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(Hypertension. 2003;41:571.)
© 2003 American Heart Association, Inc.

Scientific Contributions

_2A-Adrenergic Receptors Mediate Sympathoinhibitory Responses to Atrial Natriuretic Peptide in the Mouse Anterior Hypothalamic Nucleus

Ning Peng; Brandon D. Chambless; Suzanne Oparil; J. Michael Wyss

From the Department of Cell Biology (N.P., B.D.C., J.M.W.) and the Vascular Biology and Hypertension Program of the Department of Medicine (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 35294-0006. E-mail jmwyss{at}uab.edu

	Abstract

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In the rat, activation of ₂-adrenergic receptors in the anterior hypothalamic nucleus inhibits sympathetic nervous system activity. Furthermore, local release of atrial natriuretic peptide inhibits norepinephrine release in this nucleus, blocking local activation of ₂-adrenergic receptors, and thereby contributes to NaCl-sensitive hypertension in spontaneously hypertensive rats. To further test the specificity of this mechanism, either ₂-adrenergic receptor agonists or atrial natriuretic peptide was microinjected into anterior hypothalamic nucleus of conscious C57BL/6 mice in which the ₂-adrenergic receptor was functionally deleted by a single point mutation (n=10 per group). In control mice, microinjection of either clonidine or guanabenz (10^-3 to 10^-7 mol/L) caused a rapid fall in mean arterial pressure that lasted for several minutes. In the knockout mice there was no response to the injection of either dose of either agonist. Microinjection of atrial natriuretic peptide (10^-6 to 10^-7 mol/L) caused a rapid increase in mean arterial pressure (8.2±1.3 and 6.55±1.2 mm Hg, respectively) in the control mice that was similar to the responses previously observed in Wistar-Kyoto rats. In contrast, the microinjections did not significantly alter mean arterial pressure in the knockout mice. These experiments demonstrate that in the anterior hypothalamic nucleus of the mouse (and probably in the rat) _2A-adrenergic receptors mediate both sympathoinhibitory responses to ₂-adrenergic receptor agonists and the action of atrial natriuretic peptide.

Key Words: hypertension, experimental • hypothalamus • receptors, adrenergic • norepinephrine • rats

	Introduction

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In spontaneously hypertensive rats (SHR), high NaCl diets stimulate the sympathetic nervous system (SNS) and thereby exacerbate hypertension. Specifically, a high NaCl diet decreases norepinephrine release in the anterior hypothalamic nucleus (AHN), which in turn decreases activation of local ₂-adrenergic receptors.^1,2 This interaction is mediated, at least in part, by the neurotransmitter/neuromodulator atrial natriuretic peptide (ANP), which inhibits norepinephrine release.³ Together, these findings suggest that in the AHN, both ANP and ₂-adrenergic receptors play a role in cardiovascular regulation in SHR.

In normotensive rats, local ₂-adrenergic receptors also contribute to the sympathoinhibitory role of the AHN, and stimulation of these receptors decreases arterial pressure.¹ Thus, whereas ₂-adrenergic receptors in the AHN are important to the pathogenesis of NaCl-sensitive hypertension, they also play a role in arterial pressure regulation in normotensive rats.¹ Furthermore, in normotensive rats, norepinephrine release in AHN is regulated in part by ANP, a potent natriuretic hormone that is synthesized in the cardiac atria, released into the circulation, and regulates salt and water balance and blood pressure, primarily through actions on the kidney.^4,5 ANP is also locally synthesized in the brain, and as a neurotransmitter/neuromodulator it contributes to the central control of arterial pressure and water balance.^6–8 Microinjection of ANP into the AHN decreases norepinephrine release, thereby increasing sympathetic nervous system activity and elevating arterial pressure.^9,10 Furthermore, the concentration of ANP in AHN is higher in SHR than in normotensive Wistar-Kyoto rats (WKY),¹¹ and this appears to contribute to NaCl-sensitive hypertension in SHR.¹² Together, these results suggest that in AHN, ANP acts as a neuromodulator by decreasing activation of ₂-adrenergic receptors in the AHN.

Although these data support the role of AHN ₂-adrenergic receptors in blood pressure control and in the hypertensive effects of hypothalamic ANP, current techniques cannot specifically identify the subtype(s) of ₂-adrenergic receptors involved. All 3 subtypes of ₂-adrenergic receptors (_2A, _2B, and _2C), each of which is encoded by a separate gene,^13,14 appear to be involved in the regulation of sympathetic nervous system activity. However, the current evidence suggests that in the brain, the _2A subtype mediates most of the ₂-adrenergic receptor effects on arterial pressure.^15,16 The current study tests the hypothesis that _2A-adrenergic receptors in the AHN modulate arterial pressure and mediate the cardiovascular effects of ANP in the AHN. Selective adrenergic receptor agonists or ANP were microinjected into the AHN of transgenic mice in which the _2A-adrenergic receptor was functionally deleted (D79N mice),¹⁷ and the mean arterial pressure (MAP) and heart rate (HR) responses were measured in transgenic compared with wild-type mice.

