Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Neonatal mice
with cystic fibrosis (CF) exhibit a very high mortality due to
intestinal obstruction localized primarily to the ileum and colon. It
has been hypothesized that lack of
Cl secretion and possibly
elevated Na+ absorption contribute
to the gut problems in CF neonates. Therefore, intestines (ileum,
proximal colon, and distal colon) from normal and CF day-old mouse pups
were studied on ultra-small-aperture (0.0135 cm2) Ussing chambers. All three
regions of the normal neonatal intestine responded to forskolin with an
increase in short-circuit current, which was completely absent in the
CF intestine. The neonatal distal colon exhibited a high rate of
amiloride-sensitive electrogenic Na+ absorption, which did not
differ between the normal and CF preparations. The ileum and proximal
colon of both genotypes exhibited a small but significant electrogenic
Na+ absorption. The neonatal
proximal colon and ileum also exhibited electrogenic
Na+-glucose cotransport, which was
significantly greater in the normal compared with the CF ileum. In
addition, all three intestinal regions exhibited electrogenic
Na+-alanine cotransport, which was
significantly reduced in two of the regions of the CF neonatal
intestine. It is speculated that: 1)
the reduced rate of Na+-nutrient
cotransport in the CF intestine contributes to the lower rate of growth
in CF pups, whereas 2) the elevated
electrogenic Na+ absorption in the
neonatal intestine, coupled with an inability to secrete
Cl
, contributes to the
intestinal obstruction in the CF pups.
sodium absorption; calcium secretion; colon; ileum; mice; nutrient uptake; cystic fibrosis
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE NEONATAL MAMMAL FACES special challenges with
respect to Na+ homeostasis, as
large quantities of sodium are needed to accommodate the rapidly
expanding extracellular volume. Because the neonate consumes milk
relatively low in Na+ and
experiences a high renal loss of
Na+, the intestines may play a
relatively more important role in neonatal
Na+ homeostasis than in the adult,
with a more efficient kidney (17). Although intestinal absorption is
vitally important for growth and volume expansion in the neonate, the
importance of intestinal Cl
secretion in the neonate has recently been shown in the various mouse
models lacking the cAMP-activated
Cl
channel [cystic
fibrosis transmembrane conductance regulator (CFTR)]. In most of
these CF mouse models, the intestinal tract cannot secrete
Cl
, which is associated
with the observation that a large number of CF pups die as neonates
from intestinal obstruction and rupture (see Ref. 14 for a review).
Therefore, studies of both Na+ and
Cl
transport across the
neonatal intestine may give insight into how normal neonates balance
Na+ absorption and
Cl
secretion and give clues
as to why neonatal CF mice experience such a high rate of intestinal obstruction.
There are few studies on ion transport across the neonatal intestine.
In the rat, due to the inability to study guts of smaller neonates,
most studies have focused on pups that were greater than 8 days old.
With the exception of the limited data that have recently been
published on the colon of the Na+
channel () knockout neonatal mouse (15), there are no published data
on ion transport across the neonatal murine intestine. With the
emergence of transgenic and knockout mouse models, many of which
exhibit a neonatal lethal phenotype, study of the neonatal (and
prenatal) tissue may offer the only opportunity to test for alterations
in ion transport rates. Therefore, it is important to have techniques
to study ion transport across neonatal murine tissue.
In the present investigation, freshly excised tissue was mounted in
miniaturized Ussing chambers to measure the magnitude of electrogenic
Na+ absorption and
Cl secretion in the normal
neonatal (~24-h-old) murine colon (proximal and distal) and ileum.
For comparison, ion transport across the same regions of the neonatal
murine CF intestine was investigated to provide clues as to why these
regions exhibit such a high incidence of impaction and rupture in the
neonatal CF mouse.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Mice and mounting techniques.
The mice used in this study were from a mixed background: BAL/C, DBA/2,
C57BL/6, and 129/SVEV. Neonatal mouse pups remained with the mother
until the time of the study (12-48 h, averaging 24 h postbirth),
and they were then killed by an overdose of
CO2. A small piece of tail was
clipped, and the genotype of each pup was determined at a later time by
PCR analysis of tail DNA (27); thus the study was done blinded. Pups
were either heterozygous for CFTR (referred to as normal) or homozygous
CFTR(/
)
(cftrtm1unc;
referred to as CF). The mean body mass of the normal pups was 1.65 ± 0.7 g (n = 18), which did not
differ significantly from the CF pups (1.54 ± 0.1 g;
n = 8).
