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Departments of Physiology and Biophysics/Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present experiments were carried out to investigate the role of endogenously produced NO in modulating renal function during postnatal maturation under physiological conditions. In conscious, chronically instrumented lambs aged ~1 (n = 8) and ~6 wk (n = 8) of postnatal life, various parameters of glomerular and tubular function were measured for 1 h before and 1 h after intravenous injection of 20 mg/kg of NG-nitro-L-arginine methyl ester (L-NAME; experiment 1) or its inactive isomer D-NAME (experiment 2). After administration of L-NAME to 1-wk-old lambs, glomerular filtration rate (GFR) and filtration factor (FF) decreased by ~50% at 20 min, remaining decreased at 60 min. In 6-wk-old lambs, GFR and FF remained constant after L-NAME. Proximal fractional Na+ reabsorption decreased after L-NAME administration to lambs aged 6 wk, resulting in a prompt natriuresis; this was sustained for 60 min. There were no effects of L-NAME on proximal fractional Na+ reabsorption in 1-wk-old lambs. In 6-wk-old lambs, urinary flow rate increased by ~500%, free water clearance increased by ~50%, and urinary osmolality decreased by ~60% after L-NAME administration; no effects on these variables were measured in 1-wk-old lambs. The diuresis after L-NAME administration to 6-wk-old lambs was unaccompanied by any changes in plasma levels of arginine vasopressin. There were no effects of D-NAME on any of the measured variables. We conclude that endogenously produced nitric oxide modulates glomerular and tubular function in an age-dependent manner.
newborn; perinatal; nitric oxide; renal function; glomerular filtration rate; sodium excretion; plasma renin activity; endothelin-1; arginine vasopressin; renal vascular resistance
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE ENDOTHELIUM-DERIVED RELAXING FACTOR, nitric oxide (NO), is synthesized in various tissues in the body under basal conditions and normally influences a variety of physiological processes. Through its effects on vascular smooth muscle, NO is involved in the maintenance of organ blood flow, thereby influencing blood pressure. In addition, NO modulates renal hemodynamics and function, possesses immunomodulatory as well as cytotoxic effects, and may act as a neurotransmitter in the central nervous system. NO production is regulated by NO synthase (NOS), of which there are three different isoforms: endothelial (eNOS) and neuronal (nNOS) isoforms are constitutive, whereas the third isoform is inducible (iNOS).
In previous studies carried out in conscious, chronically instrumented lambs, we provided evidence that some of the physiological effects of NO produced by the constitutive isoforms of NOS are developmentally regulated (30-32). For example, administration of the L-arginine analog, NG-nitro-L-arginine methyl ester (L-NAME), which competitively inhibits both n- and eNOS isoforms, is associated with an increase in mean arterial pressure (MAP) in 1- and 6-wk-old lambs that is similar in both age groups; the concomitant decrease in heart rate (HR) is, however, greater at 1 than at 6 wk of age (31). Furthermore, by directly assessing the parameters governing the arterial baroreflex control of HR, we have demonstrated that NO normally modulates the HR range over which the arterial baroreflex operates at 1 but not at 6 wk of age in conscious lambs (32).
We also showed that the ability of the renal vasculature to produce NO for the same stimulus is greater at 1 than at 6 wk of postnatal life in conscious lambs (29). The role of endogenously produced NO in modulating renal hemodynamics is also greater in lambs aged 1 wk compared with 3- and 6-wk-old lambs (31). Furthermore, the renal distribution of NOS is also developmentally regulated. For example, Solhaug et al. (35) measured renal nNOS mRNA gene expression in piglets and adult pigs and observed a greater nNOS mRNA in immature compared with mature kidneys. In guinea pigs, Thompson and Weiner (37) found that NOS activity increased during fetal life to reach maximal levels in the newborn kidney, decreasing thereafter. Fischer et al. (11) investigated the postnatal development of nNOS in the kidney of rats and found that it follows a corticomedullary pattern, ranging from single cell expression in the immature nephron to its full presence in the macula densa of nephrons in the mature kidney; the strongest NOS signals were seen in the distal tubule at day 6 and in the afferent arteriole by day 2 of postnatal life (11). This suggests that NO may play a predominant role in modulating glomerular function during early growth and development, at a time when circulating levels of ANG II are high, renal vascular resistance (RVR) is elevated, and renal perfusion is low. To date, the role of NO in modulating renal function under physiological conditions during postnatal maturation has not been investigated.