	Methods

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All studies were performed in 4-month-old, D79N transgenic mice (D79N mice)¹⁷ and age-matched C57 Bl/6 mice (wild type, Harlan Sprague Dawley, Inc, Indianapolis, Ind; n=10 per group for each of the 2 experiments). Deletion of the _2A-adrenergic receptor was confirmed by Southern blot analysis of NheI-digested genomic DNA from the tail, per the method of MacMillan, et al.¹⁷ The Southern blot analyses demonstrated a clear 568-bp band in all D79N mice and no 453-bp band. In contrast, the wild-type mice showed only the 453-bp band. All animals were housed at constant temperature (21±1°C), humidity (60±5%), and 12/12 hour light/dark cycle (light from 6:00 AM to 6:00 PM). Water and food (basal diet 5001, Ralston Purina) were available ad libitum throughout the study, and body weights were measured weekly. All protocols for the use of animals were approved by the University of Alabama at Birmingham’s Institutional Animal Care and Use Committee in accordance with the NIH guide on The Humane Treatment of Experimental Animals.

Five days before the central administration of drugs, each mouse was anesthetized with a ketamine and xylazine combination (0.2 mL/20 g IP), and a guide cannula (28 gauge; fitted with a 35-gauge removable obturator) was stereotaxically implanted immediately dorsal to the right AHN. The cannula was secured in place with acrylic dental cement that was anchored to the skull by 2 stainless steel screws (the stereotaxic coordinates for the microinjections were anterior, posterior=-0.6 mm from bregma; lateral=+0.4 mm; ventral=-5.6 mm).¹⁸ After the animals recovered from anesthesia, they were individually housed for the remainder of the study. One day before the study, mice were reanesthetized with ketamine and xylazene (as above), and a cannula (PE 50 tubing fused with a small polyethylene tubing that was pulled to a tip of 100 m [OD]; Becton Dickinson Co) was implanted into the abdominal aorta through the left femoral artery for measurement of arterial pressure and heart rate. Animals were allowed to recover from the anesthesia overnight.

On the following day, each animal was placed in a small cage where it could move freely, and the polyethylene PE-50 tubing was connected to a pressure transducer. After a 30-minute equilibration period, the microinjector (100 m OD) was inserted through the guide cannula into the AHN. The inner cannula was attached to a 0.5:l Hamilton syringe. In the first experiment, 50 nL of the nonselective ₂-adrenergic receptor agonist clonidine (10^-7 mol/L or 10^-3 mol/L in artificial cerebrospinal fluid; Sigma) was injected into the AHN over a 5-second interval, and blood pressure and heart rate responses were measured for the subsequent 60 minutes. After mean arterial pressure had returned to baseline (60 minutes), the experiment was repeated using the more selective ₂-adrenergic receptor agonist guanabenz (10^-7 mol/L or 10^-3 mol/L, Sigma). In a second group of mice, 50 nL of ANP (10^-7 mol/L or 10^-6 mol/L, Peninsula Laboratories, Inc) was microinjected into the AHN using the same protocol as above, and arterial pressure and heart rate were continuously monitored for another 60 minutes.

At the end of the study, the AHN was injected with 50 nL of 2% Sky Blue (Sigma) in saline, the mice were killed; the brains were removed, cut on a freezing microtome (30-m-thick sections) and lightly stained with cresyl violet for histological verification of cannula placement. Two mice in each group were discarded because of incorrect cannula placement. In all other animals, the blue dye staining was centered in the AHN.

All data are expressed as mean±SEM and were analyzed by ANOVA with appropriate post hoc tests (Newman-Keuls) to determine the source of main effects and interactions.¹⁹

	Results

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There was no significant difference in body weight between the mutant mice (26.6±0.6 g) and the wild-type control mice (26.8± 0.7 g). The baseline mean arterial pressure and heart rate were also similar between groups (D79N, 100±4 mm Hg and 538±15 bpm; wild-type, 103±4 mm Hg and 560±12 bpm; NS).

In wild-type mice, AHN microinjection of the ₂-agonist clonidine at 10^-3 mol/L resulted in a significant decrease in mean arterial pressure and heart rate, but microinjection of 10^-7 mol/L clonidine had no consistent effect on either parameter (Figure 1). Responses to the 10^-3 mol/L dose of clonidine had a rapid onset (<20 seconds) and a duration of >20 minutes. In contrast to the wild-type mice, D79N mutant mice displayed no arterial pressure or heart rate response to microinjection of clonidine at either concentration (Figure 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Maximum changes in arterial pressure (A) and heart rate (B) in wild-type control and D79N mice after microinjection of clonidine into AHN. *P<0.05 vs D79N.

