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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION
1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and 2Division of Basic Biomedical Science, College of Medicine, University of South Dakota, Vermillion, South Dakota
Submitted 26 May 2004 ; accepted in final form 23 November 2005
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ABSTRACT |
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sympathetic nerve activity; paraventricular nucleus
In the PVN, a number of neurotransmitters and modulators, excitatory and inhibitory, converge to influence neuronal activity (10, 12, 15, 25, 40, 43). Among these modulators within the PVN are nitric oxide (NO) and ANG II. NO, as an atypical neurotransmitter, elicits multiple effects in the brain. In the hypothalamus, NO synthase (NOS)-positive neurons are found primarily in the PVN and supraoptic nucleus (3, 46). Functional studies have indicated that NO in the PVN elicits an inhibitory effect on sympathetic outflow and cardiovascular function (33, 50).
ANG II has been found to act as a neurotransmitter in the central nervous system and is involved in the regulation of sympathetic and cardiovascular activities (12, 31, 35). Components of the renin-angiotensin system, including angiotensinogen, angiotensin-converting enzyme, and the ANG II type 1 (AT1) receptor, have been found in the PVN (21, 38). Electrophysiological studies demonstrated that ANG II influences neurons in the PVN region (1, 22). Functional studies showed that ANG II within the PVN is involved in cardiovascular reflexes (31, 54, 55), suggesting that ANG II within the PVN plays a role in regulating sympathetic nerve activity and cardiovascular function.
The interactions between NO and ANG II have been observed in the peripheral circulation (4, 34) as well as the central nervous system (1, 20, 25). Electrophysiological studies on slice preparations of the forebrain indicated an interaction between NO and ANG II receptors in neuronal function (1, 20). Recent studies indicated a negative-feedback mechanism when NO was used as an inhibitory modulator of ANG II-mediated excitatory action on magnocellular cells of the PVN (1, 20). Furthermore, Li et al. (22) demonstrated that ANG II excites spinally projecting parvocellular neurons through presynaptic disinhibition, perhaps via a GABA-NO-mediated mechanism (2, 23, 51). However, the role of the interaction between NO and ANG II within the PVN in the regulation of sympathetic outflow and cardiovascular function is not well established. The purpose of the present study was to examine how the interaction between NO and ANG II within the PVN affects the subsequent regulation of sympathetic nerve activity and cardiovascular responses.
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METHODS |
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Male Sprague-Dawley rats (220–280 g body wt; Sasco Breeding Laboratories, Omaha, NE) were allowed to acclimate to our animal care facility for 1 wk before use. On the day of the experiment, each rat was anesthetized with urethane (0.75 g/kg ip) and 
-chloralose (70 mg/kg ip), and the left femoral vein was cannulated with polyethylene (PE-50) tubing for injection of supplemental anesthesia. The left femoral artery was cannulated and connected to a computer-driven data-recording and -analyzing system (MacLab; ADInstruments, Mountainview, CA) via a pressure transducer (model P231D; Gould) for recording of arterial blood pressure (AP) and heart rate (HR). The trachea was intubated to facilitate spontaneous ventilation.
Placement of Microinjection and Push-Pull Perfusion Cannulas in the PVN
The anesthetized rat was placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA). A longitudinal incision was made on the head, and the bregma was exposed. The coordinates for the PVN (1.5 mm posterior to bregma, 0.4 mm lateral to the midline, and 7.8 mm ventral to the dura) were determined from the atlas of Paxinos and Watson (36). A small burr hole was made in the skull. For the microinjections, a thin needle (0.5 mm OD, 0.1 mm ID) connected to a microsyringe (0.5 µl; model 7000.5; Hamilton) was lowered into the PVN unilaterally. For push-pull perfusion, a probe (0.7 mm OD, 0.2 mm ID) was lowered unilaterally into the PVN. Typically, the tip of the push-pull cannula was placed on the dorsal aspect of the main part of the PVN (i.e., on top of the dorsal cap region of the PVN) to avoid excess damage to the PVN, which was subsequently verified histologically. The push and pull cannulas were connected to a pump that infused and returned artificial cerebrospinal fluid (aCSF; in mM: 145 NaCl, 3.5 KCl, 1.0 MgCl2, and 1.3 CaCl2, pH 7.2) at a constant flow rate of 2 µl/min. The returned perfusate was collected as a fraction at 10-min intervals. The samples were rapidly frozen in –70°C for nitrate/nitrite (NOx) measurement.