Therefore, the objective of the present experiments was to investigate the role of endogenously produced NO in modulating glomerular and tubular function during postnatal maturation under physiological conditions. To this end, the effects of L-NAME, as well as its inactive isomer D-NAME, on various parameters of glomerular and tubular function were measured in conscious, chronically instrumented lambs aged 1 and 6 wk. To provide us with information regarding secondary or indirect effects of L-NAME, cardiovascular and endocrine responses were also measured.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed in two groups of conscious, chronically instrumented sheep aged 1 wk (8 ± 1 days; 6.3 ± 0.4 kg body wt; n = 8) and 6 wk (40 ± 2 days; 11.6 ± 1.5 kg body wt; n = 8) at the time of study. Lambs were obtained from a local source (AndLyn Ranch, Alberta, Canada) and housed with their mothers in individual pens in the vivarium of the Health Sciences Centre of the University of Calgary, except during training, surgery, and experiments. All surgical and experimental procedures were carried out in accordance with the "Guide to the Care and Use of Experimental Animals" provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.
Surgical procedures. Surgery was performed on lambs aged 2-5 days (for experiments at ~1 wk) and 35-38 days (for experiments at ~6 wk) using aseptic techniques as previously described (29, 30). Anesthesia was induced with a mask and halothane (3-4%) in oxygen, the trachea was intubated, and anesthesia was maintained by ventilating the lungs with halothane (0.5-1%) in a mixture of nitrous oxide and oxygen (3:2).
Catheters were inserted into left and right femoral veins and arteries (PE-160, Intramedic), advanced to the inferior vena cava and abdominal aorta for later intravenous infusions, arterial sampling, and pressure measurements, and tunneled subcutaneously to exit the lamb on right and left flanks. By means of an abdominal midline incision, the bladder was then exposed, and a catheter was inserted directly across the bladder wall using a specially adapted feeding tube (8 Fr, Medi-Craft) for continuous collection of urine and measurement of urinary flow rate during experiments. Through a right flank incision, the right renal artery was carefully dissected free of tissue, and a precalibrated ultrasonic flow transducer was placed around the renal artery (3-4S, Transonics Systems, Ithaca, NY) as previously described (29, 30) for measurement of renal blood flow (RBF). Upon closure of incisions, all catheters and the flow transducer cable were secured in a body jacket (Lomir, Montreal, Canada) for safe storage between experiments. Antibiotics (5.0 mg/kg enrofloxacin, Baytril) were administered intramuscularly at surgery and at 12-h intervals thereafter for 48 h. Lambs were allowed to recover from surgery in a critical care unit for small animals (Shor-line, Schroer Manufacturing), with adjustable oxygen supply. All lambs were able to stand within 60 min of completion of surgery, at which time they were returned to the vivarium. Experiments were not begun until at least 3 days had elapsed after the day of surgery. During this period, animals were trained to rest comfortably in a supportive sling in the laboratory environment.Experimental procedures.
Two experiments were carried out in each animal at intervals of
24-48 h and in random order. On the day of an experiment, each
lamb was removed from the vivarium and placed in a supportive sling in
the laboratory environment for at least 60 min. During this time, the
bladder was allowed to drain. A priming dose of [14C]inulin (0.5 µCi/kg) in dextrose was injected
intravenously followed by constant intravenous infusion at 0.25 µCi · kg
1 · h1 (0.5 ml · kg1 · h1) for later
measurement of glomerular filtration rate (GFR). An intravenous
infusion of 5% dextrose in 0.9% sodium chloride was started at a rate
of 4.17 ml · kg1 · h1 and
continued for the duration of the experiment to assist in maintaining
fluid balance. Lithium chloride was injected intravenously as a bolus
of 200 µmol/kg for later determination of proximal tubular
Na+ reabsorption, according to the methods described by
Thomsen et al. (39) and Lumbers et al. (23).
Arterial and venous catheters were connected to pressure transducers
(Statham, P23Db, West Warwick, RI) for measurement of arterial and
venous pressures; the flow transducer cable was connected to a flow
meter (Transonics Systems) for measurement of RBF. Pressures and RBF
were recorded continuously onto a polygraph (Grass Instruments, model
7, West Warwick, RI) and simultaneously to an IBM personal computer at
200 Hz using the data-acquisition and analysis software CVSOFT (Odessa
Systems, Calgary, Alberta, Canada).
