylyl cyclase, methylene blue, significantly attenuated the
inhibitory effect of NO on K+ transport. In addition,
application of 8-bromo-cGMP in the presence of the cGMP-specific
phosphodiesterase inhibitor mimicked the effect of NO donors on
K+ fluxes.
The mechanisms responsible for K+ transport in the large
intestine consist of two opposite fluxes: secretion and absorption (3).
K+ secretion is mediated by
Na+-K+-ATPase and
Na+-K+-2Cl
cotransporter, both
located in the basolateral membrane of colonocytes. These enzymes
stimulate K+ uptake across the basolateral membrane,
leading to K+ secretion across the apical membrane through
K+ channels (30). K+ absorption occurs via
K+-dependent ATPases located in the apical membrane, mainly
in the distal colon. Several lines of evidence suggest that there are at least two K+-absorptive pumps, namely, an
ouabain-insensitive H+-K+-ATPase and an
ouabain-sensitive Na+-independent K+-ATPase (1,
7, 17). Besides transcellular K+ transport, paracellular
pathways can also contribute to net K+ flux, but the
colonic paracellular route is believed to have low conductance and be
anion selective; therefore, its contribution to K+
transport under normal conditions may be neglected (20). In this study,
the finding that the effect of different NO donors on K+
transport was observed in the absence of changes in transepithelial conductance strongly supports the concept that K+ is mainly
transported transcellularly. However, the effect of NO on individual
K+ transporters remains to be evaluated.
In this study we observed that mucosal L-arginine inhibited
both serosal-to-mucosal and mucosal-to-serosal fluxes, whereas serosal addition of L-arginine did not alter ion fluxes. On
the other hand, SNAP inhibited unidirectional fluxes, depending on the
side of addition. Indeed, it has been shown that L-arginine affects intestinal water and ion transport following intraluminal infusion but not when infused intraperitoneally (19, 24). We may assume
that L-arginine added to the mucosal side is converted by
NOS to NO, which inhibits both apical and basolateral K+
transporters. Although NO is lipophilic and should easily traverse a
plasma membrane, our results may suggest that NO produced by SNAP/SNP
acts near the site of its production, due to its rapid inactivation under aerobic conditions (11). Therefore, NO produced in
the lumen could affect only apical K+ transporters, whereas
NO produced at the serosal side could affect only basolateral
K+ transporters. Further in vitro studies are required to
evaluate this hypothesis.
The effects of L-arginine and NO donors (SNAP and SNP) on
the electrophysiological parameters (Isc and PD)
are controversial. Similar opposite changes in Isc
following SNAP/SNP or L-arginine addition to the intestine
have been reported (18, 28, 29, 34, 37, 39, 42), but the ionic
mechanisms for these responses are not fully elucidated. It has been
suggested that Cl
is the primary ion involved in
NO-induced changes of Isc, although alterations in
Na+ flux may also affect this value (18, 42). In our study,
we found a discrepancy between changes in electrical parameters and K+ fluxes following NO addition. Changes in
Isc occured within 20 min, whereas the maximal
inhibition of Js
m and Jm
s was observed after 30 min of treatment. Moreover,
Isc and PD changed in opposite directions after
L-arginine or SNAP/SNP, whereas K+ fluxes were
inhibited by all NO donors. Therefore, a detailed evaluation of the
effects of NO precursors on different ion fluxes and of their relative
contribution to Isc is probably needed to address
these controversial findings.
It has been shown that NOS is increased in active idiopathic ulcerative
colitis (21), suggesting a role for NO in the pathogenesis of this
condition. NO is generated by a number of immunologic cell types that
have been shown to be present in increased quantities in the lamina
propria and the lumen of the inflamed bowel. Moreover, in vivo studies
have indicated NO involvement in the pathophysiology of secretion
induced by Escherichia coli heat stable enterotoxin (31). Our
results demonstrate that K+ absorption and/or
secretion in the rat distal colon can be regulated by locally produced
NO and that this effect may depend on the side of NO action. Taken
together, these results suggest that the NO system is an important
regulator of K+ transport during normal and pathological conditions.
 |
ACKNOWLEDGEMENTS |
This work was supported by the Swedish Medical Research Council
(project no. 11555) and by the Wiberg Foundation. R. Aizman was
supported by a scholarship from the Karolinska Institute.
 |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: G. Celsi, Research Laboratory, Astrid
Lindgren Children's Hospital, S-17176 Stockholm, Sweden.
Received 10 June 1998; accepted in final form 7 October 1998.
 |
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