(Hypertension. 1995;25:828-833.)
© 1995 American Heart Association, Inc.
Articles |
Acute Hypertension Increases Norepinephrine Release in the Anterior Hypothalamic Area
From the Department of Cell Biology (N.P., K.K., J.M.W.) and the Vascular Biology and Hypertension Program of the Department of Medicine (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 Neurons in the anterior hypothalamic area play an important role in NaCl-sensitive hypertension in spontaneously hypertensive rats, and previous studies have suggested that baroreceptor feedback modifies the activity of these neurons. To test the hypothesis that the release of norepinephrine in the anterior hypothalamic area is modified by arterial baroreceptor reflex feedback and that this reflex release is disturbed in spontaneously hypertensive rats on a high NaCl diet, we used the push-pull technique to measure the release of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol in the anterior hypothalamic area. Seven-week-old male spontaneously hypertensive and normotensive Wistar-Kyoto rats were placed on a high (8%) or a basal (1%) NaCl diet for 2 weeks. The high NaCl diet elevated mean arterial pressure and greatly reduced basal norepinephrine metabolite levels in the anterior hypothalamic area of the spontaneously hypertensive (but not the control) rats (305±32 pg/10 min in the rats consuming 1% NaCl and 93±9 pg/10 min in the rats consuming 8% NaCl). An infusion of tramazoline (an imidizoline that causes long-lasting hypertension) that increased arterial pressure by 25 mm Hg elevated anterior hypothalamic area norepinephrine metabolite concentrations significantly more in the spontaneously hypertensive rats on the 1% NaCl diet (to 392±46 pg/10 min) than in those on the 8% NaCl diet (to 113±18 pg/10 min). In contrast, in Wistar-Kyoto rats the tramazoline-induced increase in arterial pressure elevated anterior hypothalamic area norepinephrine metabolite concentrations slightly more in rats on the 8% NaCl diet than in those on the 1% NaCl diet. These data suggest that baroreflex activation increases norepinephrine release in the anterior hypothalamic area of the awake rat and that a high NaCl diet blunts this response in spontaneously hypertensive (but not Wistar-Kyoto) rats.
Key Words: sympathetic nervous system • rats, inbred WKY • hypertension, sodium-sensitive • hypothalamus • sodium
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Introduction |
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The anterior hypothalamic area (AHA) contributes to arterial pressure regulation in normotensive animals.1 2 An increase in the release of norepinephrine from nerve terminals in the AHA causes a decrease in arterial pressure due to sympathoinhibition.3 4 Previous studies from our laboratory have shown that in young spontaneously hypertensive rats of the Okamoto strain (SHR), ingestion of a high NaCl diet exacerbates hypertension (ie, increases arterial pressure by approximately 20 mm Hg after 2 weeks on the diet), increases peripheral sympathetic nervous system activity, and greatly decreases the norepinephrine content of the AHA.5 Subsequent studies indicated that dietary NaCl supplementation decreases the local release of norepinephrine from nerve terminals in the AHA of NaCl-sensitive SHR but has no effect on norepinephrine release in the AHA of NaCl-resistant SHR or normotensive Wistar-Kyoto (WKY) rats.6 7 Furthermore, continuous infusion of the
2-adrenergic receptor agonist clonidine into the AHA
prevents the dietary NaCl–induced exacerbation of hypertension in
SHR.8 This finding 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 raises arterial
pressure.9 10 The mechanisms by which dietary NaCl excess alters norepinephrine release in AHA have not yet been elucidated, but baroreflex-induced release of norepinephrine could play a role. Previous studies suggested that baroreflex activation modifies norepinephrine release in several hypothalamic nuclei. In the posterior hypothalamic area (a sympathoexcitatory area of the brain), activation of the arterial baroreflex decreases norepinephrine release, and sinoaortic denervation elevates extracellular norepinephrine in this nucleus.11 12 13 A similar inverse relationship exists between arterial pressure and norepinephrine release in the paraventricular nucleus of the hypothalamus, another sympathoexcitatory area of the brain.14 15 The baroreflex-mediated release of norepinephrine in both of these nuclei has been reported to be disturbed in SHR compared with controls on a basal NaCl diet.13 14 In marked contrast to the inverse relationship between norepinephrine release and baroreflex activation in the paraventricular and the posterior hypothalamic nuclei, baroreflex feedback is directly related to norepinephrine release in the AHA of the rabbit.16 Furthermore, our group and others have reported that the baroreflex is blunted in SHR.17 18