70°C for later determination of urinary electrolytes (Na+, K+,
Li+) and urinary osmolality. Arterial blood (2.5 ml) was
also removed at the end of each urinary collection period for immediate
measurement of Hct. The remaining blood was centrifuged, and
supernatant was removed and stored at 70°C for later determination
of plasma electrolytes (Na+, K+,
Li+) and plasma osmolality. Additional blood (12 ml) was
removed at 30 min during control measurements and 20 and 60 min after administration of L-NAME or D-NAME for later
measurement of plasma renin activity (PRA) and plasma levels of
arginine vasopressin (AVP) and endothelin-1 (ET-1). Removed blood was
replaced with previously harvested maternal blood to avoid any
hemodynamic effects of sampling.
At the end of the first experiment, lambs were returned to the vivarium
where they were housed with their mothers until the second experiment
24 to 48 h later. At the end of the second experiment, lambs were
administered a lethal dose of pentobarbital sodium and on
postmortem examination, placement of catheters was verified, and the
zero offset of the flow transducer was determined; right and left
kidneys were removed and immediately weighed.
Analytic procedures. Urinary and plasma [14C]inulin levels were measured immediately after each experiment by liquid scintillation (Wallace 1410, Turku, Finland). Urine and plasma samples were later thawed to room temperature, and urinary and plasma electrolytes (Na+, K+, Li+) and osmolalities were measured using a flame photometer (IL-943, Lexington, MA), and micro-osmometer (Advanced Instruments model 3MO, Needham Heights, MA), respectively. Hematocrit (Hct) was determined in duplicate using a microhematocrit centrifuge (Clay Adams, Parsippany, NJ) and careful measurements using calipers and the methods of Brace (7). PRA and plasma levels of AVP and ET-1 were later determined on thawed plasma samples using standard radioimmunoassay procedures (15, 28, 33).
Computations.
GFR was calculated as the clearance of [14C]inulin.
Fractional reabsorption (FR) of electrolytes (x) was determined as the
ratio of electrolyte clearance (Cx) to GFR as follows:
FRx (%) = [1(Cx/GFR)]×100. Proximal
tubular Na+ reabsorption was assumed equal to fractional
Li+ clearance (CLi/GFR), because
Li+ is reabsorbed parallel to Na+ and water and
exclusively by the proximal tubule (39). Limitations to
the Li+ clearance method include 1) impairment
of tubular Na+ reabsorption at high plasma Li+
concentrations and 2) Li+ reabsorption by distal
nephron segments in the presence of Na+ depletion
(38). To avoid these limitations, plasma Li+
levels were kept <0.3 mmol/l and all animals were administered a
continuous intravenous infusion of 5% dextrose in 0.9% sodium chloride throughout the study. Free water clearance
(CH2O) was calculated as the difference
between urinary flow rate (V) and osmolar clearance. Filtration
fraction (FF) was determined as GFR/RPF, where RPF (ml/min) = [1(RBF×Hct)]. The transtubular K+ gradient (TTKG) was
calculated as
UK+/PK+/(UOsm/POsm).
MVP)/RBF, where MVP is mean venous pressure. Cardiovascular variables were averaged over consecutive 20-min intervals using a
spreadsheet (Excel, Microsoft Office).
Statistical analyses.
Because values obtained during the three consecutive control 20-min
periods were similar, these were averaged to one value (Control).
Changes from Control were evaluated using SPSS for Windows (version
10.0) and ANOVA procedures for repeated measures over time, factors
being age (1 wk, 6 wk) and drug (L-NAME,
D-NAME). Where the F value was significant, a
Newman-Keuls multiple comparison procedure was applied to determine
where the significant difference(s) occurred. Significance was accepted
at the 95% confidence interval. All values in the text, including
data in Figs. 1-4 and Tables 1-4 are presented as means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiovascular effects of L-NAME. Baseline mean and DAP, MVP, and RBF were higher in 6- than 1-wk-old lambs; HR and RVR were lower in 6- than 1-wk-old lambs (Table 1).
There was an increase in MAP 20 min after L-NAME administration (P < 0.001) that was similar in both age groups (P > 0.05; Table 1) and resulted from changes in both systolic arterial pressure and diastolic arterial pressure in both age groups (Table 1). Mean venous pressure remained unaltered after L-NAME administration in both age groups of lambs. HR decreased within 20 min of L-NAME administration in both age groups (P < 0.001) and remained below control levels at 60 min; this decrease in HR was greater in 1- than in 6-wk-old lambs (P < 0.001; Table 1). RVR increased within 20 min of L-NAME administration to both age groups (P < 0.001) and was accompanied by a decrease in RBF (P < 0.001). Both the increase in RVR and the accompanying decrease in RBF after L-NAME administration were greater in lambs aged 1 wk compared with 6 wk (P < 0.001; Table 1) and were sustained for at least 60 min at 1 wk but not 6 wk (Table 1).Renal effects of L-NAME. Baseline RPF, GFR, UNaV, and UKV were lower in lambs aged 1 wk compared with lambs aged 6 wk (Table 2).