Solutions and drugs.
The tissues were bathed bilaterally (10 ml/side) in Krebs bicarbonate
buffer having the following composition (in mM): 140 Na+, 120 Cl, 5.2 K+, 1.2 Mg2+, 1.2 Ca2+, 2.4 HPO2
4, 0.4 H2PO
4, and 25 HCO
3. Glucose (5 mM) was added to the
basolateral side of all tissues as substrate, and 5 mM mannitol was
added to the apical side to maintain osmolarity. When glucose (or
alanine) was added apically, an equal quantity of mannitol was added
basolaterally. In some experiments, tissues were bathed bilaterally
with nominally Cl
-free
bicarbonate buffer (referred to as 0 Cl
buffer in text) in which
115 mM sodium gluconate replaced the NaCl,
MgSO4 (1.2 mM) replaced
MgCl2, and
CaCl2 (1.2 mM) was replaced by
calcium gluconate (6 mM calcium gluconate was added to overcome the
Ca2+ chelating effects of
gluconate). Bumetanide (10
4
M) and carbachol (10
4 M)
were added to the basolateral side of the tissue, forskolin was added
bilaterally (10
5 M), and
all other drugs were added apically. All drugs and chemicals were
obtained from Sigma (St. Louis, MO).
Statistics. All data are expressed as means ± SE. A Student's t-test was used to compare two groups.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Basal bioelectrics.
Despite the small exposed surface area of the neonatal intestinal
preparations, measurable and stable bioelectric parameters were
obtained. Typical records of the short-circuit current
(Isc) for a
normal and CF distal colon are shown in Fig.
1. The basal bioelectric data obtained from
the three intestinal regions studied for normal and CF preparations are
shown in Table 1. For the distal and
proximal colonic preparations, both the
Isc and potential difference (PD) were significantly lower in the CF preparations. The
tissue resistance
(Rt) was
significantly lower in the CF proximal colon and ileum compared with
that of the respective tissues of the normal neonates.
|
|
Forskolin response.
Forskolin elevates intracellular cAMP levels in intestinal cells and in
normal mouse intestine induces
Cl secretion through the
CFTR Cl
channel (2, 13).
Bilateral forskolin addition
(10
5 M) induced a
significant increase in
Isc in all three
intestinal regions from the normal neonates (Figs.
1A and
2). In the normal neonatal intestine, the
forskolin response is primarily a
Cl
secretory response.
[In bilateral Cl
-free
buffer, the magnitude of the response (distal colon) is reduced to 6.5 ± 1.2 µA · cm
2
(n = 7, compare with Fig. 2), and in
bilateral Cl
-free,
HCO
3-free buffer, the forskolin
response was found to be 0 ± 0, n = 4; see Ref. 11 for details of buffer composition.] In the CF
neonatal intestine, forskolin was completely without effect in all
three intestinal regions studied (Figs. 1B and 2).
|
Carbachol response.
In all three intestinal regions of the normal neonate, the
Ca2+-mobilizing agent carbachol
(104 M basolateral) induced
a significant change in
Isc that resulted in a large positive
Isc (Fig.
3, A and
C). In the normal neonatal intestine
bathed with Krebs buffer, bumetanide induced a decrease in the
carbachol-stimulated
Isc, consistent
with a Cl
secretory
response (Fig. 3, A and
D). To test further whether the
change in Isc
reflected in part a Cl
secretory response, the normal neonatal distal colon was bathed in
Cl
-free buffer. Under these
conditions, carbachol failed to induce an increase in
Isc (Fig.
4).
|
|
Amiloride response.
Amiloride was used to estimate the fraction of the basal
Isc that reflects
electrogenic Na+ absorption. The
distal colonic epithelia of both genotypes exhibited a large response
to amiloride (Fig. 1). In the distal colon of both genotypes, the
entire basal Isc
was inhibited by amiloride, and the polarity of the basal
Isc was reversed
with drug treatment (Figs. 1 and
5A). The
magnitude of the amiloride-sensitive
Isc did not
differ between the two genotypes (Fig.
