(Hypertension. 1996;27:578-583.)
© 1996 American Heart Association, Inc.
Articles |
Acute Saline Infusion Decreases Norepinephrine Release in the Anterior Hypothalamic Area
From the Department of Cell Biology (N.P., J.M.W.) and Department of Medicine, Vascular Biology and Hypertension Program (Q.C.M., S.O., J.M.W.), University of Alabama at Birmingham.
Correspondence to J. Michael Wyss, PhD, Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0019.
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Abstract |
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Abstract Ingestion of a high NaCl diet elevates arterial pressure in spontaneously hypertensive rats, at least in part, by reducing the release of norepinephrine in the anterior hypothalamic area. The mechanism by which dietary NaCl excess alters anterior hypothalamic area norepinephrine release is unknown. Plasma Na+ is slightly elevated after ingestion of a meal; therefore, in the present study we tested the hypothesis that a small increase in plasma Na+ could reduce the release of norepinephrine in the anterior hypothalamic area and elevate arterial pressure. Male spontaneously hypertensive rats were randomized to be fed a diet containing either 1% (basal) or 8% (high) NaCl at age 7 weeks and were maintained on the diets for 2 weeks. Age-matched normotensive Wistar-Kyoto rats received a basal NaCl diet only. All rats were instrumented with a push/pull cannula, and 5 days later, the baseline release of 3-methoxy-4-hydroxyphenyl glycol (the major metabolite of norepinephrine in brain) was measured in awake, freely moving rats. Rats were then challenged with an intravenous infusion (75 µL/min) of hypertonic (2.7%) saline for 20 minutes. In spontaneously hypertensive rats fed a basal NaCl diet, the hypertonic saline infusion elevated mean arterial pressure by 12% and reduced the concentration of the norepinephrine metabolite in the anterior hypothalamic area by 19%; these alterations persisted after termination of the hypertonic saline infusion. Spontaneously hypertensive rats maintained on the high NaCl diet showed greatly reduced arterial pressure and norepinephrine metabolite responses. In normotensive control rats compared with the hypertensive rats fed the basal NaCl diet, the hypertonic saline had considerably less effects on arterial pressure and norepinephrine metabolite levels in the anterior hypothalamic area, and the responses were significantly shorter. Thus, a small elevation in plasma Na+ can reduce the release of norepinephrine in the anterior hypothalamic area. This response is greatly exaggerated in spontaneously hypertensive rats fed a basal (but not a high) NaCl diet, suggesting that a postprandial rise in NaCl could initiate the fall in norepinephrine and thereby contribute to the rise in arterial pressure in spontaneously hypertensive rats ingesting a high NaCl diet.
Key Words: baroreflex • hypothalamus • sodium chloride, dietary • sympathetic nervous system • rats, inbred WKY
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Introduction |
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In young, salt-sensitive SHR, ingestion of a high NaCl diet exacerbates hypertension (arterial pressure increases by approximately 20 mm Hg after 2 weeks on the diet), increases peripheral sympathetic nervous system activity, and greatly decreases norepinephrine release in the AHA.1 In contrast, a high NaCl diet has no effect on norepinephrine release in the AHA of NaCl-resistant SHR or normotensive WKY.2 3 The decrease in AHA norepinephrine appears to have a pivotal role in the resultant salt-sensitive hypertension because continuous infusion of the
2-adrenergic receptor agonist clonidine into the AHA
prevents the dietary NaCl–induced exacerbation of hypertension in
SHR.4 The AHA contributes to arterial pressure
regulation in normotensive animals,5 6 and an
increase in
the release of norepinephrine from nerve terminals in the
AHA decreases arterial pressure by decreasing sympathetic
nervous system activity.7 8 These and other data led
to
the hypothesis that in SHR a high NaCl diet inhibits the release of
norepinephrine in the AHA, reducing sympathoinhibition and
thereby raising arterial pressure.9 10 11
However, the mechanism or mechanisms by which dietary NaCl excess
triggers these reductions in the release of norepinephrine
and increases sympathetic nervous system activity remain unclear. In the present study, we tested the hypothesis that an increase in plasma Na+ decreases norepinephrine release in the AHA of the rat and that this effect is augmented in SHR compared with normotensive rats. Plasma Na+ concentration is known to increase transiently after food intake,12 and we have demonstrated that NaCl-sensitive SHR have a deficit in their ability to excrete a plasma Na+ load.13 Preliminary experiments have demonstrated that plasma Na+ concentration is increased by approximately 2 to 3 mmol/L in SHR and WKY within 60 minutes of the normal initiation of eating (9:00 PM compared with normal noneating period, 9:00 AM; N.P., Q.C.M., S.O., J.M.W., unpublished data). This increase in plasma Na+ is sufficient to be detected by neurons in the hypothalamus and circumventricular organs of the rat.14 15 16 17 The normal response to the increase in plasma Na+ consists of an increase in the release of vasopressin and an elevation in sympathetic nervous system activity.18 We hypothesized that the coordinated response of the nervous system to the increased plasma Na+ concentration includes a decrease in the activity of sympathoinhibitory neurons in the AHA and that this response is greater in magnitude and duration in SHR than in WKY, leading to a greater increase in arterial pressure. This may trigger the postprandial increase in arterial pressure that forms the basis of NaCl-sensitive hypertension in SHR.