GFR and FF decreased by ~50% within 20 min of L-NAME administration to 1-wk-old lambs (P < 0.001) and remained below control levels for at least 60 min (Fig. 1). GFR and FF remained constant after L-NAME administration to 6-wk-old lambs (Fig. 1). There were no significant effects of L-NAME on RPF at 1 or 6 wk of age (Fig. 1). In 6-wk-old lambs, fractional Na+ reabsorption decreased within 20 min of L-NAME administration (Table 3); this resulted from a decrease in proximal fractional Na+ reabsorption at 20 min from 80.8 ± 4.4 to 60.9 ± 12.0% as well as an increase in distal fractional Na+ reabsorption from 19.0 ± 4.2 to 35.7 ± 11.0%. In 1-wk-old lambs, there were no significant effects of L-NAME on fractional Na+ reabsorption, and proximal and distal Na+ reabsorptions remained constant at 61.2 ± 12.4 and 36.0 ± 11.4%, respectively. Fractional K+ reabsorption also decreased in 6-wk-old lambs, but not 1-wk-old lambs (Table 3). Age-dependent effects of L-NAME were also evident in Na+ and K+ clearances (Table 3). In addition, within 20 min of L-NAME administration, there was an increase in the urinary Na+-to-K+ ratio and the TTKG in lambs aged 6 wk but not 1 wk (Table 3); these effects were sustained for 60 min. There were no significant effects of L-NAME on urinary flow or Na+ or K+ excretion rates in lambs aged 1 wk despite a marked and sustained diuresis, natriuresis, and kaliuresis in 6-wk-old lambs (Fig. 2). There were also no significant effects of L-NAME on CH2O or UOsm in lambs aged 1 wk. In 6-wk-old lambs, there was an increase in CH2O by 40 min and a further increase at 60 min (Fig. 3). UOsm decreased within 20 min of L-NAME administration and remained decreased at 60 min (Fig. 3).Effects of L-NAME on plasma and whole blood measurements. Effects of L-NAME on plasma Na+ and K+ levels, plasma osmolality, and Hct are shown in Table 4.
In both groups of lambs, PRA decreased 20 min after L-NAME and remained below control levels at 60 min (Fig. 4), whereas plasma levels of AVP and ET-1 remained constant after L-NAME administration (Fig. 4).Physiological effects of D-NAME. D-NAME had no effects on any of the measured or calculated variables in either age group of lambs.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present experiments were carried out to investigate the renal effects of endogenously produced NO during postnatal maturation by measuring glomerular and tubular responses to L-NAME in conscious lambs age 1- and 6 wk of life. Novel findings of our studies are as follows: L-NAME administration was associated with 1) a ~50% decrease in GFR and FF in 1- but not 6-wk-old lambs, 2) a decrease in proximal Na+ reabsorption and total fractional Na+ and K+ reabsorption leading to a natriuresis and kaliuresis in 6- but not 1-wk-old lambs, 3) a diuresis accompanied by an increase in CH2O and a decrease in UOsm at 6 wk but not 1 wk. These data provide new evidence that the glomerular and tubular effects of endogenously produced NO are developmentally regulated under physiological conditions.
We also previously reported age-dependent effects of L-NAME on HR (31). These observations were also confirmed in the present study and can be explained by our recent findings that NO modulates the arterial baroreflex control of HR in an age-dependent manner (32). We also recently measured (30, 31) dose-dependent effects of endogenously produced NO on RVR and demonstrated that NO modulates RVR under physiological conditions in young lambs. In response to administration of L-NAME, there was a pronounced increase in RVR in lambs aged 1, 3, and 6 wk of age, although the magnitude of this effect was greatest at 1 wk compared with 3 and 6 wk (31). These findings provided evidence that the role of NO in modulating renal vascular tone under physiological conditions predominates early in life. This age-dependent effect of L-NAME on RVR was confirmed in the present study and confirms previous observations in anesthetized newborn animals (34). In addition, we previously demonstrated age-dependent effects on renal vascular tone of intra-arterial administration of ACh (29), a muscarinic agonist known to elicit a vasodilation by producing NO. For example, we observed a greater renal vasodilation in newborns than in older lambs after ACh administration; this held true for all doses of ACh tested (29). Furthermore, Török and Gerova (40) measured the dose-dependent relaxation to ACh of aortic rings obtained from fetal, newborn, and adult dogs and observed an age-dependent decrease in endothelium-dependent relaxation. Taken together, these studies provide evidence that under normal physiological conditions, the capacity of the newborn vasculature to release NO for a given stimulus is also greater than that seen later in life. To the current literature, the present findings provide new information that the renal effects of endogenously produced NO are developmentally regulated, with greatest effects on GFR observed soon after birth and greatest effects on tubular function observed later in life.