Recording of Renal Sympathetic Nerve Discharge
The left kidney was exposed through a retroperitoneal flank incision. A branch of the renal nerve was isolated from the fat and connective tissue. The nerve was placed on a pair of thin bipolar platinum electrodes. The nerve-electrode junction was insulated electrically from the surrounding tissue with silicone gel (Sil-Gel 604 AB; Wacker). The electrical signal was amplified (10,000 times) with a Grass amplifier (model P55) with high- and low-frequency cutoff of 1,000 and 100 Hz, respectively. The output signal from the amplifier was rectified and integrated (20-ms time constant) and stored for later analysis using a computer-run data acquisition system (MacLab). The signal recorded at the end of the experiment (after the rat was dead) was considered background noise. Nerve discharge was calculated by subtraction of the background noise from the actual recorded value. Basal nerve discharge was defined by subtraction of the background noise from the actual nerve discharge before administration of drugs into the PVN. The peak response of renal sympathetic nerve discharge (RSND) to administration of drugs into the PVN during the experiment (averaged over 20–30 s) was subsequently expressed as percent change from baseline.
Measurement of NO Release in Perfusates From the PVN
NO concentration in the samples of perfusates from the PVN was measured as its NOx metabolites with use of a chemiluminescence detector (model 280 NO analyzer; Sievers). A standard curve for NaNO3 concentration (0.1, 0.5, 1, 2.5, 5, and 10 µM, 100-µl working volume, injected into the NO analyzer) was generated for each experiment, and the software provided with the NO analyzer was used to compare unknown samples (40 µl of sample + 160 µl of buffer solution, 100 µl injected in duplicate) with the standard curve. This program takes into account the peak response and the total area of the curve generated by standard and unknown samples. All measurements were performed at least in duplicate and then averaged to represent the mean for each sample.
Administration of Antisense to Neuronal NOS and Adenoviral Transfection of Neuronal NOS Gene Into the PVN
The neuronal NOS (nNOS) antisense sequence used in this study, 5'-ACGTGTTCTCTTCCATG-3', was designed according to the rat nNOS mRNA sequence (GenBank accession no. NM 052799). The target site chosen for the antisense oligodeoxynucleotide (AS-ODN) was the AUG translation initiation codon and nearby downstream sequence. The mismatch ODN (MS-ODN), consisting of the same number of bases in random order, was used as a control. The MS-ODN sequence was 5'-CATGTGCTCTCCTTAGT-3'. ODNs were modified with phosphorothioate ODNs to improve their stability. Each ODN was diluted in sterile aCSF to a concentration of 1 mM. The ODNs were administered into the PVN by unilateral microinjections of 100 nl of solution. This dose and protocol were based on our previous successful use of this AS-ODN against nNOS within the PVN (47) and our preliminary studies.
Adenoviral vectors carrying the rat nNOS gene sequence (Ad.nNOS) or the 
-galactosidase (-Gal) gene (Ad.-Gal, as a control vector) were transfected into the PVN as previously described for two brain areas, the PVN and rostral ventrolateral medulla (RVLM) (28, 48). Microinjection into the PVN was performed as described above. The adenoviral vectors were delivered into the PVN by unilateral microinjections of 50 nl of solution (1 x 108 plaque-forming units/ml final concentration) of Ad.nNOS or Ad.-Gal under pentobarbital sodium (40 mg/kg) anesthesia. After the injection, the wounds were sutured. At 3 days after injection, the rats were used for functional experiments as described for our previous use of Ad.nNOS to overexpress nNOS within the PVN and RVLM (28, 48).