Several studies suggest that baroreceptor information can alter the
activity of neurons in the AHA,19 20 21 22 23 24 25 26 and studies using
electrical stimulation,27 lesions,28 29 and
chemical injection4 30 31 indicate that the AHA has a
sympathoinhibitory function. Large injections of the anterior
hypothalamus with norepinephrine or 2-adrenoceptor
agonists lower blood pressure in normotensive rats,1 3 and
small, discrete injections of clonidine into the AHA reduce blood
pressure and heart rate in normotensive and hypertensive rats by means
of an 2-adrenergic receptor mechanism.4 In
contrast, microinjections of clonidine into the lateral or posterior
hypothalamic areas cause increases in blood pressure and heart
rate.4 Together, these findings suggest that the neurons
of the AHA subserve a sympathoinhibitory function and are activated by
local release of norepinephrine.
From the above data, we hypothesized that the baroreflex-induced release of norepinephrine in the AHA is decreased in SHR and that this is further blunted by a high NaCl diet in these animals. We used the push-pull perfusion method to measure extracellular release of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol (MOPEG) in the AHA, and the results of the present study indicate that baroreceptor activation increases the release of norepinephrine in the AHA in the awake rat (both SHR and WKY rats) and that in SHR this relationship is blunted by dietary NaCl supplementation.
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Methods |
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Seven-week-old male SHR and WKY rats (Harlan Sprague Dawley, Inc) were placed on a high NaCl diet (Custom Purina diet containing 8% NaCl; ICN Biochemicals, Inc) or remained on a basal (1%) NaCl diet (diet No. 5001, Ralston Purina). There were 8 to 10 rats in each diet-strain group. Food and water were available ad libitum throughout the study. All animals were housed (3 per cage initially and 1 per cage after surgery) at constant temperature (24±1°C), humidity (60±5%), and light cycle (6 AM to 6 PM). Heart rate, systolic arterial pressure (indirect tail-cuff method), and body weight were measured weekly.
Two weeks after the initiation of the 8% NaCl diet, the rats from both
diet groups were anesthetized with sodium pentobarbital (50 mg/kg IP),
and a stainless steel guide cannula (24-gauge) fitted with a removable
31-gauge obturator (extending 0.5 mm past the tip of the outer cannula)
was stereotaxically implanted above the AHA. The tip of the guide
cannula was positioned so 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, -8.0 mm).32 The
cannula was secured in place with acrylic cement that was anchored to
the skull by three stainless steel screws. After recovery from
anesthesia, all animals were placed in individual cages and maintained
on their diet until the time of study. Three days after the
implantation of the guide cannula, the animals were anesthetized with
sodium methohexital (60 mg/kg IP). Catheters (PE-10 fused to PE-50
tubing, Becton Dickinson) were implanted in the abdominal aorta through
the right femoral artery for measurement of arterial pressure and in
the right femoral vein for intravenous infusion of tramazoline (an
imidizoline that causes long-lasting peripheral vasoconstriction and
hypertension, probably because of its -agonist
effects11 ; Karl Thomee GmbH). 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 6 hours after implantation of the cannulas). On the day of the experiment, each animal was placed in a small cage that allowed free movement, and the arterial line was attached to a pressure transducer for recording blood pressure. After the rats had adapted to these conditions (as evidenced by a stable blood pressure signal and resting posture), 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 with artificial cerebral spinal fluid (ACSF [mmol/L: NaCl 119, KCl 3.3, CaCl2 1.3, MgCl2 1.2, Na2HPO4 0.5, NaHCO3 21.0, and glucose 3.4]; adjusted to pH 7.4 with 1N HCl) was then begun. 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 fractions in plastic tubes containing 25 µL of a 0.5N perchloric acid–EDTA solution (0°C) and subsequently stored at -20°C. After a 70-minute baseline collection period (seven samplesx10 minutes), each animal was infused intravenously with tramazoline (50 µL/mL) to raise mean arterial pressure (MAP) approximately 25 mm Hg above baseline for 20 minutes (infusion rate, approximately 10 µL/min). After drug administration, perfusate samples were collected and MAP was monitored for an additional 100 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 blind to the group designation of the sections examined.