5A). Although the residual
(postamiloride)
Isc exhibited by
the CF distal colons was about threefold greater (more negative) than
that of the normal distal colons, this difference did not reach
statistical significance (P = 0.09).
The proximal colons from both groups of mice exhibited small but
significant responses to amiloride, which were similar for the two
groups (Fig. 5B). Likewise, the
ileal tissue exhibited a small response to amiloride that did not
differ between the CF and normal tissue (Fig.
5B). (Note scale difference compared with Fig. 5A.)
|
Electrogenic
Na+-glucose
cotransport.
In some of the regions of the mammalian gut (primarily the jejunum),
apical addition of glucose elicits a significant increase in
Isc due to
electrogenic Na+-glucose-coupled
absorption (37). In the neonatal proximal colon and ileum of both
genotypes, addition of 10 mM apical glucose elicited a significant
increase in Isc
(Fig. 6). It appears that in the neonatal
gut the magnitude of this electrogenic response decreases from proximal
to distal regions of the intestine. In the neonatal CF ileum, the
response was significantly reduced compared with that in the normal
ileum (Fig. 6). In all tissues, the glucose-stimulated
Isc was inhibited
with phloridzin (104 M
apical, data not shown).
|
Electrogenic
Na+-alanine
cotransport.
Intestinal tissues also possess a number of different transport systems
for amino acids, which reflect differences in the physicochemical
properties of amino acids (10). Several of the transport systems couple
apical amino acid entry to Na+
entry, inducing an electrogenic response. The entry of the neutral amino acid alanine uses such an entry system, with apical addition of
alanine inducing an increase in
Isc. All
intestinal regions studied exhibited a significant increase in
Isc in response
to 10 mM apical alanine addition (Fig. 7).
Again, the intestines exhibited regional differences, with the proximal
regions exhibiting the larger response. In all CF tissues, the
magnitude of response was approximately one-half to one-third that seen
in normal tissue (Fig. 7).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The capacity for intestinal
Cl secretion appears to be
present at birth. Robust Cl
secretory responses have been reported in normal neonatal rat intestine
(21). In the normal neonatal murine intestine,
Cl
(and possibly
HCO
3 to a much lesser extent) secretory responses to forskolin were detected in all three regions of
intestine studied (Fig. 2). Interestingly, it has been reported that
CFTR mRNA was not detected by Northern blot in the small intestine of
the 8-day-old mouse pup (8). The jejuna of the normal newborn mouse
does respond to forskolin with a secretory response (unpublished
observation). However, the forskolin response in the normal neonatal
mouse intestine may be reduced compared with the adult (12). As
expected, and as previously reported for all intestinal regions of the
adult CF mouse (14), the neonatal CF intestine was completely
unresponsive when stimulated by an agent that elevates cAMP (forskolin)
and induces Cl
secretion
via CFTR (Fig. 2).
Much of the published data suggest that intestinal epithelia possess
only one apical Cl channel,
CFTR (1, 3, 19). However, this is still controversial and some groups
suggest that intestinal epithelia may possess a separate apical
Ca2+-mediated
Cl
secretory pathway (26,
35). In intestinal tissue with functional CFTR, agents that increase
intracellular Ca2+ can induce
Cl
secretory responses. It
is thought that the mechanism is an agonist-induced increase in
intracellular Ca2+, which
activates a basolateral K+
conductance, hyperpolarizes the cell membrane, and increases the
driving force for Cl
secretion via CFTR (1, 3). Thus, in the absence of CFTR in intestinal
epithelia, Ca2+-mobilizing agents
would not be expected to induce
Cl
secretion. In all
regions of the normal neonatal mouse intestine studied (Fig. 3),
carbachol, a Ca2+-mobilizing
agent, induced Cl
secretion
(29, 33). It has been previously reported that, in the normal adult
mouse distal colon and jejunum, carbachol and bethanachol also induce a
Cl
secretory response (5,
12).
The neonatal CF ileum and proximal colon were, as expected, completely
unresponsive to carbachol (Fig. 3C).