Experimental Protocols
Experiment 1: effect of microinjection of the NOS inhibitor NG-monomethyl-L-arginine into the PVN on ANG II-induced changes in RSND, AP, and HR.
In the first group of rats (n = 6), ANG II (0.05, 0.5 and 1.0 nmol in 25, 50, and 100 nl of aCSF, respectively) was injected into the PVN at 30-min intervals in a random order. In the second group of rats (n = 6), each dose of ANG II was administered 2 min after injection of 0.1 nmol (50 nl) of NG-monomethyl-L-arginine (L-NMMA) into the PVN. RSND, AP, and HR responses were recorded after each application. In previous experiments, we observed that microinjection of L-NMMA into the PVN produces an increase in RSND, which begins at 
4–5 min, and a peak response, which occurs at 8–12 min (0.1 nmol/50 nl) (50). As a control, similar volumes of aCSF (25, 50, and 100 nl) were injected into the PVN. These aCSF injections into the PVN did not produce any significant change in RSND, AP, or HR over the time frame of these experiments (26).
To determine whether the responses to ANG II administration into the PVN were mediated by AT1 receptors, in another group of rats (n = 5), ANG II (1.0 nmol in 100 nl) was administered after injection of the AT1 antagonist losartan (1.0 nmol in 50 nl).
To determine whether the enhanced responses to ANG II administration after blockade of NO into the PVN were mediated by AT1 receptors, in another group of rats (n = 6), we observed the responses to ANG II (0.2 nmol) before and after injection of L-NMMA (0.1 nmol in 50 nl) alone or losartan (1.0 nmol in 50 nl) + L-NMMA.
To validate that the RSND, AP, and HR responses to ANG II or L-NMMA were not due to a peripheral action, in five rats, responses to intravenous injections of 1.0 nmol of ANG II with or without 0.1 nmol of L-NMMA were examined.
Experiment 2: effect of manipulations of the nNOS gene in the PVN on ANG II-induced changes in RSND. We used nNOS-specific AS-ODN to nNOS to examine the role of NO in the PVN in the response to ANG II. Previously, we demonstrated the depression of nNOS synthesis by nNOS antisense, which was confirmed by immunohistochemical staining and Western blot analysis (47). We determined the effect of inhibiting the expression of nNOS within the PVN on sympathetic outflow before and 1 h after ODN injections: AS-ODN-injected rats (n = 5) and MS-ODN-injected rats (n = 5) were subjected to unilateral microinjection of 0.2 nmol of ANG II into the PVN, and RSND, AP, and HR responses were recorded.
Conversely, using adenovirus transfer techniques to overexpress nNOS within the PVN, we examined the effect of overexpression of nNOS within the PVN on the response to ANG II. We previously confirmed the efficacy and time course of overexpression of nNOS within the PVN by immunohistochemistry and Western blot analysis (28). We determined the effect of overexpression of nNOS within the PVN on sympathetic outflow 3 days after adenoviral gene transfection of the PVN: Ad.nNOS-transfected rats (n = 5) and Ad.-Gal-transfected rats (n = 5) were subjected to unilateral microinjection of 0.2 nmol of ANG II into the PVN, and RSND, AP, and HR responses were recorded.
Experiment 3: effect of microinjection of losartan into the PVN on RSND, AP, and HR responses to L-NMMA. To determine the effect of endogenous ANG II on NO-mediated changes in RSND, AP, and HR, losartan was administered before L-NMMA. In the first group of rats (n = 6), 0.025, 0.05, and 0.1 nmol of L-NMMA in 25, 50, and 100 nl, respectively, was injected into the PVN at 30-min intervals in a random order. In the second group of rats (n = 6), each dose of L-NMMA was administered in a random order 2 min after injection of 1 nmol of losartan (50 nl) into the PVN. RSND, AP, and HR responses were recorded after each application.
