Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202
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ABSTRACT |
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Nitric
oxide (NO) inhibits transport in various nephron segments,
and the thick ascending limb of the loop of Henle (TALH) expresses NO synthase (NOS). However, the effects of NO on
TALH transport have not been extensively studied. We hypothesized that endogenously produced NO directly decreases NaCl transport by the TALH.
We first determined the effect of exogenously added NO on net chloride
flux (JCl). The
NO donor spermine NONOate (SPM; 10 µM) decreased
JCl from 101.2 ± 9.6 to 65.0 ± 7.7 pmol · mm1 · min
1,
a reduction of 35.5 ± 6.4%, whereas controls did not decrease over
time. To determine whether endogenous NO affects cortical TALH
transport, we measured the effect of adding the NOS inhibitor NG-nitro-L-arginine methyl ester
(L-NAME), the substrate
L-arginine (L-Arg), or its enantiomer
D-arginine
(D-Arg) on
JCl.
L-NAME and D-Arg did not alter
JCl; in contrast,
addition of 0.5 mM L-Arg decreased JCl by
40.2 ± 10.4% from control. The inhibition of chloride flux by 0.5 mM L-Arg was abolished by
pretreatment with L-NAME,
indicating that cortical TALH NOS is active, but production of NO is
substrate-limited in our preparation. Furthermore, cortical TALH
chloride flux increased following removal of 0.5 mM
L-Arg from the bath, indicating
that the reductions in chloride flux observed in response to
L-Arg are not the result of
NO-mediated cytotoxicity. We conclude that
1) exogenous NO decreases cortical TALH JCl;
2) cortical TALHs produce NO in the
presence of L-Arg, which
decreases JCl;
and 3) the response of cortical
TALHs to L-Arg is reversible in
vitro. These data suggest an important role for locally produced NO,
which may act via an autocrine mechanism to directly affect TALH sodium
chloride transport. Thus TALH NO synthesis and inhibition of chloride
transport may contribute to the diuretic and natriuretic effects of NO
observed in vivo.
nitric oxide synthase; arginine; kidney; loop of Henle
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INTRODUCTION |
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RECENT STUDIES INDICATE that renal nitric oxide (NO) is an important controller of urinary sodium excretion. NO may enhance natriuresis by inhibiting transport along the nephron as well as altering renal hemodynamics and glomerular filtration rate (GFR) (26). Several in vivo studies support the hypothesis that NO exerts direct tubular effects on sodium excretion by demonstrating that it increases when NO production is stimulated (15) and decreased when NO synthase (NOS) is inhibited (14) in the absence of changes in renal hemodynamics. In humans, stimulation of NO synthesis with L-arginine increased urinary sodium excretion (12). Moreover, in dogs intrarenal bradykinin infusion caused natriuresis and diuresis in the absence of alterations in GFR and renal blood flow (14). The increase in urinary sodium excretion was prevented by pretreatment with the NOS inhibitor NG-monomethyl-L-arginine, indicating that the renal excretory response was likely mediated by NO. Conversely, inhibition of renal NOS with intrarenal N G-nitro-L-arginine methyl ester (L-NAME) inhibited pressure natriuresis without changing GFR (18), whereas chronic renal medullary infusion of L-NAME promoted sodium and water retention (21). These findings indicate that NO plays an important role in the control of urinary sodium excretion, although they do not address whether NO exerts direct effects on nephron transport.
Functional studies also indicate that NO directly affects sodium and water absorption. Roczniak and Burns (27) demonstrated that NO inhibits amiloride-sensitive sodium entry in proximal tubule cells, whereas our laboratory has found that NO inhibits both sodium absorption (29) and osmotic water permeability (6) in the cortical collecting duct. Taken together, the previous findings support a functional role for locally produced NO in the regulation of nephron sodium and water homeostasis.
Indirect evidence supports the tubular existence of NOS, and hence NO production. NOS mRNA has been detected with RT-PCR in various nephron segments including the glomeruli, proximal tubules, thick ascending limb of the loop of Henle (TALH), and the cortical and inner medullary collecting ducts (23). Tojo et al. (31) reported preliminary data demonstrating immunoreactivity in cortical collecting ducts of normal rats and later described positive immunolabeling of constitutively expressed NOS in the TALH (32). More recently, NOS protein expression has been demonstrated in the inner and outer medulla using Western blots (22).
Currently, the effects of NO on TALH transport have not been extensively studied. We hypothesized that endogenous NO, acting as an autacoid, decreases sodium chloride absorption in the TALH. Our findings indicate that exogenous and endogenous NO inhibits chloride absorption in isolated perfused TALHs.