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Methods |
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Seven-week-old, male SHR (Harlan Sprague-Dawley) were assigned at random to be fed either a high NaCl diet (Purina chow containing 8% NaCl; ICN Biochemicals) or a basal (1%) NaCl diet (diet No. 5001, Ralston Purina) (eight rats were in each diet/strain group). Normotensive, age-matched WKY (Harlan Sprague-Dawley) were maintained on the basal NaCl diet. Food and water were available ad libitum throughout the study. All animals were housed (three per cage initially and one per cage after surgery) at constant temperature (24±1°C), humidity (60±5%), and light/dark cycle (light, 6:00 AM to 6:00 PM). Heart rate, systolic arterial pressure (via indirect tail-cuff method), and body weight were measured weekly.
Two weeks after initiation of the diets, rats were anesthetized with sodium pentobarbital (50 mg/kg IP), and a stainless steel guide cannula (24 gauge) fitted with a removable, 31-gauge obturator (which extended 0.5 mm past the tip of the outer cannula) was stereotaxically implanted above the AHA (tip of the guide cannula was positioned so that it would be 0.6 mm dorsal to the AHA [the stereotaxic coordinates measured from the bregma were anterior, -1.6 mm; lateral, +0.7 mm; and ventral, -8.1 mm ]).19 The cannula was secured in place with acrylic cement that was anchored to the skull with three stainless steel screws. After recovery from anesthesia, all animals were placed into individual cages and maintained on their diet until the time of study. Five days after implantation of the guide cannula, animals were anesthetized with sodium methohexital (60 mg/kg IP). Catheters (PE-10 fused to PE-50 tubing, Becton Dickinson) were implanted into the abdominal aorta through the right femoral artery for measurement of arterial pressure and into the right femoral vein for intravenous infusion of saline. The free ends of the catheters were externalized between the scapulae and secured in place with dental acrylic.
The push/pull perfusion was performed after the animals had recovered from anesthesia (at least 2 hours after implantation of the catheters). On the day of the experiment, each animal was placed into a small cage that allowed free movement, and the arterial line was attached to a pressure transducer for recording blood pressure. After adaptation to these conditions (as demonstrated by a stable blood pressure signal and resting posture [approximately 30 minutes]), the push/pull assembly was inserted into the guide cannula so that its tip extended 1 mm beyond the guide cannula. Polyethylene tubing (PE-20) was connected to the inflow and outflow of the push/pull assembly and to two identically calibrated rabbit pumps (Rainin Instruments). The perfusion was then begun with ACSF (119 mmol/L NaCl, 3.3 mmol/L KCl, 1.3 mmol/L CaCl2, 1.2 mmol/L MgCl2, 0.5 mmol/L Na2HPO4, 21.0 mmol/L NaHCO3, and 3.4 mmol/L glucose, adjusted to pH 7.4 with 1N HCl). The ACSF was pushed through the inner cannula and drawn up between the inner cannula and guide cannula at a rate of 10 µL/min. After a 30-minute equilibration period, during which perfusate was discarded, perfusate was collected in 10-minute increments in plastic tubes containing 25 µL of a 0.5N perchloric acid/EDTA solution (0°C) and subsequently stored at -20°C.