Experiment 4: effect of perfusion of ANG II into the PVN on NO release. After a 40 min-equilibration period, the push-pull perfusate from the PVN was collected for a 30-min control period in anesthetized rats. After collection of two 20-µl samples (total of 40 µl) over 20 min, 1.0 nmol of ANG II (n = 5) was infused into the PVN within 1 min. Then two more 20-µl samples were collected over 20-min intervals during and after ANG II infusion (total of 40 µl), and another 40-µl sample was collected during the recovery period. In some additional rats (n = 4), samples were collected over the same time course without ANG II infusion for time controls. NOx concentration in the perfusate samples (40 µl) was measured using the Sievers NO analyzer as described above.
Brain Histology
After the experiment, the rat was killed and the brain was removed and fixed in 10% formalin for 
24 h. The brain was then frozen, and serial transverse sections (30 µm) were cut with a cryostat (–18°C). The sections were mounted on microscope slides and stained using 1% neutral red. The location of the injection within the PVN was verified under a microscope with x40 magnification (Fig. 1). The microinjections that terminated in the boundaries of the PVN were considered effective. For the purposes of analysis, only the animals in which dye was deposited within or <0.5 mm from the boundaries of the PVN were considered histologically targeted. The 50- to 200-nl injection volumes targeting the PVN would be expected to distribute the drug in or within <0.5 mm from the rostrocaudal and mediolateral boundaries of the PVN (39).
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RSND, AP, and HR responses to the various doses of drugs are expressed as percent changes from baseline. AP and HR responses to drugs are expressed as the difference between the basal value and the value after each dose of drug. The results in the same group of rats before and after administration of L-NMMA were subjected to paired t-test (see Fig. 4). The data were subjected to two-way repeated-measures ANOVA followed by comparison for individual differences using the Newman-Keuls test (49). P < 0.05 was considered to indicate statistical significance. Values are means ± SE.
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RESULTS |
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Administration of ANG II (n = 6) or ANG II + L-NMMA (n = 6) into the PVN significantly increased RSND, AP, and HR. The ANG II-induced increase in RSND usually peaked within 1 min after microinjection and was followed by a recovery phase (Fig. 2). Prior administration of L-NMMA enhanced the ANG II-induced increase in RSND. Figure 2 illustrates a typical time course of the change in RSND and AP in response to administration of ANG II (0.5 nmol) and ANG II (0.5 nmol) + L-NMMA (0.1 nmol) into the PVN. Because the peak RSND responses to ANG II or L-NMMA occurred in different time courses, it appears unlikely that the enhanced response to ANG II + L-NMMA was due to a simple addition of the two independent effects. In Table 1, AP, HR, and RSND responses to administration of L-NMMA or losartan before administration of ANG II indicate no significant changes compared with baseline.
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To further determine the effect of NO on ANG II-mediated changes in RSND within the PVN, we used the antisense technique to block nNOS. We tested the effect of inhibition of nNOS expression within the PVN by using antisense to nNOS. Administration of AS-ODN caused an increase in baseline for RSND, AP, and HR after 1 h (32.7 ± 6.2%, 12.6 ± 2.0 mmHg, and 16.2 ± 3.8 beats/min, respectively, n = 5). In AS-ODN-injected rats, RSND and HR responses to ANG II were significantly increased compared with baseline, even though the new baseline was higher after AS-ODN (Fig. 5A). MS-ODN injection did not significantly affect the basal level of RSND, AP, and HR or the responses of these parameters to ANG II (Fig. 5).