Some renal effects of NO were previously investigated in newborn
animals. In two different studies, Ballèvre et al. (2, 3) administered L-NAME intravenously to
pentobarbital sodium-anesthetized and mechanically ventilated newborn
rabbits and reported little change in GFR, urinary flow, and
Na+ excretion rates. Morikawa et al. (24)
studied the effects of intravenous
N
-nitro-L-arginine
(L-NNA) in diethyl ether-anesthetized and mechanically ventilated newborn piglets and reported a decrease in both medullary and cortical blood flows during L-NNA infusion, providing
evidence that NO plays a role in intrarenal blood flow distribution
early in life. Solhaug et al. (36) measured dose-dependent
effects of intrarenal infusion of L-NAME in pentobarbital
sodium-anesthetized and mechanically ventilated 3-wk-old piglets as
well as adult pigs. They reported a decrease in GFR of 40-50% in
both age groups at the highest dose tested; no other parameters of
renal function were reported. These previous observations appear to
contradict our current findings of significant age-dependent
differences in the glomerular and tubular responses to
L-NAME in conscious young sheep. Although species
differences cannot be ruled out at this time, data obtained from the
above-mentioned studies should be interpreted with caution for the
following reasons. First, animals were studied acutely under anesthesia
and after surgery, which significantly alters newborn renal function
(1). Second, renal effects of NO are altered during
elevations of ANG II that would result from the effects of surgery and
anesthesia (9). Third, Losonczy et al. (22)
reported that acute, nonsterile surgery in anesthetized rats induces
the expression of iNOS, leading to local production of NO even in the
presence of L-NAME. Therefore, the present study in
conscious lambs trained to the laboratory environment and resting
quietly during experiments provides new information regarding
physiological effects of NO during postnatal maturation.
In adult animals, it is well known that NO modulates glomerular ultrafiltration (19) and plays an important role in tubuloglomerular feedback (42). In the present study in conscious 1-wk-old lambs, we observed a decrease in GFR by ~50% in the presence of L-NAME, whereas there was no effect on GFR in older animals. This occurred in the presence of a similar increase in MAP in both age groups and an increase in RVR in both age groups, albeit a greater increase in RVR at 1 wk. Because NO relaxes glomerular mesangial cells from adult rat kidneys in vitro (27), the observed decrease in GFR in 1- but not 6-wk-old lambs could result from an age-dependent effect of NO production from glomerular mesangial cells, thereby suggesting age-dependent effects of NO in modulating the filtration coefficient. An alternative explanation is that there is an age-dependent effect of endogenously produced NO on net filtration pressure through its vasodilatory effects on afferent arteriolar tone. This premise is supported by an age-dependent distribution of renal nNOS mRNA gene expression and localization (11, 35, 37). Furthermore, Kullaprawithaya et al. (21), using elegant laser capture microdissection techniques, recently reported that macula densa nNOS mRNA gene expression is greater in newborn piglets than older pigs. Taken together, our observations of age-dependent effects of L-NAME on GFR support a greater localization of NOS to regions close to afferent arterioles and/or mesangial cells early in life, although NOS measurements in the developing ovine kidney are necessary to confirm this postulate.
In the present study, after administration of L-NAME to 6-wk-old lambs, and hence removal of endogenously produced NO, we observed a decrease in proximal fractional Na+ reabsorption, leading to a natriuresis. Similar to our observations in 6-wk-old lambs, systemic NO synthesis inhibition results in a natriuresis when administered to adult rats (4-6, 8, 17). This natriuresis appears to be attenuated or abolished in the absence of renal sympathetic nerves (4, 18, 19). It is, therefore, possible that the age-dependent natriuretic effects of L-NAME in conscious lambs in the present study result, at least in part, from differences in the effects of endogenously produced NO in modulating basal renal sympathetic nerve activity. This premise warrants further investigation.