After a 90-minute baseline collection period, each animal was infused intravenously with hypertonic saline (2.7%; infusion rate, approximately 70 µL/min) for 20 minutes. In preliminary studies in SHR and WKY, we found that this infusion resulted in approximately a 3 mmol/L increase in plasma Na+ during the infusion and a return of plasma Na+ to baseline concentration within 20 minutes. After saline administration, perfusate samples were collected, and MAP was monitored for an additional 90 minutes (recovery). At the conclusion of the experiment, 0.3% pontamine sky blue dye in ACSF was perfused for 3 minutes, and the animal was killed with an overdose of ether. The brain was removed and sectioned for histological verification of cannula placement by an investigator who was blinded to the group designation of the sections examined.
Two subsequent experiments that followed the above protocol were used to test whether the exaggerated cardiovascular and AHA MOPEG (the major extracellular metabolite of norepinephrine in the brain) responses observed in SHR (compared with WKY) were the result of a higher sensitivity of SHR to the infusion of a particular concentration of hypertonic saline. In the first of these experiments, 5% saline was infused in WKY according to the above protocol. In the second of these experiments, 1.8% saline was infused according to the above protocol in SHR that were fed a basal NaCl diet.
Monoamines and metabolites in the perfusate were measured with HPLC-EC as described previously.2 3 Quantification of compounds of interest in each HPLC-EC sample was achieved by comparing peak heights with those obtained after injection of known quantities of the compound (standard). The elution profile of a standard preparation (250 pg in 25 µL) of monoamines and their metabolites clearly resolved the peak for MOPEG. In addition to MOPEG, dopamine, serotonin, and their metabolites (3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid, respectively) were consistently detected with this technique, but norepinephrine was typically undetectable.
Statistical Analysis
Results are expressed as
mean±SEM. The data were
analyzed with the use of ANOVA with appropriate post-hoc
tests (Newman-Keuls) to determine the source of main effects and
interactions.20
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Results |
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In SHR, maintenance on the 8% (compared with the 1%) NaCl diet for 2 weeks significantly elevated MAP (8% [n=7], 167±4 mm Hg; 1% [n=9], 146±3 mm Hg; P<.05; Fig 1
).
MAP in the WKY fed the basal NaCl diet was 105±2 mm Hg (n=13;
Fig 2). Resting heart rate was similar in SHR (391±8
bpm) and
WKY (380±10 bpm); the high NaCl diet did not alter resting heart rate
(379±7 bpm). There were no significant differences in body weight
between the two SHR groups (1% NaCl diet, 236±6 g; 8% NaCl diet,
232±6 g), but the WKY weighed slightly less (214±3 g).
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In SHR fed the basal NaCl diet, the hypertonic (2.7%) saline resulted
in a significant increase in arterial pressure within the
first minute after initiation of the infusion, but the response did not
peak until 10 to 20 minutes after initiation (Fig 1A
). After
termination of the infusion, arterial pressure decreased
toward baseline levels but remained significantly elevated for the
remainder of the experiment. In the SHR fed the high NaCl diet, the
hypertonic saline infusion resulted in a more gradual elevation in
arterial pressure, which continued to rise after cessation
of the infusion (Fig 1B). In WKY, arterial pressure rose
gradually during the infusion of 2.7% NaCl, with a peak response of
6±2 mm Hg (P<.05) during the second 10-minute infusion
period. After cessation of the infusion, arterial pressure
returned toward baseline (Fig 2). In WKY infused with 5% NaCl,
arterial pressure increased more rapidly and displayed a
higher peak response (Fig 3). Isotonic saline infusion
caused no consistent change in arterial pressure in
control experiments in SHR and WKY (not shown).