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-Gal-transfected rats (Fig. 5B; n = 5). Experiment 3: Effect of Losartan on L-NMMA-Induced Changes in RSND, AP, and HR
Microinjection of L-NMMA (0.025, 0.05, and 0.1 nmol, n = 6) into the PVN induced significant increases in RSND, AP, and HR in a dose-dependent manner, reaching 38 ± 6%, 13 ± 3 mmHg, and 24 ± 8 beats/min, respectively, at the highest dose. Prior administration of the AT1 receptor antagonist losartan (1.0 nmol, n = 6) into the PVN did not influence the L-NMMA-induced increases in RSND, AP, and HR (Fig. 6). This result suggests that endogenous NO within the PVN does not exert tonic inhibition on AT1 function (endogenous ANG II effect) in sympathetic outflow. The increase in RSND induced by NO blockade by L-NMMA is independent of endogenous ANG II action.
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In the 20 min during and after perfusion of ANG II (1.0 nmol) into the PVN, NOx concentration in the push-pull samples was significantly greater than that before perfusion (P < 0.05, n = 5; Fig. 7), indicating that ANG II stimulation within the PVN increases NO release. During recovery, NOx returned to basal levels. There were no significant changes in the levels of NOx from the PVN perfusate over the time frame of this experiment in the absence of ANG II.
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DISCUSSION |
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The PVN is one of the five major central nervous system sites that directly control sympathetic outflow (41), and it is the only site located in the hypothalamus. The parvocellular neurons of the PVN are known to be preautonomic neurons involved in mediation of the neural component of cardiovascular reflexes by influencing RSND (14, 27). However, the possible neurotransmitters and the interactions among them involved in regulating sympathetic function via the PVN have not been fully established. The results of this study indicate that ANG II within the PVN via AT1 receptors regulates sympathetic outflow. The components of the renin-angiotensin system, including angiotensinogen, angiotensin-converting enzyme, and the AT1 receptor, have been found in the PVN (21, 38), suggesting that ANG II may act as a modulator in the PVN. The action of ANG II within the PVN on the regulation of body fluid balance has been reported previously (6). Our present study functionally demonstrates that ANG II in the PVN plays a role in modulating autonomic activity. With its roles in autonomic function and in fluid balance and vasopressin release, ANG II within the PVN is critical for regulating cardiovascular functions and maintaining homeostasis.
Since the first demonstration that NO acts as a neuronal messenger in cerebellar granule cells (13), NO has been reported to be involved in various physiological activities as a nonconventional neurotransmitter, including sympathetic and cardiovascular functions (33). NOS-positive neurons have been found predominantly in the PVN (46). It has been reported that NO exerts an inhibitory effect on the functions of the hypothalamic nucleus (24, 29). Functional studies from our laboratory indicate that NO in the PVN elicits an inhibitory effect on sympathetic nerve activity (33, 50). Previously, an electrophysiological experiment using brain slices found that NO inhibition enhanced ANG II action on PVN neurons (1, 20). In the present study, we observed that ANG II-induced increases in RSND could be enhanced by inhibition of endogenous NO synthesis by L-NMMA. This effect was further confirmed by use of antisense to nNOS to block nNOS expression. This suggests that specifically nNOS within the PVN is involved in the inhibitory influence on the excitatory effect of ANG II on RSND. In contrast, increasing NO function by overexpression of nNOS using adenoviral gene transfection decreased the excitatory response to ANG II. All these observations suggest that NO has an inhibitory effect on the excitatory action of ANG II on preautonomic neurons within the PVN. Taken together, these results demonstrate that NO within the PVN, mainly derived from nNOS, exerts an inhibitory effect on sympathetic outflow.
On the other hand, ANG II has been found to regulate NOS activity and NOx levels, indicating NO release. Previous studies revealed that ANG II regulates the activities of NOS (56). ANG II increases nNOS activity and NO release by increasing intracellular calcium concentration. In this study, using the push-pull method, we observed that perfusion of ANG II into the PVN induced an increase in NO release, suggesting a role for ANG II in regulation of NOS action and NO level within the PVN.