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METHODS |
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Preparation of isolated nephron segments. Cortical TALHs were obtained from male Sprague-Dawley rats weighing 120-150 g (Charles River Breeding Laboratories, Wilmington, MA) which had been maintained on a diet containing 0.22% sodium and 1.1% potassium (Purina, Richmond, IN) with water provided ad libitum for at least 5 days. On the day of the experiment, rats were anesthetized with ketamine (100 mg/kg body wt ip) and xylazine (100 mg/kg body wt ip), and the abdominal cavity was opened to expose the kidney. The kidney was bathed in ice-cold saline and removed. Coronal slices were cut and placed in oxygenated physiological saline at 12°C. Cortical TALHs were dissected from medullary rays in the same solution under a stereomicroscope.
TALH perfusion. Cortical TALHs
(ranging from 0.5 to 0.75 mm in length) were transferred to a
temperature-regulated chamber and perfused between concentric glass
pipettes at 37°C as described previously (N. H. Garcia, B. A. Stoos, and J. L. Garvin, unpublished observations). The
composition of the basolateral bath and perfusate was (in mM) 114 NaCl,
25 NaHCO3, 2.5 NaH2PO4,
4 KCl, 1.2 MgSO4, 6 alanine, 1 trisodium citrate, 5.5 glucose, 2 calcium dilactate, and 5 raffinose. The solution was bubbled with 5%
CO2-95%
O2 before and during the
experiment, and the pH of the bath was 7.4. The osmolality of the bath
solution was 290 ± 3 mosmol/kgH2O as
measured by freezing-point depression. The basolateral bath was
exchanged at a rate of 0.5 ml/min, and tubules were perfused between
5-10 nl · mm1 · min
1.
Time control experiments were conducted for each protocol to determine
the stability of tubular transport.
Net chloride flux. The effects of an NO donor, 1,3-propanediamine, N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]-butyl]C10H26N6O2 (spermine NONOate; Cayman Chemical, Ann Arbor, MI), an NOS inhibitor, L-NAME (Sigma Chemical, St. Louis, MO), and the substrate for NOS, L-arginine and its isomer D-arginine (Sigma Chemical), were tested on net chloride flux in isolated perfused TALHs.
Spermine NONOate (SPM) spontaneously decomposes in aqueous solution at physiological pH with the resultant liberation of NO (20). Previous computer simulations in our laboratory using the CHEMKIN program (4) have determined that 10 µM SPM results in an immediate bath concentration of 80-90 nM NO, which declines over a 40-min period to 50-60 nM (6).
The typical experimental protocol was as follows. After a control period consisting of three basal measurements, one of the compounds was then added to the bath. Twenty minutes later, three additional collections were made. SPM, L-Arg, D-Arg, and L-NAME were added to the bath as indicated in the text. In one series of experiments, L-Arg was present in the bath solution during the control period, and was then removed to determine recovery of chloride flux following exposure to endogenous NO. Chloride concentrations were determined in samples of perfusate and collected fluid using a fluorometric technique that has been described in detail elsewhere (5). Briefly, nanoliter samples of tubular fluid, perfusion solution, or NaCl standards were drawn into calibrated glass micropipettes and injected into a stream of an aqueous solution containing a chloride-sensitive dye, 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ; Molecular Probes, Eugene, OR). The solution passes by a photomultiplier tube, which causes the dye to fluoresce, and the chloride in the injected sample quenches the fluorescence of the dye. The resulting deflection from baseline is proportional to the chloride concentration of the injected sample and is recorded on a standard chart recorder. The resolution of this assay is 2-3 mM of NaCl.
Because chloride reabsorption was not accompanied by significant fluid reabsorption, net chloride flux (JCl) was calculated according to the formula
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Statistics. Experimental results are expressed as mean ± SE. Data were evaluated with a Student's paired t-test. The criterion for statistical significance was P < 0.05 in all experiments.
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RESULTS |
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Figure 1 illustrates the effect of the NO
donor SPM (10 µM) on chloride flux in seven isolated thick ascending
limbs. During the control period, tubules absorbed chloride at a rate
of 101.2 ± 9.6 pmol · mm1 · min
1.
After the tubules were treated with 10 µM SPM, they absorbed chloride
at a rate of 65.0 ± 7.7 pmol · mm
1 · min
1.
Perfusion rates did not differ during the two periods. Time controls
showed no reduction in chloride absorption over a 2-h period. Thus 10 µM SPM inhibited chloride flux by 35.5 ± 6.4% (P < 0.01).