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In SHR fed the 1% NaCl diet, basal MOPEG concentration in the AHA
before saline infusion averaged 262±15 pg/10 min (Fig
1A). The
hypertonic saline infusion resulted in a 19% reduction in MOPEG in the
AHA; this response was rapid in onset (Fig 1A). After
termination of
the hypertonic saline infusion, AHA MOPEG returned toward baseline
concentrations but remained significantly reduced throughout the
postinfusion period. All eight SHR in this group displayed a reduction
in AHA MOPEG in the initial 10 minutes of the infusion, and none of
these rats displayed a return to baseline values at the end of the
experiment. In a subsequent experiment, another group of SHR fed a
basal NaCl diet (n=6) was infused with 1.8% NaCl, as above. The 1.8%
NaCl infusion resulted in no significant change in arterial
pressure, but a small (9%) decrease in AHA MOPEG occurred that was
sustained throughout the postinfusion period.
In agreement with our previous studies, maintenance on the high
NaCl diet reduced extracellular MOPEG in AHA of SHR by approximately
55%; AHA MOPEG in SHR fed the 8% NaCl diet averaged 120±10 pg/10 min
(Fig 1B). Twenty minutes after initiation of the hypertonic
saline
infusion, AHA MOPEG concentration had decreased by 8% in this group; a
decrease was observed at this time point in all rats in the group
(P<.05; Fig 1B). After termination of the infusion,
AHA
MOPEG concentration returned toward baseline values but was
variable during most of the postinfusion period (Fig 1B).
In WKY, MOPEG in the AHA before infusion was 105±10 pg/10 min (Fig
2).
During the hypertonic saline infusion, AHA MOPEG concentration
decreased transiently and very slightly in all rats (P<.05;
Fig 2). Because the response to the 2.7% NaCl infusion was very
slight
in WKY, in a subsequent experiment four age-matched WKY were
infused with 5% saline at the same infusion rate. The 5% hypertonic
saline infusion resulted in no consistent change in AHA MOPEG
in this group (Fig 3).
In all groups, the hypertonic saline–induced rise in arterial pressure evoked a decrease in heart rate. The magnitude of the baroreflex response was greater in WKY (-33±4 bpm; SHR, -21±2 bpm; P<.05) fed the basal NaCl diet, despite the much smaller pressor response in the WKY. In SHR fed the high (compared with the basal) NaCl diet, the heart rate decrease was significantly less in magnitude (-8±4 bpm decrease), but when measured as a ratio of change of heart rate to change in arterial pressure, the responses from the two groups were nearly the same.
Histological examination demonstrated that nearly all cannula placements were within the AHA. Three cannula placements were outside of the AHA, and these rats were eliminated from further analysis on that basis. Data from eight rats were eliminated because of inadequate push/pull perfusion.
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Discussion |
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The results demonstrate that acute increases in plasma Na+ cause a moderate increase in arterial pressure and a decrease in MOPEG in the AHA of both SHR and WKY. The responses are much greater in magnitude and duration in SHR than in WKY fed a basal NaCl diet. In contrast, in SHR fed a high (compared with basal) NaCl diet for 2 weeks, the responses are much less and similar to those of WKY fed the basal NaCl diet.
Normally, arterial pressure and AHA norepinephrine release are directly rather than inversely related. Previous research from our laboratory11 has demonstrated that in both SHR and WKY, an increase in arterial pressure induced by systemic administration of tramazoline or phenylephrine increases AHA MOPEG. This increase is greater in SHR than in WKY fed a basal NaCl diet, and in SHR but not in WKY the response was blunted by maintenance on a high NaCl diet for 2 weeks. Given these previous findings, it could be predicted that the acute increase in arterial pressure that resulted from infusion of hypertonic (2.7%) saline in the present study would cause an increase in AHA MOPEG. We observed the opposite: a decrease in AHA MOPEG. Thus, the normal pressor-related increase in AHA MOPEG was blocked in all three experimental groups after saline infusion. Instead, a small (for WKY fed a basal NaCl diet and for SHR fed a high NaCl diet) or relatively large (for SHR fed a basal NaCl diet) decrease occurred in AHA MOPEG. These data demonstrate that compared with the other two groups, SHR fed a basal NaCl diet are much more responsive to increases in either arterial pressure or plasma Na+ concentration. This suggests that in SHR fed a basal NaCl diet (compared with SHR fed a high NaCl diet or with WKY), AHA neurons may be more responsive to many challenges.