Monoamines and metabolites in the perfusate were measured using high-performance liquid chromatography with electrochemical detection (HPLC-EC), as described previously.6 7 Quantitation 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, the major extracellular metabolite of norepinephrine in the brain. In addition to MOPEG, dopamine and serotonin and their metabolites (3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid) were also consistently detected by this technique, but norepinephrine was typically undetectable.
Statistics
The results are expressed as mean±SEM. The data were analyzed
by ANOVA with appropriate post hoc tests (Newman-Keuls) to determine
the source of main effects and interactions.33
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Results |
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In SHR, maintenance on the 8% NaCl diet for 2 weeks compared with the 1% NaCl diet significantly elevated MAP (162±2 mm Hg [n=8] and 143±2 mm Hg [n=7], respectively; P<.05). In contrast, MAP was not altered in WKY rats on the high NaCl diet compared with WKY rats on the basal NaCl diet (118±3 mm Hg [n=7] and 121±3 mm Hg [n=10], respectively; Fig 1). The infusion of tramazoline rapidly (within 20 seconds) increased MAP approximately 25 mm Hg in all groups (Fig 1) and maintained this elevation stably for 20 minutes. Resting heart rate was significantly higher in SHR (418±12 beats per minute [bpm]) than in WKY rats (367±8 bpm; Fig 2); the high NaCl diet did not alter resting heart rate (SHR, 394±8 bpm; WKY rats, 360±6 bpm). Tramazoline infusion induced a similar maximum baroreflex inhibition of heart rate (P<.05) in SHR (-22±3%) and WKY rats (-26±2%) on the basal NaCl diet. The high NaCl diet did not affect the bradycardic response to tramazoline in WKY rats (-25±3%) but significantly blunted the response in SHR (-11±2%; Fig 2). There were no significant differences in body weight among the four groups of rats.
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In agreement with our previous studies, maintenance on the high NaCl diet reduced extracellular MOPEG in AHA of SHR by approximately 70%. In the SHR on the 1% NaCl diet, basal MOPEG concentration in the AHA prior to tramazoline infusion averaged 305±32 pg/10 min, while in the SHR on the 8% NaCl diet it averaged 93±9 pg/10 min (Fig 3). The high NaCl diet caused a slight (but significant) reduction in the basal concentration of MOPEG in the AHA of WKY rats (1% NaCl, 94±6 pg/10 min; 8% NaCl, 79±5 pg/10 min; Fig 2), but this reduction was small (16%) compared with that observed in SHR (70%).
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In SHR, the tramazoline infusion increased MAP approximately 25 mm Hg (mean, 26±3 mm Hg) for 20 minutes and raised AHA MOPEG concentration to 392±46 pg/10 min (28±3%, maximum increase; P<.05) in the 1% NaCl group and to 113±18 pg/10 min (21±2%, maximum increase; P<.05) in the 8% NaCl group (Fig 3); both the absolute and the percent responses were significantly greater in the SHR on the 1% NaCl diet compared with the SHR on the 8% NaCl diet (P<.05). AHA MOPEG levels returned toward baseline when the infusion of tramazoline was stopped and after blood pressure had returned toward baseline levels. In WKY rats, a similar increase in arterial pressure elevated AHA MOPEG concentration significantly in both groups, but the elevation was significantly less in the WKY rats fed 1% NaCl (to 117±5 pg/10 min [22±3%]) compared with those fed 8% NaCl (to 104±7 pg/10 min [33±3%]). AHA MOPEG concentration returned toward baseline after the infusion was ended, but the duration of the response was longer in WKY rats than in SHR. Also, the tramazoline-induced rise in MOPEG in the AHA was somewhat slower in both SHR and WKY rats on the high NaCl diet than in those on the basal NaCl diet. It should be noted that the perfusate takes about 5 minutes to traverse the tubing between the push-pull cannula and the collector; thus, the initial sample after tramazoline infusion (or the cessation of the infusion) is a combination of the baseline MOPEG concentration and the MOPEG concentration during (or after) infusion.