However, in the distal colon of the neonatal CF mouse carbachol induced
an increase in
Isc that did not
differ significantly in magnitude from that of the normal neonatal
distal colon (Fig. 3, B and
C). It is speculated that this
response in CF distal colon is most likely due to a carbachol-induced
decrease in basal K+ secretion.
This inhibitory response could be mediated by the same intracellular
signaling mechanism by which carbachol induces Cl secretion (29), i.e.,
the Ca2+-induced increase in
basolateral K+ conductance
hyperpolarizes the apical membrane, thereby reducing the driving force
for K+ secretion.
For this hypothesis to be tenable, the distal colon must exhibit basal
K+ secretion. The aldosterone
levels in neonatal mice have been reported to be very high (6), and the
distal colon of the adult aldosterone-stimulated mouse exhibits
electrogenic K+ secretion (13).
Others have also reported electrogenic
K+ secretion by the distal colon
of aldosterone-stimulated rats (32). Furthermore, the neonatal rat
distal colon, subjected to high aldosterone levels,
exhibits a rate of electrogenic K+
secretion that is significantly greater than that seen in the adult
distal colon (22). In the aldosterone-stimulated CF adult murine colon,
the rate of electrogenic K+
secretion exceeds that of normal mice and the reversal of the polarity
of Isc after
amiloride treatment reflects the component of electrogenic
K+ secretion (13). In the CF
neonates, the postamiloride residual Isc was ~70%
greater (more negative) than that exhibited by the normal distal
colons. However, this difference was not significant. K+ secretion likely accounts for
the reversal of
Isc polarity in the amiloride-treated normal and CF neonatal distal colons (Fig. 5A). Further evidence that the CF
neonatal distal colon secretes K+
comes from the response to bumetanide. Bumetanide increased the magnitude of Isc
(postcarbachol) in the CF distal colons (Fig. 3,
B and
D), reflecting the drug-induced
inhibition of electrogenic K+
secretion (5, 22). The
Cl-dependent response in
the normal neonatal distal colon suggests that
Cl
secretion masks this
component of the carbachol response in these tissues. The failure of
the proximal colon and ileum of the CF neonate to exhibit the same
carbachol response as seen in the distal colon probably is due to the
low or absent spontaneous K+
secretion in these intestinal regions, even when aldosterone stimulated
(13).
The distal colon of the newborn mouse (24 h old) exhibited a substantial amiloride-sensitive Na+ absorption (Figs. 1 and 5). We have previously reported that the preterm (fetal) murine distal colon (~24 h before birth) also exhibited a significant amiloride-sensitive Isc (15). The magnitude of the fetal amiloride response was less than that exhibited by the newborn distal colon, which likely correlates with the higher aldosterone level in the neonatal pups (6) In the neonatal mouse, plasma aldosterone levels begin to rise significantly 2 days before birth and peak at birth, remaining well above the adult level for up to 2 wk after birth (6). In contrast to the neonatal distal colon, the distal colon of the adult mouse on a normal diet exhibits no or very little electrogenic amiloride-sensitive Na+ absorption (5, 13), likely reflecting the low levels of aldosterone in adult mice on a normal diet (13). In all species examined, including the human, electrogenic colonic Na+ absorption appears to correlate with a dramatic increase in serum aldosterone in the perinatal period (9, 17, 20, 23). In contrast to the distal colon, it has been reported that the neonatal human kidney is insensitive to amiloride (17, 25). Similar findings have been reported for the neonatal rat kidney (28), adding support to the hypothesis that, in the neonate, Na+ absorption by the colonic epithelia may play a relatively more important role in Na+ homeostasis than in the adult.
In the present study, there was no significant difference in the magnitude of the amiloride-sensitive Isc in the distal colon of normal and CF pups. These findings contrast with those from the aldosterone-stimulated adult mouse, in which we found that the CF distal colonic epithelia exhibited a significantly greater rate of electrogenic Na+ absorption than did normal colonic epithelia (13).
The proximal colon of neonatal mice exhibited a small but detectable amiloride-sensitive Isc that did not differ between the genotypes (Fig. 5). This finding contrasts with data from adult mice on a normal diet in which neither normal nor CF proximal colons exhibited an amiloride-sensitive Isc (13). In normal adult mice on a low-Na+ diet (high aldosterone), the proximal colon still exhibited no amiloride-sensitive Na+ transport (13), a finding similar to that reported for the adult rat (36). In contrast, the proximal colon of adult CF mice on a low-Na+ diet exhibited amiloride-sensitive electrogenic Na+ absorption (13).