Microinjection of the more selective ₂-adrenergic receptor agonist guanabenz into the AHN caused significant decreases in arterial pressure and heart rate in wild-type mice at the both 10^-3 mol/L and 10^-7 mol/L concentrations (Figure 2). These responses had a rapid onset (<20 seconds) and lasted >20 minutes (Figure 3A). In D79N mice, microinjection of guanabenz into AHN at either concentration caused no change in mean arterial pressure or heart rate (Figures 2 and 3B).

View larger version (14K): [in this window] [in a new window]   Figure 2. Maximum changes in arterial pressure (A) and heart rate (B) in wild-type control and D79N mice after microinjection of guanabenz into AHN. *P<0.05 vs D79N.

View larger version (13K): [in this window] [in a new window]   Figure 3. Changes in arterial pressure and heart rate in wild-type control (A) and D79N (B) mice after microinjection of guanabenz into AHN. Note that in A both heart rate and arterial pressure are significantly different from baseline for the 20 minutes after microinjection. There was no significant heart rate or arterial pressure response to the microinjection in D79N mice.

In the second experiment, microinjection of either 10^-7 mol/L or 10^-6 mol/L ANP into the AHN of wild-type mice caused a rapid (<20 seconds), significant increase in MAP and heart rate (Figure 4) that lasted for >20 minutes. Conversely, in D79N mice, mean arterial pressure and heart rate were not significantly altered by ANP microinjection into AHN at either concentration (Figure 4).

View larger version (17K): [in this window] [in a new window]   Figure 4. Changes in arterial pressure (A) and heart rate (B) in wild-type control and D79N mice after microinjection of ANP into AHN. *P<0.05 vs D79N.

Control for Specificity of Responses
Pilot analysis of 50 nL Sky Blue injections into the mouse AHN indicates that the 50 nL injections reached most parts of the anterior hypothalamic nucleus within 10 minutes. Furthermore, we placed control injections (n=5 in wild-type mice only) of clonidine at a distance of 2 mm dorsal or caudal to AHN. These elicited either no response or a pressor response during the initial 2 minutes. Microinjections of 50 nL of the vehicle into the AHN had no effect on MAP or heart rate in wild-type mice (n=3, data not shown).

	Discussion

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The present study demonstrates that microinjection of clonidine or guanabenz into the AHN causes a rapid fall in arterial pressure and heart rate in wild-type C57bl/6 mice that is similar to that previously observed in both normotensive and hypertensive rats.^1,9 In contrast, D79N mutant mice, which lack a functional _2A-adrenergic receptor, do not have cardiovascular responses to microinjection of either drug into the AHN. Together, these findings support the hypothesis that _2A-adrenergic receptors mediate the cardiovascular response to norepinephrine release in the AHN of the mouse brain. Furthermore, microinjection of ANP into AHN increases arterial pressure and heart rate in wild-type but not in D79N mutant mice, indicating that the _2A-adrenergic receptor in the AHN is requisite for this response in the mouse. Thus, although the identity of the subtype of ₂-adrenergic receptor that mediates similar responses in the rat is as yet unknown, the present results strongly suggest that the _2A-adrenergic receptor is the most likely candidate.

Previous studies using transgenic mice have suggested a role for each ₂-adrenergic receptor subtype in cardiovascular control. _2A-Adrenergic receptors are widely expressed in the central nervous system and play a key role in cardiovascular regulation. In D79N mice, the hypotensive effects of intravenous ₂-agonists are eliminated and the activation of _2A-adrenergic receptors decreases sympathetic nervous system activity.^15,17 In contrast, the hypotensive effect of intravenous ₂-agonist injections is significantly increased in _2B-adrenergic receptor knockout mice, and stimulation of _2B-adrenergic receptors in vascular smooth muscle induces hypertension. In the brain, stimulation of _2B-adrenergic receptors appears to counteract the action of adrenergic agonists on _2A-adrenergic receptors, and the _2B-adrenergic receptor may contribute to salt-sensitive hypertension.^14,15 The _2C-adrenergic receptors do not appear to contribute importantly to cardiovascular regulation.¹⁵ Our data strongly support a sympathoinhibitory role of the _2A-adrenergic receptor in the brain.