After L-NAME administration, we observed no changes in plasma AVP levels similar to recent observations in conscious water-loaded dogs (26). Despite this, in 6-wk-old lambs, urinary flow rate increased by ~500%, and urinary osmolality decreased by ~60% within 20 min of L-NAME administration and in the absence of any changes in GFR. Moreover, the timing of this early diuretic response to L-NAME in 6-wk-old lambs preceded any significant changes in CH2O. It is possible that NO plays a permissive role in AVP- induced water permeability in principal cells of the cortical collecting ducts (CCD) in 6-wk-old lambs. In fact, immunoreactivity to nNOS is present in principal cells but not intercalated cells of CCD cells of adult rat kidneys. In contrast, in vitro studies carried out in isolated perfused rat CCD (12, 13) showed that NO decreases AVP-stimulated water permeability. It is possible that the discrepancy between our observations from the whole animal and those from isolated perfused CCD reflects differences between in vivo and in vitro actions of NO on AVP-stimulated water transport. These present findings have not, however, been reported in other mammals, so species differences cannot be ruled out at this time.
Studies by Kramer et al. (20) carried out in primary cultures of mouse juxtaglomerular cells showed a stimulatory effect of NO on renin secretion that is slow acting, calcium dependent, and independent of cGMP or cAMP activity. The decrease in PRA after removal of endogenously produced NO to conscious lambs in vivo in the present study is in keeping with these in vitro findings and confirms previous in vivo observations in conscious adult rabbits (14). Although the inhibitory effects on renin secretion of an increase in renal perfusion pressure after L-NAME administration cannot be ruled out at this time, it is possible to conclude that age-dependent glomerular and tubular responses to L-NAME do not result from secondary age-dependent effects of circulating levels of angiotensin II.
Perrella et al. (25) measured a small but significant increase in ET-1 levels from ~8 to 10 pg/ml during NO synthesis inhibition in pentobarbital sodium-anesthetized dogs. There was, however, no effect of circulating levels of ET-1 in the present study in conscious lambs and in a previous study in conscious water-loaded dogs (26). From this we can conclude that the age-dependent renal responses to L-NAME cannot be attributed to any secondary age-dependent differences in circulating levels of ET-1.
In conclusion, endogenously produced NO modulates glomerular filtration soon after birth, with little effect on tubular function. Later in development, the role of NO in modulating tubular water and electrolyte reabsorption predominates. These age-dependent renal effects of endogenously produced NO cannot be attributed to secondary effects on renal perfusion pressure or plasma levels of ANG II, ET-1, or AVP.
Perspectives
In human infants, endogenous NO production (assessed by urinary NO
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ACKNOWLEDGEMENTS |
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This work was supported by grants provided by the Canadian Institutes for Health Research and the Kidney Foundation of Canada. Dr. A. Sener was supported by a Pharmaceutical Manufacturing Association of Canada/Medical Research Council graduate studentship during the tenure of these studies. Dr. F. Smith is a Heritage Senior Medical Scholar supported by the Alberta Heritage Foundation for Medical Research.
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FOOTNOTES |
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A portion of this work was presented as a poster to the Annual Meetings of Experimental Biology, 2000, and published in the proceedings (Sener A and Smith FG, FASEB J 14: A287.12, 2000). This work also forms part of the thesis dissertation of Dr. A. Sener.
Address for reprint requests and other correspondence: F. G. Smith, Dept. of Physiology & Biophysics, Faculty of Medicine, Univ. of Calgary, 3330 Hospital Drive, NW, Calgary, Alberta, T2N 4N1 Canada (E-mail: fsmith{at}ucalgary.ca).
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. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00628.2001
Received 22 October 2001; accepted in final form 13 December 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Bailie, MD,
Alward CT,
Sawyer DC,
and
Hook JB.
Effect of anesthesia on cardiovascular and renal function in the newborn piglet.
J Pharmacol Exp Ther
208:
298-302,
1979
2.
Ballevre, L,
Thonney M,
and
Guignard JP.
Role of nitric oxide in the hypoxemia-induced renal dysfunction of the newborn rabbit.
Pediatr Res
39:
725-730,
1995[ISI][Medline].
3.
Ballevre, L,
Thonney M,
and
Guignard JP.
Nitric oxide modulates glomerular filtration and renal blood flow of the newborn rabbit.
Biol Neonate
69:
389-398,
1997.
4.
Baylis, C,
Braith R,
Santmyire BR,
and
Engels K.
Renal nerves do not mediate vasoconstrictor responses to acute nitric oxide synthesis inhibition in conscious rats.
J Am Soc Nephrol
8:
887-892,
1997[Abstract].
5.
Baylis, C,
Harton P,
and
Engels K.
Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney.
J Am Soc Nephrol
1:
875-881,
1990[Abstract].
6.
Baylis, C,
Harvey J,
Santmyire BR,
and
Engels K.