AHA has a sympathoinhibitory function, and
norepinephrine activates AHA neurons. Electrical
stimulation of AHA reduces blood pressure and heart rate in both
normotensive and hypertensive rats, whereas electrical stimulation of
neurons in surrounding nuclei, including the
paraventricular, ventromedial, and posterior
hypothalamic nuclei, increases blood pressure and heart
rate.21 22 Large lesions of the AHA produce
fulminating
hypertension in normotensive rats,23 and in SHR,
bilateral, neurotoxin-induced lesions that are restricted to the
AHA result in blood pressure increases equal to those induced by high
NaCl diets.24 This is in marked contrast to posterior
hypothalamic area lesions or lesions in the anteroventral third
ventricular area, both of which tend to decrease blood
pressure.25 Injections of norepinephrine or
2-adrenoceptor agonists in high doses dissolved in large
volumes of vehicle solution lower blood pressure in normotensive
rats,21 26 and small, discrete (<50 µL)
injections of
clonidine into the AHA reduce blood pressure and heart rate in
both normotensive and hypertensive rats.26 In contrast,
microinjections of clonidine into the lateral or posterior hypothalamic
areas cause increases in blood pressure and heart rate. Together, these
findings suggest that the neurons of the AHA subserve a
sympathoinhibitory function and are activated
by local release of norepinephrine.
Although evidence for AHA involvement in dietary NaCl–sensitive hypertension in SHR is strong, there has been no clear hypothesis as to how dietary NaCl alters AHA norepinephrine release. Previous studies of 24-hour regulation of arterial pressure carried out in our laboratory demonstrated that during nighttime feeding, a high NaCl diet transiently elevates plasma Na+ concentration by approximately 2 to 4 mmol/L (N.P., Q.C.M., S.O., J.M.W., unpublished data). It has been suggested27 that osmosensitive neurons in the hypothalamus display an altered firing rate when challenged by an increase in plasma Na+ of this magnitude. This led us to hypothesize that the transient postprandial elevation in plasma Na+ concentration inhibits the activity of AHA neurons, possibly via a decrease in AHA norepinephrine release. In the present study, a small increase in plasma Na+ (approximately equal to that resulting from ingestion of a high NaCl–containing meal) decreased AHA norepinephrine release. The magnitude and duration of this effect were greater in SHR than in WKY. In SHR, AHA MOPEG remains suppressed for more than 1 hour after the cessation of the saline infusion; whereas in WKY, AHA MOPEG levels returned to baseline within 10 to 20 minutes after the infusion. This difference in the duration of the AHA MOPEG reduction does not appear to be the result of inefficient buffering of the plasma Na+ by the SHR. In a preliminary experiment, in both SHR and WKY, plasma Na+ concentrations returned to basal conditions within 20 minutes after the termination of a similar hypertonic saline infusion (N.P., Q.C.M., S.O., J.M.W., unpublished results from our laboratory). A more detailed study of plasma Na+ regulation in these rats will be necessary before these issues can be resolved fully, but there does not appear to be a gross defect in regulation of plasma Na+ concentration in SHR.