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The TALH has been reported to contain NOS (1, 23). Thus we hypothesized
that TALH NOS is active and that the resulting NO inhibits chloride
transport. To test this, we examined the effect of
L-NAME on TALH chloride
absorption. Figure 2 illustrates the effect
of 5 mM L-NAME on chloride flux
in five isolated TALH segments. Initially, tubules absorbed chloride at
a rate of 60.0 ± 10.4 pmol · mm1 · min
1.
After adding 5 mM L-NAME to the
bath, TALH chloride absorption was not significantly different from
control (63.2 ± 18.4 pmol · mm
1 · min
1;
n = 5). Thus in vitro inhibition of
NOS in the TALH does not appear to affect chloride absorption.
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The finding of NOS in the TALH was inconsistent with
L-NAME's apparent lack of
effect on TALH chloride transport. However, our bath and perfusion
solutions do not normally contain
L-Arg, the substrate for NOS.
Therefore, the possibility existed that thick ascending limb NOS
activity is substrate-limited in vitro. We next examined the effects of
L-Arg on chloride absorption in isolated TALHs. Figure 3 illustrates the
effects of 0.5 mM L-Arg on
chloride flux in six isolated TALHs. During the control period, tubules
absorbed chloride at a rate of 86.7 ± 19.5 pmol · mm1 · min
1.
After the tubules were treated with 0.5 mM
L-Arg, they absorbed chloride at
a rate of 38.6 ± 7.5 pmol · mm
1 · min
1.
To determine whether the inhibitory effects of arginine were specific to the L-isomer, we
next evaluated the effects of
D-Arg on TALH
JCl. During the
control period, tubules absorbed chloride at a rate of 60.5 ± 14.3 pmol · mm
1 · min
1.
Similarly, after the tubules were treated with 0.5 mM
D-Arg, they absorbed chloride at
a rate of 60.3 ± 10.8 pmol · mm
1 · min
1
(n = 5). Thus addition of 0.5 mM
L-Arg to the bath inhibited chloride absorption in isolated TALHs by 40.2 ± 10.4%
(P < 0.02), indicating that the
transport-inhibiting effects of arginine are specific for the
L-isomer and that thick
ascending limb NOS is constitutively active and substrate-limited in
vitro.
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Because L-Arg may have decreased
TALH chloride absorption by an NOS-independent mechanism, we examined
whether the effects of L-Arg on
TALH chloride absorption could be inhibited by
L-NAME. Figure
4 illustrates the effects of 0.5 mM
L-Arg on chloride flux in
L-NAME-treated (5 mM) tubules.
In contrast to L-Arg treatment alone, 0.5 mM L-Arg had no
significant effect on chloride absorption by TALHs pretreated with
L-NAME (change of 10.9 ± 11.8 pmol · mm1 · min
1).
These experiments indicate that NOS inhibition prevented
L-Arg-induced reduction of TALH
chloride transport by blocking production of NO from exogenous
L-Arg.
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NO has been demonstrated to exert cytotoxic effects. To examine the
possibility that the reduction in transport observed with SPM and
L-Arg was not secondary to
cytotoxic effects of NO, we evaluated the ability of cortical TALHs to
increase chloride flux following recovery from NO production. Figure
5 illustrates the effects of removing 0.5 mM L-Arg from the bath. During
the initial period in the presence of 0.5 mM
L-Arg, tubules absorbed chloride at a rate of 41.3 ± 7.4 pmol · mm1 · min
1.
Thirty minutes following removal of 0.5 mM
L-Arg from the bath, they
significantly increased chloride flux to a rate of 68.2 ± 8.0 pmol · mm
1 · min
1
(P < 0.05). These findings indicate
that the reductions in chloride flux observed in response to 0.5 mM
L-Arg administration were not
secondary to cytotoxic effects of NO.
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DISCUSSION |
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We believe this is the first study to show that 1) exogenous NO inhibits chloride absorption in the rat cortical TALH and 2) this segment expresses NOS, which in turn can produce NO and thereby decrease JCl. The finding of NO-induced reductions in TALH JCl agrees with previous reports from our laboratory and others demonstrating an inhibitory effect of NO on sodium and water absorption in other nephron segments, including the proximal convoluted tubule (27), cortical collecting ducts (29), and inner medullary collecting ducts (30).
Our current findings support in vivo data which suggest that renal NO exerts direct effects on urinary sodium excretion. Previous investigators have demonstrated that when NO synthesis inhibitors are administered intrarenally, they lower urinary sodium excretion (18, 21, 30), whereas intrarenal administration of NO donors induce natriuresis (19), and agents which stimulate NO synthesis produce natriuresis without affecting GFR (2, 14). These data suggest that NO exerts direct tubular effects to regulate sodium excretion. The current data indicate that at least part of the tubular effect may reside in the TALH, where NO inhibits chloride and presumably sodium absorption.