The neonatal murine ileum from both CF and normal mice exhibited a small but measurable amiloride-sensitive Isc that did not differ between the two genotypes. Neither normal nor CF adult murine ileum (normal diet) exhibits a detectable amiloride-sensitive Isc (unpublished observations). No data are available on the amiloride response of the adult CF or normal mouse ileum stimulated by high levels of aldosterone.
In summary, in the neonatal mouse, it appears that amiloride-sensitive Na+ absorption is upregulated in the intestine in both the normal and CF pups compared with adult mice on a normal diet. This undoubtedly is primarily due to the high aldosterone levels measured in neonatal mice.
Electrogenic Na+-coupled glucose absorption is an important means of intestinal uptake of both Na+ and glucose. Although this cotransporter is thought to be principally expressed in the small intestine in adult mammals, the neonatal intestine appears to have a more widespread expression of functional cotransporter activity. Both the proximal colon and ileum of the newborn mouse exhibited electrogenic Na+-glucose cotransport (Fig. 6). In preterm and 2-day-old rat distal colon, glucose increased rectal PD, suggesting the presence of a functional Na+-glucose cotransporter at this site (24). However, after day 2, the response was lost (24). Similar findings were reported for the proximal colon of the newborn pig (16). The importance of the brush-border Na+-glucose cotransporter in the human neonate is evidenced by the profuse, fatal diarrhea that results from a mutation in the gene coding the cotransporter proteins (SGLT1) (37).
In the ileum of the neonatal CF mouse, Na+-glucose transport was found to be significantly less than in the normal neonatal ileum (Fig. 6). The data for adult CF mouse jejunal Na+-glucose transport relative to normal are conflicting. It has been reported that there was no significant difference in Na+-glucose cotransport between normal and CF adult intestine (11, 34). De Jonge et al. (7), however, have reported that in the adult CF murine jejunum Na+-glucose cotransport is decreased.
Electrogenic Na+-amino acid cotransport is primarily expressed in the small intestine (16). Interestingly, the absorptive capacity for amino acid has been found to be greater in the distal part of the small intestine (ileum) than in the more proximal region (10). Neonatal rabbit ileum (4) and porcine colon (16) have been reported to exhibit Na+-amino acid cotransport. Our data also indicate that the ileum of the normal neonatal mouse exhibits electrogenic Na+-alanine cotransport (Fig. 7). We also found that the neonatal CF intestine exhibited a significantly lower rate of Na+-alanine cotransport in the proximal and distal colon compared with normal intestine (Fig. 7).
In the rodent much of the Na+ that is absorbed by the intestine is coupled with either glucose or amino acids (21). The significantly decreased rate of Na+-glucose and -alanine cotransport in the CF intestine (especially if a similar decrease is reflected in the neonatal CF jejunum) may be one explanation as to the significantly slower weight gain in the CF pups compared with their normal counterparts (27). The mechanism by which Na+-nutrient cotransport in the neonatal intestine is diminished is not known. It has been reported that inflammation diminishes Na+-nutrient cotransport in the rabbit ileum (30, 31). Histological examination of neonatal CF intestine revealed no inflammation. However, newborn CF mouse pups exhibited distended, mucin-filled crypts in the ileum and excess mucus in the lumen of both the ileal and colonic regions (unpublished observation).
Data have been provided on the pattern of electrogenic
Na+ absorption and
Cl secretion across three
regions of the normal and CF neonatal murine intestine. In most CF
mouse models, there is a very high rate of death due to intestinal
problems during the first 3 days postbirth, with some strains of CF
mice exhibiting a >90% mortality during the neonatal period (18).