Histological examination demonstrated that the push-pull cannulas were positioned in the AHA of all animals included in the study. The average diameter of the pontamine sky blue dye perfusion was 1.5 mm, and in a typical coronal section, the perfusate was at least 70% confined to the AHA. Three animals were eliminated from the study because of incorrect placement of the inner cannula.
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Discussion |
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In genetically predisposed individuals, diets high in NaCl cause the development or exacerbation of hypertension, typically associated with an increase in sympathetic nervous system activity,34 35 but the mechanistic relationship between increased sympathetic nervous system activity, blood pressure, and dietary NaCl excess remains enigmatic. Hypertension in the SHR bears many similarities to primary hypertension in humans.36 37 In both SHR and humans, dietary NaCl excess increases arterial pressure, at least in part, through the sympathetic nervous system.38 Exposure of young SHR to a high NaCl diet for 2 weeks causes a tonic increase in arterial pressure and peripheral sympathetic nervous system activity and a decrease in norepinephrine stores in the AHA but not in other regions of the hypothalamus or brain stem.6 Subsequent studies demonstrate that exposure to a high NaCl diet significantly reduces the turnover and the release of norepinephrine selectively in the AHA.5 7 In contrast, excess dietary NaCl does not elevate arterial pressure nor does it decrease norepinephrine release in the AHA of WKY rats.5 6 7 The current results confirm the findings of these earlier studies. In SHR, the high NaCl diet, compared with the basal NaCl diet, reduced baseline resting MOPEG levels in the AHA by approximately 70%. The high NaCl diet also caused a small but statistically significant decrease (approximately 16%) in AHA MOPEG levels in WKY rats. This suggests that even in NaCl-resistant rats, a high NaCl diet causes a small decrease in basal AHA norepinephrine release, but that this decrease is greatly exaggerated in NaCl-sensitive SHR.
The present results show that a tramazoline-induced elevation in arterial pressure results in the release of norepinephrine in the AHA of both SHR and WKY rats. Tramazoline directly increases arterial pressure by its action on peripheral adrenergic and/or imidizoline receptors, and this elevates baroreceptor feedback, which decreases heart rate. This suggests that the effects observed in the present study are baroreflex mediated. Studies in the rabbit indicate that norepinephrine turnover in the AHA is increased during baroreflex activation and decreased during baroreceptor unloading.11 16 This response contrasts with the inverse relationship between MAP and norepinephrine release in several other areas of the hypothalamus, including the lateral and posterior hypothalamic areas and the paraventricular nucleus.11 12 13 14 15 The latter nuclei contain a predominance of sympathoexcitatory neurons, and norepinephrine release in these nuclei is associated with an increase in sympathetic nervous system activity. Thus, in all three hypothalamic nuclei, baroreflex activation elicits an appropriate response, ie, decreased activation of the sympathetic nervous system by means of the paraventricular and posterior hypothalamic nuclei and increased sympathoinhibition by means of the AHA.
Our initial hypothesis was that AHA norepinephrine release after baroreflex activation is blunted in SHR compared with WKY rats, and that the high NaCl diet further decreases the response. In SHR (compared with WKY rats) on the basal NaCl diet, baroreflex activation elicited an augmented AHA MOPEG response, thus refuting the first part of our hypothesis. However, the results confirmed the second part of the hypothesis. The high NaCl diet differentially affected the response of AHA MOPEG to baroreceptor activation in SHR compared with WKY rats. In SHR, the high NaCl diet blunted the response, and in WKY rats it augmented the response. This increase in baroreflex gain may contribute to the resistance of this strain to the hypertensive effects of dietary NaCl excess.