Pressor and renal vasoconstrictor responses to acute systemic nitric oxide synthesis inhibition are independent of the sympathetic nervous system and angiotensin II.
J Pharmacol Exp Ther
288:
693-698,
1999
7.
Brace, RA.
Blood volume in the fetus and methods for its measurement.
In: Animal Models in Fetal Medicine, edited by Nathanielsz PW.. Ithaca, NY: Perinatology, 1984, p. 19-36.
8.
De Nicola, L,
Blantz RC,
and
Gabbai FB.
Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat.
J Clin Invest
89:
1248-1256,
1992.
9.
Deng, X,
Welch WJ,
and
Wilcox CS.
Role of nitric oxide in short-term and prolonged effects of angiotensin II on renal hemodynamics.
Hypertension
27:
1173-1179,
1996
10.
Endo, A,
Ayusawa M,
Minato M,
Takada M,
Takahashi S,
and
Harada K.
Physiological significance of nitric oxide and endothelin-1 in circulatory adaptation.
Pediatr Int
42:
26-30,
2000[ISI][Medline].
11.
Fischer, E,
Schnermann J,
Briggs JP,
Kriz W,
Ronco PM,
and
Bachmann S.
Ontogeny of NO synthase and renin in juxtaglomerular apparatus of rat kidneys.
Am J Physiol Renal Fluid Electrolyte Physiol
268:
F1164-F1176,
1995
12.
Garcia, NH,
Pomposiello SI,
and
Garvin JL.
Niric oxide inhibits ADH-stimulated osmotic water permeability in cortical collecting ducts.
Am J Physiol Renal Fluid Electrolyte Physiol
270:
F206-F210,
1996
13.
Garcia, NH,
Stoos BA,
Carretero OA,
and
Garvin JL.
Mechanism of the nitric oxide-induced blockade of collecting duct water permeability.
Hypertension
27:
679-683,
1996
14.
Goyer, M,
Bui H,
Chou L,
Evans J,
Keil LC,
and
Reid IA.
Effect of inhibition of nitric oxide synthesis on vasopressin secretion in conscious rabbits.
Am J Physiol Heart Circ Physiol
266:
H822-H828,
1994
15.
Haber, E,
Koerner T,
Page LB,
Kliman B,
and
Purnode A.
Application of a radioimmunoassay for angiotensin I to the physiological measurements of plasma renin activity in normal human subjects.
J Clin Endocrinol Metab
29:
1349-1355,
1969[ISI][Medline].
16.
Honold, J,
Pusser NL,
Nathan L,
Chaudhuri G,
Ignarro LJ,
and
Sherman MP.
Production and excretion of nitrate by human newborn infants: neonates are not little adults.
Nitric Oxide Biol Chem
4:
35-46,
2000[ISI][Medline].
17.
Johnson, RA,
and
Freeman RH.
Pressure natriuresis in rats during blockade of the L-arginine/nitric oxide pathway.
Hypertension
19:
333-338,
1992
18.
Khraibi, AA.
Role of renal nerves in natriuresis of L-NMMA infusion in SHR and WKY rats.
Am J Physiol Renal Fluid Electrolyte Physiol
269:
F17-F21,
1995
19.
Kone, BC,
and
Baylis C.
Biosynthesis and homeostatic roles of nitric oxide in the normal kidney.
Am J Physiol Renal Physiol
272:
F561-F578,
1997
20.
Kramer, BK,
Ritthaler T,
Ackermann M,
Holmer S,
Schricker K,
Riegger AJ,
and
Kurtz A.
Endothelium-mediated regulation of renin secretion.
Kidney Int
46:
1577-1579,
1994[ISI][Medline].
21.
Kullaprawithaya, U,
Zhao H,
Dong KW,
Dong XQ,
and
Solhaug MJ.
Localization and laser capture microdissected quantification of macula densa neuronal nitric oxide synthase, nNOS, during postnatal renal development.
FASEB J
15:
A832,
2001.
22.
Losonczy, G,
Bloch JF,
Samsell L,
Schoenl M,
Venuto R,
and
Baylis C.
Impact of surgery on nitric oxide in rats: evidence for activation of inducible nitric oxide synthase.
Kidney Int
51:
1943-1949,
1997[ISI][Medline].
23.
Lumbers, ER,
Hill KJ,
and
Bennett VJ.
Proximal and distal tubular activity in chronically catheterized fetal sheep compared with the adult.
Can J Physiol Pharmacol
66:
697-702,
1988[ISI][Medline].
24.
Morikawa, I,
Togari H,
Hyodo J,
and
Suzuki T.