This high death rate correlates temporally with the high electrogenic
amiloride-sensitive Na+ absorption
(undoubtedly secondary to the elevated aldosterone levels) in the
colonic epithelia and to a lesser extent in the ileum. Electrogenic
Na+-nutrient cotransport (although
less than normal) is also well developed at birth, especially in the
proximal colon and ileum (and undoubtedly the jejunum) of the neonatal
CF mouse. Therefore, the two regions most vulnerable to blockage and
rupture exhibit a very high degree of electrogenic
Na+ absorption at birth. This high
rate of Na+ absorption, coupled
with the complete inability to secrete
Cl
in CF intestines, is
predicted to increase net isotonic volume absorption in this region in
CF and predispose the gut contents of these murine intestinal regions
to dessication, resulting in impaction, blockage, and rupture.
In conclusion, the present study provides data on neonatal murine
intestinal ion transport that demonstrate the feasibility of
physiological studies on the neonatal murine intestine. The capacity to
study the neonatal intestinal epithelium is useful to define phenotypic
alterations in intestinal ion transport of various transgenic and
knockout mouse models that may present as neonatal lethals and thus
preclude study of these mutations in adult intestine. Also, gut disease
affecting the neonate can be modeled and studied with these
preparations. Ion transport across the normal neonatal murine intestine
exhibits many similarities to the adult murine intestine, including
Cl secretion mediated by
both an increase in cAMP (forskolin) and an elevation of intracellular
Ca2+ (carbachol). In contrast to
the adult murine distal colon (normal diet), the neonatal distal colon
(normal and CF) exhibits a high rate of electrogenic
amiloride-sensitive Na+
absorption. In addition, the neonatal murine distal colon, proximal colon, and ileum (normal and CF) exhibit significant
Na+-nutrient cotransport. The
importance of these Na+-nutrient
cotransport pathways in the adult murine intestine has not been
investigated in these intestinal regions. However, these transport
pathways are significantly reduced in the proximal colon and ileum of
the CF neonate, compared with the
normal neonate, which may partially explain the lower rate of growth of
these CF pups. It is speculated that the various types of electrogenic Na+ transport in the colon and
ileum may be a variable that adds to the absence of cAMP or
Ca2+-regulated
Cl
secretion to predispose
the neonatal CF mouse to intestinal obstruction and rupture.
![]() |
ACKNOWLEDGEMENTS |
---|
The helpful comments and support of Dr. R. C. Boucher are gratefully appreciated.
![]() |
FOOTNOTES |
---|
This study was supported by National Heart, Lung, and Blood Institute Specialized Center of Research Grant HL-42384.
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 and other correspondence: B. R. Grubb, Cystic Fibrosis/Pulmonary Research and Treatment Center, 7011 Thurston-Bowles Bldg., CB 7248, The Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248 (E-mail: bgrubb{at}med.unc.edu).
Received 7 December 1998; accepted in final form 29 March 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Anderson, M. P.,
and
M. J. Welsh.
Calcium and cAMP activate different chloride channels in the apical membrane of normal and cystic fibrosis epithelia.
Proc. Natl. Acad. Sci. USA
88:
6003-6007,
1991[Abstract].
2.
Clarke, L. L.,
B. R. Grubb,
S. E. Gabriel,
O. Smithies,
B. H. Koller,
and
R. C. Boucher.
Defective epithelial chloride transport in a gene targeted mouse model of cystic fibrosis.
Science
257:
1125-1128,
1992[Medline].
3.
Clarke, L. L.,
B. R. Grubb,
J. R. Yankaskas,
C. U. Cotton,
A. McKenzie,
and
R. C. Boucher.
Relationship of a non-CFTR mediated chloride conductance to organ-level disease in cftr(/
) mice.
Proc. Natl. Acad. Sci. USA
91:
479-483,
1994[Abstract].
4.
Cooke, H. J.,
and
D. C. Dawson.
Transport characteristics of isolated newborn rabbit ileum.
Am. J. Physiol.
234 (Endocrinol. Metab. Gastrointest. Physiol. 3):
E257-E261,
1978
5.
Cuthbert, A. W.,
L. J. MacVinish,
M. E. Hickman,
R. Ratcliff,
W. H. Colledge,
and
M. J. Evans.
Ion-transporting activity in the murine colonic epithelium of normal animals and animals with cystic fibrosis.
Pflügers Arch.
428:
508-515,
1994[Medline].
6.
Dalle, M.,
J. Giry,
M. Gay,
and
P. Delost.
Perinatal changes in plasma and adrenal corticosterone and aldosterone concentrations in the mouse.