In SHR compared with WKY rats, heart rate and lumbar sympathetic activity responses to arterial and cardiopulmonary baroreflex activation are blunted, and a high NaCl diet further decreases cardiopulmonary baroreflex gain in SHR but not in WKY rats.39 40 41 In contrast, 2-week exposure to the high NaCl diet increases lumbar sympathetic nerve responses to arterial baroreflex activation in SHR, suggesting that it may buffer the rise in arterial pressure.17 The present study confirms the previous findings by demonstrating that dietary NaCl excess blunts the reflex bradycardic response to increased arterial pressure in SHR but not in WKY rats. Thus, although baroreflex activation increases norepinephrine release in the AHA, and increases it more in SHR than in WKY rats on the basal NaCl diet (present results), this increase in norepinephrine release does not result in a normal baroreflex-mediated decrease in heart rate (present results and Reference 1717 ) or sympathetic nerve activity17 in SHR on a basal NaCl diet.
Previous studies suggest that imbalances in the baroreflex-mediated delivery of norepinephrine to other hypothalamic nuclei may contribute significantly to hypertension. In SHR (compared with WKY rats) on a basal NaCl diet, the norepinephrine levels in the posterior hypothalamic area are significantly elevated, but denervation of the baroreflex elevates norepinephrine content of the posterior hypothalamic area of WKY rats to the levels observed in SHR,13 suggesting that the baroreflex restrains the release of norepinephrine in the posterior hypothalamic area of WKY rats. In contrast, sinoaortic denervation has no effect on norepinephrine release in the posterior hypothalamic area of SHR.13 Furthermore, in mature SHR and Sprague-Dawley rats, decreases in arterial pressure increase the release of norepinephrine in the paraventricular nucleus of the hypothalamus. This response is attenuated in young (developing hypertensive) SHR,15 suggesting that baroreflex feedback to the paraventricular nucleus is blunted in young SHR.
The mechanism responsible for the selective reduction in norepinephrine release in the AHA in dietary NaCl–supplemented SHR is unclear. One clue to the mechanism may be found in the SHR on the basal NaCl diet. Our previous studies and this one indicate that much more norepinephrine is released in the AHA of SHR than of WKY rats on a basal NaCl diet; no similar elevation of norepinephrine release was observed in any other nucleus studied.5 6 7 The increased release of norepinephrine in the AHA of SHR might be a compensatory response to chronic hypertension, a response that is blocked in the SHR on a high NaCl diet.
Our previous studies suggested that atrial natriuretic peptide (ANP) in the AHA plays an important role in dietary NaCl–sensitive hypertension in SHR, probably by reducing the release of norepinephrine in the AHA of SHR.42 43 ANP is in overabundance in the AHA of SHR42 ; it presynaptically inhibits norepinephrine release,44 45 and blockade of ANP in the AHA reduces arterial pressure in SHR but not in WKY rats.43 We speculate that the overabundance of ANP in AHA contributes to the decreased baroreflex-mediated release of norepinephrine from the AHA of SHR on a high NaCl diet.
In summary, these data demonstrate that in the awake rat, norepinephrine is released in the AHA in response to activation of the arterial baroreceptor reflex. Furthermore, these findings indicate that this reflex-mediated norepinephrine release in the AHA is blunted by a high NaCl diet in SHR but not in WKY rats.
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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 a grant from the American Heart Association.
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References |
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J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
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A. S. Budzikowski, F. Vahid-Ansari, G. S. Robertson, and F. H. H. Leenen Patterns of Neuronal Activation During Development of Sodium Sensitive Hypertension in SHR Hypertension, December 1, 1997; 30(6): 1572 - 1577. [Abstract] [Full Text]
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N. Peng, Q. C. Meng, S. Oparil, and J. M. Wyss Acute Saline Infusion Decreases Norepinephrine Release in the Anterior Hypothalamic Area Hypertension, March 1, 1996; 27(3): 578 - 583. [Abstract] [Full Text]
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