Nitric oxide modulates premature renal circulation in hypoxic newborn piglets.
Biol Neonate
74:
22-30,
1998[ISI][Medline].
25.
Perrella, MA,
Hildebrand FL, Jr,
Margulies KB,
and
Burnett JC, Jr.
Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function.
Am J Physiol Regulatory Integrative Comp Physiol
261:
R323-R328,
1991
26.
Peterson, TV,
Emmeluth C,
and
Bie P.
Renal effects of nitric oxide synthase inhibition in conscious water-loaded dogs.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R584-R590,
2001
27.
Raij, L,
and
Baylis C.
Glomerular actions of nitric oxide.
Kidney Int
48:
20-32,
1995[ISI][Medline].
28.
Saito, Y,
Nakao K,
Shirakami G,
Jougasaki M,
Yamada T,
Itoh H,
Mukoyama M,
Arai H,
Hosoda K,
Suga SI,
Ogawa Y,
and
Imura H.
Detection and characterization of endothelin-1-like immunoreactivity in rat plasma.
Biochem Biophys Res Commun
163:
1512-1516,
1989[ISI][Medline].
29.
Sener, A,
and
Smith FG.
Acetylcholine chloride and renal haemodynamics during postnatal maturation in conscious lambs.
J Appl Physiol
87:
1296-1300,
1999
30.
Sener, A,
and
Smith FG.
Dose dependent effects of nitric oxide synthase inhibition on systemic and renal haemodynamics in conscious lambs.
Can J Physiol Pharmacol
77:
1-7,
1999[ISI][Medline].
31.
Sener, A,
and
Smith FG.
Renal hemodynamic effects of L-NAME during postnatal maturation in conscious lambs.
Pediatr Nephrol
16:
868-873,
2001[ISI][Medline].
32.
Sener, A,
and
Smith FG.
Nitric oxide modulates the arterial baroreflex control of heart rate in conscious lambs in an age-dependent manner.
Am J Physiol Heart Circ Physiol
280:
H2255-H2263,
2001
33.
Skowsky, WR,
Rosenbloom A,
and
Fisher DA.
Radioimmunoassay measurement of arginine vasopressin in serum: development and application.
J Clin Endocrinol Metab
38:
278-287,
1974[ISI][Medline].
34.
Solhaug, MJ,
Ballèvre L,
Guignard JP,
Granger JP,
and
Adelman RD.
Nitric oxide in the developing kidney.
Pediatr Nephrol
10:
529-539,
1996[ISI][Medline].
35.
Solhaug, MJ,
Dong XQ,
Adelman RD,
and
Dong KW.
Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R1453-R1459,
2000
36.
Solhaug, MJ,
Wallace MR,
and
Granger JP.
Endothelium-derived nitric oxide modulates renal hemodynamics in the developing piglet.
Pediatr Res
34:
750-754,
1993[ISI][Medline].
37.
Thompson, LP,
and
Weiner CP.
Acetylcholine relaxation of renal artery and nitric oxide synthase activity of renal cortex increase with fetal and postnatal age.
Pediatr Res
40:
192-197,
1996[ISI][Medline].
38.
Thomsen, K,
Holstein-Rathlou NH,
and
Leyssac PP.
Comparison of three methods of measures of proximal tubular reabsorption: lithium clearance, occlusion time, micropuncture.
Am J Physiol Renal Fluid Electrolyte Physiol
241:
F348-F355,
1981.
39.
Thomsen, K,
Schou M,
Steiness I,
and
Hansen HE.
Lithium as an indicator of proximal sodium reabsorption.
Pflügers Arch
308:
180-184,
1969[ISI][Medline].
40.
Török, J,
and
Gerova M.
Vascular responses after long-term inhibition of nitric oxide synthesis in newborn dogs.
Physiol Res
45:
323-328,
1996[ISI][Medline].
41.
Tsukahara, H,
Hiraoka M,
Hori C,
Tsuchida S,
Hata I,
Nishida K,
Kikuchi K,
and
Sudo M.
Urinary nitrite/nitrate excretion in infancy: comparison between term and preterm infants.
Early Hum Dev
47:
51-56,
1997[ISI][Medline].
42.
Wilcox, CS,
Welch WJ,
Murad F,
Gross SS,
Taylor G,
Levi R,
and
Schmidt HHHW
Nitric oxide synthase in macula densa regulates glomerular capillary pressure.
Proc Natl Acad Sci USA
89:
11993-11997,
1992
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P < 0.05 compared with
1-wk-old lambs.
) and 6 wk (
).
* P < 0.05 compared with C; 