J. Endocrinol.
76:
303-309,
1978[Abstract].
7.
De Jonge, M. R.,
A. G. M. Bot,
I. Bronsveld,
B. Scholte,
J. Bijman,
and
M. Sinaasappel.
Reduced active and enhanced passive absorption of glucose across jejunal mucosa of cftr/
mice (Abstract).
Pediatr. Pulmonol. Suppl.
14:
245,
1997.
8.
De Lisle, R. C.,
M. Petitt,
K. S. Isom,
and
D. Ziemer.
Developmental expression of a mucinlike glycoprotein (MUCLIN) in pancreas and small intestine of CF mice.
Am. J. Physiol.
275 (Gastrointest. Liver Physiol. 38):
G219-G227,
1998
9.
Ferguson, D. R.,
P. S. James,
J. Y. F. Paterson,
J. C. Saunders,
and
M. W. Smith.
Aldosterone induced changes in colonic sodium transport occurring naturally during development in the neonatal pig.
J. Physiol. (Lond.)
292:
495-504,
1979[Abstract].
10.
Ganapathy, V.,
M. Brandsch,
and
F. H. Leibach.
Intestinal transport of amino acids and peptides.
In: Physiology of the Gastrointestinal Tract, edited by L. R. Johnson,
D. H. Alpers,
E. D. Jacobson,
J. Christensen,
and J. H. Walsh. New York: Raven, 1994, p. 1773-1794.
11.
Grubb, B. R.
Ion transport across the jejunum in normal and cystic fibrosis mice.
Am. J. Physiol.
268 (Gastrointest. Liver Physiol. 31):
G505-G513,
1995
12.
Grubb, B. R.
Ion transport across the murine intestine in the absence and presence of CFTR.
Comp. Biochem. Physiol. A Physiol.
188A:
277-283,
1997.
13.
Grubb, B. R.,
and
R. C. Boucher.
Enhanced colonic Na+ absorption in CF versus normal mice.
Am. J. Physiol.
272 (Gastrointest. Liver Physiol. 35):
G393-G400,
1997
14.
Grubb, B. R.,
and
S. E. Gabriel.
Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis.
Am. J. Physiol.
273 (Gastrointest. Liver Physiol. 36):
G258-G266,
1997
15.
Hummler, E.,
P. Barker,
C. Talbot,
Q. Wang,
C. Verdumo,
B. Grubb,
J. Gatzy,
M. Burnier,
J. D. Horisberger,
F. Beermann,
R. Boucher,
and
B. C. Rossier.
A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism (PHA-1).
Proc. Natl. Acad. Sci. USA
94:
11710-11715,
1997
16.
James, P. S.,
and
M. W. Smith.
Methionine transport by pig colonic mucosa measured during early post-natal development.
J. Physiol. (Lond.)
262:
151-168,
1976[Abstract].
17.
Jenkins, H. R.,
T. R. Fenton,
N. McIntosh,
M. J. Dillon,
and
P. J. Milla.
Development of colonic sodium transport in early childhood and its regulation by aldosterone.
Gut
31:
194-197,
1990[Abstract].
18.
Kent, G.,
R. Iles,
C. E. Bear,
L. J. Huan,
U. Griesenbach,
C. McKerlie,
H. Frndova,
C. Ackerley,
D. Gosselin,
D. Radzioch,
H. O'Brodovich,
L. C. Tsui,
M. Buchwald,
and
A. K. Tanswell.
Lung disease in mice with cystic fibrosis.
J. Clin. Invest.
100:
3060-3069,
1997
19.
Mall, M.,
M. Bleich,
M. Schuerlein,
J. Kuehr,
H. H. Seydewitz,
M. Brandis,
R. Greger,
and
K. Kunzelmann.
Cholinergic ion secretion in human colon requires coactivation by cAMP.
Am. J. Physiol.
275 (Gastrointest. Liver Physiol. 38):
G1274-G1281,
1998
20.
O'Loughlin, E. V.,
D. M. Hunt,
and
D. Kreutzmann.
Postnatal development of colonic electrolyte transport in rabbits.
Am. J. Physiol.
258 (Gastrointest. Liver Physiol. 21):
G447-G453,
1990
21.
Pacha, J.