A postinfusion increase in blood volume could also contribute to the effects noted in the present study. We have previously observed a reduction in natriuretic responses in SHR compared with WKY,13 and this reduction may cause a slightly greater increase in blood volume in the SHR. However, it seems unlikely that a differential increase in blood volume has an important role in the initiation of the hypertensive or neurotransmitter responses observed in this study. Volume expansion by intravenous infusion of whole blood causes nearly identical increases in arterial pressure in SHR and WKY,28 and infusion of normal saline at a rate of 0.5 mL/min (ie, a greater volume challenge than that resulting from the present hypertonic saline infusion) causes no change in arterial pressure.13
The time course of the responses to blood pressure increase versus
saline loading is different in SHR than in WKY. In SHR, a 20-minute
infusion of tramazoline causes rapid increases in both
arterial pressure and AHA MOPEG that last for approximately
30 minutes.11 In WKY, a similar tramazoline infusion
causes a 30-minute increase in arterial pressure and a
rapid increase in AHA MOPEG, but the increase in AHA MOPEG lasts
significantly longer (
50 minutes) in WKY than in SHR. A hypertonic
saline challenge causes a very different result. In the present
study, we demonstrate that an infusion of 2.7% saline elicits a rapid
increase in arterial pressure and a rapid decrease in AHA
MOPEG in SHR fed a basal NaCl diet, but both responses persist for more
than 1 hour (far beyond the duration of the stimulus). Conversely, in
WKY, a similar hypertonic saline infusion elicits a rapid and very
brief increase in arterial pressure and a decrease in AHA
MOPEG. These differences in time course of the responses are likely
related to the finding that SHR have a competent arterial
(high pressure) baroreflex29 and thus can respond
efficiently to increases in arterial pressure. In contrast,
SHR (compared with WKY) display extremely blunted
cardiopulmonary baroreflex responses to volume
loading.13 Because the cardiopulmonary
baroreflex has an important role in reducing sympathetic nervous system
activity after volume loading, the decreased
cardiopulmonary baroreflex response in SHR compared with
that in WKY may contribute to the extended duration of the
arterial pressure and AHA MOPEG responses observed in SHR
in the present study, and this may have a role in dietary
NaCl-sensitive hypertension in SHR.13 29
Neurons in the circumventricular organs, especially in the organum vasculosum of the lamina terminalis, appear to have a primary role in detecting alterations in plasma Na+ and transmitting this information to nuclei in the hypothalamus.18 30 31 Infusion of hypertonic saline14 15 16 17 or maintenance on a high NaCl diet18 increases the activity of neurons in the organum vasculosum and in several sympathoexcitatory hypothalamic nuclei (including the paraventricular nucleus), leading to an increase in sympathetic nervous system activity and the release of vasopressin into the blood. This coordinated response returns plasma Na+ concentration toward normal levels, albeit at the expense of increasing blood volume. In contrast to the extensive studies into the effect of plasma Na+ on sympathoexcitatory neurons, the effect of plasma Na+ excess on the activity of neurons in sympathoinhibitory nuclei of the hypothalamus has not been studied rigorously; however, Oldfield et al14 suggested that although the infusion of hypertonic saline increases c-fos immunostaining (indicative of an increase in neuronal activity) in the paraventricular nucleus, it appears to decrease c-fos immunostaining in AHA neurons.
Our previous studies in the SHR suggest that the activity of neurons in the AHA is decreased by dietary NaCl excess, and we propose that the neurons in sympathoexcitatory nuclei of the brain are thereby under less tonic restraint than are comparable neurons in control, NaCl-resistant WKY. Our recent studies suggest that the neurons in AHA of SHR fed a basal NaCl diet respond robustly to increases in arterial pressure29 32 33 and to increases in plasma Na+ but that in SHR fed a high NaCl diet, these neurons are much less responsive to the challenges, perhaps because norepinephrine release in AHA is greatly reduced by the high NaCl diet. Our initial evidence suggests that the reduction in norepinephrine in the AHA of SHR fed a high NaCl diet may be related to the inhibition of norepinephrine release by excess atrial natriuretic peptide in the AHA,34 35 36 37 but the relations among plasma Na+, brain atrial natriuretic peptide release, and AHA norepinephrine release remain speculative. Conversely, our studies clearly demonstrate that much more norepinephrine is released in the AHA of the SHR than in WKY fed a basal diet and that no similar elevation of norepinephrine release is observed in any other nucleus that we have studied in this model.1 2 3 4 The increased release of norepinephrine in the AHA of SHR might be a compensatory response to chronic hypertension—a response that is disrupted by repetitive, daily plasma Na+ increases.
In summary, these data demonstrate that a relatively small increase in plasma Na+, induced by an intravenous infusion of hypertonic saline, leads to an increase in arterial pressure and a decrease in norepinephrine release in the AHA. Both responses are exaggerated (in both magnitude and duration) in SHR compared with those in WKY fed a basal NaCl diet, and maintenance on a high NaCl diet blunts the responses in SHR. This suggests that in SHR, exposure to a high NaCl diet initially causes an excess reduction of AHA-mediated sympathoinhibition. We propose that continued exposure to a high NaCl diet leads to a reduction in norepinephrine release in this nucleus and a resulting sympathetically mediated exacerbation of hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health grants HL-37722, HL-47081, and HL-07457 and by a Grant-in-Aid from the American Heart Association, Alabama Affiliate.
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References |
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