Excess dietary sodium chloride significantly contributes to hypertension in "salt-sensitive" individuals, for example,²⁰ and studies have begun to elucidate the mechanism(s) by which plasma sodium and chloride can alter the activity of neurons in cardiovascular control nuclei. The circumventricular organs in the rostral hypothalamus monitor plasma sodium and osmolality directly.^21,22 In SHR, the organum vasculosum of the lamina terminalis (OVLT) appears to be the primary monitor of plasma sodium concentration. In SHR fed a high NaCl diet, indirect projections from the OVLT to the AHN appear to be responsible for a decrease in norepinephrine release, a rapid rise in arterial pressure, increased sympathetic nervous system activity, and peripheral vasoconstriction.²³ Long-term administration of an ₂-adrenergic receptor agonist in AHN blocks the NaCl-sensitive rise in arterial pressure in SHR but has no significant effect on arterial pressure in normotensive control animals or in SHR on a basal NaCl diet.²⁴ Acute AHN microinjection of a blocking antibody to ANP causes a significant dose-related decrease in MAP and HR in SHR-S but not in WKY, indicating that ANP in the AHN exerts tonic control over blood pressure in SHR. Furthermore, in SHR, the increase in ANP and/or decrease in the clearance receptor for ANP (ANP C receptor) results in potent inhibition of norepinephrine release in the AHN.^12,25 This suggests that ANP is an important link between excess NaCl intake and decreases in norepinephrine in the AHN.²⁶ The present results suggest that ANP plays a similar role in the mouse AHN and that this effect is mediated by _2A-adrenergic receptors.

The ANP content of the brain is altered in several models of salt-sensitive hypertension in the rat. SHR display a high ANP content in AHN, and these differences appear to precede the development of the hypertension.^10,26,27 Endogenous ANP in brain inhibits the release of norepinephrine from CNS nerve terminals¹² and can thereby influence cardiovascular regulation.^9,28 In SHR, microinfusion into AHN of ANP or cANP (ANP_4–28, which blocks the ANP C-receptor and thereby increases extracellular ANP in the brain by inhibiting its clearance) significantly decreases extracellular norepinephrine concentration and release, thereby increasing arterial pressure.³ In the present study, microinjection of ANP into the AHN caused a rise in arterial pressure in wild-type mice but not in D79N _2A-adrenergic receptor-mutant mice. This indicates that ANP has a similar pressor effect in the AHN of both rats and mice and suggests that in both species, the central mechanism of ANP in the AHN involves norepinephrine release and _2A-adrenergic receptors. Finally, wild-type mice are similar to normotensive, NaCl-resistant WKY in that they did not have an increase in arterial pressure in response to dietary NaCl excess.²⁹

Because the mouse brain is so small, caution must be exercised in interpreting these results as AHN-specific. The mouse AHN is 0.5 mm in circumference and 1 mm in total length. Analysis of 50 nL Sky Blue injections into the mouse AHN indicates that 50 nL injections can reach most parts of the nucleus and within 10 minutes typically diffuse to an area 20% greater in size than AHN. This is similar to the size estimates that we calculated using titrated clonidine in rats.¹ Furthermore, in control experiments, injection of clonidine at a distance of 2 mm dorsal or caudal to AHN elicited either no response or a pressor response in the initial 2 minutes. In addition, the responses to clonidine injections into the AHN were dose-related, and microinjections of 50 nL of the vehicle into the AHN had no effect on MAP or heart rate in wild-type mice (n=3, data not shown). Thus, the responses that we report were not due to the mechanical pressure imposed by the microinjection. Furthermore, the concentrations of agonists used in these studies are within the range that we have previously used in the rat.¹ The 10^-7 mol/L dose of the ₂-adrenergic receptor agonist is in the physiological range, that is, <100 times the kD of the ₂-adrenergic receptor. Also, the onset of the cardiovascular responses were rapid, reaching a peak within 60 seconds. If diffusion were an important factor in the results, a longer latency to initial and peak responses would be expected. Taken together, these observations suggest that our microinjections selectively activated neurons in the AHN in the wild-type mouse.

In the mouse, the cardiovascular response to the microinjection of the ₂-adrenergic receptor agonists clonidine and guanabenz into the AHN is mediated by _2A-adrenergic receptors. Furthermore, the hypertensive effect of microinjection of ANP into AHN also appears to be mediated by local AHN _2A-adrenergic receptors. Both of these mechanisms appear to be common to rat and mouse.

	Acknowledgments

 
This work was funded by grants HL37722 and NS41071 (J.M.W.) from the National Institutes of Health. We thank Dr Lee Limbird of Vanderbilt University (HL25182 and HL43671) for the original breeder mice.

Received October 7, 2002; first decision October 24, 2002; accepted January 8, 2003.

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This Article Abstract Full Text (PDF) All Versions of this Article: 41/3/571    most recent 01.HYP.0000056998.83031.22v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Peng, N. Articles by Wyss, J. M. Search for Related Content PubMed PubMed Citation Articles by Peng, N. Articles by Wyss, J. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CLONIDINE GUANABENZ ACETATE Related Collections Autonomic, reflex, and neurohumoral control of circulation Receptor pharmacology Hypertension - basic studies