The TALH is critical in the control of sodium excretion, absorbing ~25% of the filtered load of sodium (13). The TALH is impermeable to water, and thus absorption of salt by this nephron segment both establishes and maintains the hypertonic medullary solute gradient as well as generating dilute tubular fluid (11, 24). Therefore, factors that directly alter TALH sodium chloride absorption may have potent effects on urinary sodium chloride excretion and concentrating ability. Our findings indicate that nanomolar concentrations of NO likely exert a direct influence on TALH absorptive function and that NO plays an important role in the maintenance of normal body fluid balance.
The specific NOS isoform(s) active in the TALH under the conditions of the present studies is unknown. However, our data demonstrating inhibition of chloride absorption with L-Arg, and the attenuation of this response with L-NAME, indicate that the NOS isoform involved is constitutively active. Previous investigators have demonstrated that the so-called constitutively expressed NOS isoforms [i.e., endothelial (eNOS) and neuronal (nNOS)] require increases in intracellular calcium to become activated (33). In contrast, inducible NOS (iNOS) does not require an increase in intracellular calcium to become activated (33). In our preparation, it is unlikely that the intracellular calcium concentration was elevated to levels above those normally occurring in unstimulated cells in vivo, which suggests that the NOS mediating the conversion of L-Arg to NO in the TALH was not eNOS or nNOS. If iNOS is mediating this response, then it would support the findings of previous investigators who detected the transcript for a constitutively active iNOS isoform in the TALH (23).
The mechanism by which NO inhibits chloride absorption in the TALH is currently unknown. NO has been shown to act via a variety of second messenger cascades, although most of its effects are mediated by cGMP (3). In particular, NO-induced natriuresis is linked to cGMP production in the kidney (10). Our laboratory has previously shown that NO increases cGMP in collecting duct cells by activating soluble guanylate cyclase (28) and that NO increases cGMP in the TALH (N. H. Garcia, B. A. Stoos, and J. L. Garvin, unpublished observations). We have also shown that NO inhibits transport of water in the cortical collecting duct by stimulation of cGMP-dependent protein kinase (7). Neant and Bailly (25) reported that cGMP inhibits TALH chloride absorption. Thus it is possible that NO inhibits transport in the TALH via stimulation of soluble guanylate cyclase with a resultant increase in cGMP. We have previously demonstrated that NO stimulates activation of cGMP-dependent protein kinase in cortical collecting ducts (7). The Na-K-2Cl cotransporter, Na-K-ATPase, apical K channel, or basolateral Cl channels could be directly phosphorylated by this enzyme and in turn directly or indirectly decrease chloride transport.
In this regard, Lu et al. (16, 17) used patch-clamp techniques and determined that NO stimulates apical TALH K+ channels, which these authors suggested would increase TALH transport. Any discrepancies between the current findings and those of Lu et al. (16, 17) may be attributed to the multiple intracellular effects of NO and the different techniques used in the two studies. Because the current studies directly measured transepithelial chloride flux, we believe the net effect of endogenously produced NO is inhibition of the Na-K-2Cl cotransporter, whereas increases in K+ channel activity are likely secondary effects caused by concentration-dependent effects of NO to affect changes in intracellular pH or Ca2+ concentrations. Further studies will be required to elucidate the mechanism, signal transduction cascade, and intracellular effectors that mediate the effects of NO on TALH transepithelial chloride transport.
In summary, we have found that exogenous NO inhibits chloride absorption by the isolated perfused TALH. The inhibition of chloride transport is mimicked by the basolateral administration of L-Arg and inhibited by L-NAME, indicating that the TALH is capable of producing NO under unstimulated conditions, and this NO inhibits transport via an autocrine mechanism. The involvement of locally produced NO to act via an autocrine mechanism is supported by the reversibility of the response following the removal of substrate. Furthermore, the ability of tubules to increase chloride flux following removal of L-Arg indicates that reductions in transport observed with NO donors or L-Arg is not secondary to any cytotoxic effects of NO. The requirement for exogenous L-Arg suggests that the TALH NOS is substrate-limited in vitro. The effect of NO on TALH chloride absorption may partially explain the effects of NO to increase urinary sodium excretion in vivo.
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ACKNOWLEDGEMENTS |
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Portions of this work were conducted during the tenure of an American Heart Association Fellowship Grant awarded to C. F. Plato.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL28-982 and HL02-891.
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: J. L. Garvin, Division of Hypertension and Vascular Research, Dept. of Internal Medicine, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, MI 48202.
Received 27 May 1998; accepted in final form 1 October 1998.
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