Epithelial ion transport in the developing intestine.
Physiol. Res.
42:
365-372,
1993.
22.
Pacha, J.,
M. Popp,
and
K. Capek.
Potassium secretion by neonatal rat distal colon.
Pflügers Arch.
410:
362-368,
1987[Medline].
23.
Pacha, J.,
M. Popp,
and
K. Capek.
Amiloride-sensitive sodium transport of the rat distal colon during early postnatal development.
Pflügers Arch.
409:
194-199,
1987[Medline].
24.
Potter, G. D.,
and
S. M. Burlingame.
Glucose-coupled sodium absorption in the developing rat colon.
Am. J. Physiol.
250 (Gastrointest. Liver Physiol. 13):
G221-G226,
1986[Medline].
25.
Raux-Eurin, M. C.,
M. T. Pham-Huu-Trung,
D. Marrec,
and
F. Girard.
Plasma aldosterone concentrations during the neonatal period.
Pediatr. Res.
11:
182-185,
1977[Abstract].
26.
Rozmahel, R.,
M. Wilschanski,
A. Matin,
S. Plyte,
M. Oliver,
W. Auerbach,
A. Moore,
J. Forstner,
P. Durie,
J. Nadeau,
C. Bear,
and
L. Tsui.
Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor.
Nat. Genet.
12:
280-287,
1996[Medline].
27.
Snouwaert, J.,
K. K. Brigman,
A. M. Latour,
N. N. Malouf,
R. C. Boucher,
O. Smithies,
and
B. H. Koller.
An animal model for cystic fibrosis made by gene targeting.
Science
257:
1083-1088,
1992[Medline].
28.
Stephenson, G.,
M. Hammet,
G. Hadaway,
and
J. W. Funder.
Ontogeny of renal mineralocorticoid receptors and urinary electrolyte responses in the rat.
Am. J. Physiol.
247 (Renal Fluid Electrolyte Physiol. 16):
F665-F671,
1984[Medline].
29.
Strabel, D.,
and
M. Diener.
Evidence against direct activation of chloride secretion by carbachol in the rat distal colon.
Eur. J. Pharmacol.
274:
181-191,
1995[Medline].
30.
Sundaram, U.,
and
A. B. West.
Effect of chronic inflammation on electrolyte transport in rabbit ileal villus and crypt cells.
Am. J. Physiol.
272 (Gastrointest. Liver Physiol. 35):
G732-G741,
1997
31.
Sundaram, U.,
S. Wisel,
V. M. Rajendren,
and
A. B. West.
Mechanism of inhibition of Na+-glucose cotransport in the chronically inflamed rabbit ileum.
Am. J. Physiol.
273 (Gastrointest. Liver Physiol. 36):
G913-G919,
1997
32.
Sweiry, J. H.,
and
H. J. Binder.
Characterization of aldosterone-induced potassium secretion in rat distal colon.
J. Clin. Invest.
83:
844-851,
1989[Medline].
33.
Tabcharani, J. A.,
R. A. Harris,
A. Boucher,
J. W. L. Eng,
and
J. W. Hanrahan.
Basolateral K channel activated by carbachol in the epithelial cell line T84.
J. Membr. Biol.
142:
241-254,
1994[Medline].
34.
Van Doorninck, J. H.,
P. J. French,
E. Verbeek,
R. H. P. C. Peters,
H. Morreau,
J. Bijman,
and
B. J. Scholte.
A mouse model for the cystic fibrosis F508 mutation.
EMBO J.
14:
4403-4411,
1995[Abstract].
35.
Veeze, H. J.,
D. J. Halley,
J. Bijman,
J. C. de Jongste,
H. R. de Jonge,
and
M. Sinaasappel.
Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype.
J. Clin. Invest.
93:
461-466,
1994[Medline].
36.
Will, P. C.,
J. L. Lebowitz,
and
U. Hopfer.
Induction of amiloride-sensitive sodium transport in the rat colon by mineralocorticoids.
Am. J. Physiol.
238 (Renal Fluid Electrolyte Physiol. 7):
F261-F268,
1980[Medline].
37.
Wright, E. M.
The intestinal Na+/glucose cotransporter.
Annu. Rev. Physiol.
55:
575-589,
1993[Medline].