On the basis of these observations, we hypothesize a negative-feedback loop between ANG II and NO systems within the PVN: As an excitatory neurotransmitter, ANG II activates the preautonomic neurons within the PVN and induces an increase in sympathetic outflow. Meanwhile, ANG II also stimulates nNOS and induces an increase in NO release. NO, in turn, exerts an inhibitory effect on ANG II excitatory action. We presume that this negative-feedback mechanism plays an important role in maintaining the balance between excitatory and inhibitory mechanisms within the PVN and in preventing sympathetic overexcitation. Previously, we observed a similar negative-feedback mechanism between glutamate and NO within the PVN in regulation of sympathetic outflow (26). Thus we propose that NO within the PVN plays a general role in buffering the actions of the excitatory systems, including glutamate and ANG II. When the excitatory systems are initiated, the NO system is stimulated and NO release is increased. The increased NO, in turn, elicits an inhibitory effect on the excitatory components in the PVN. NO may elicit the inhibitory effect via direct and indirect mechanisms. Recent studies indicated that NO mediates GABAergic inhibitory postsynaptic potentials (22). Another study indicated that a GABAergic mechanism was involved in NO inhibition of the firing activity of PVN neurons (24). All these data suggest that a GABAergic mechanism may be involved in the NO-mediated inhibitory action. In addition, NO has been found to directly regulate the excitatory components, such as ANG II receptors and glutamate receptors. For example, it has been found that NO derivatives attenuate the activity of glutamate NMDA receptors by reducing or oxidizing certain residues (19). NO has also been found to downregulate AT1 receptor expression in vascular smooth muscle cells (4) and myocardium (17). Thus the direct action of NO on the excitatory mechanisms, including glutamate and ANG II systems, may also be the important mechanism of NO inhibition in these excitatory components in the PVN.
We observed that although ANG II stimulation in the PVN induces the excitatory responses, the AT1 receptor antagonist losartan did not induce significant changes in the baseline values of RSND, AP, and HR (Table 1), suggesting that endogenous ANG II does not exert a tonic excitatory effect on basal sympathetic outflow. In this study, we tested the possibility that NO also exerts a tonic inhibition on endogenous ANG II action at rest. We observed that blockade of NO production with L-NMMA induced an increase in RSND. However, blockade of the AT1 receptor with losartan did not influence the L-NMMA-induced increase in RSND, suggesting that endogenous NO may not tonically inhibit the endogenous action of ANG II under normal conditions. It appears that only when the ANG II system is initiated, the ANG II-stimulated increase in NO inhibits the action of ANG II. However, the results of this study cannot exclude the tonic inhibition on ANG II action by other inhibitory mechanisms, such as the GABA system in the PVN.
The PVN is one of the critical structures involved in neuroendocrine and autonomic regulation and maintenance of homeostasis in the internal environment. The PVN receives afferent fibers from the brain stem and subfornical organ, as well as higher levels of the central nervous system (37, 45). The incoming signals may include internal environmental challenges and physical and emotional stresses. The PVN neurons integrate these signals and send output to the pituitary, median eminence, brain stem (RVLM), and spinal cord to influence endocrine and autonomic functions (10, 44). The correct or appropriate output from the PVN depends on the balance of the excitatory and inhibitory mechanisms. Recently, more studies suggest that a breakdown in the PVN integration may contribute to some pathophysiological conditions, including hypertension (11) and heart failure (25, 32). We recently observed a significant reduction of NOS-positive cells in the PVN in rats with heart failure (52). In such a condition, when ANG II action is increased (as is in heart failure), the amount of NO released is insufficient to exert an adequate feedback inhibition. This alteration may overexcite the ANG II system and increase sympathetic outflow. Indeed, the activated renin-angiotensin system driving the PVN neurons in heart failure has recently been reported (53). This imbalance of inhibitory and excitatory mechanisms within the PVN may contribute to the elevated sympathetic nervous outflow observed in hypertension (11) and heart failure (25, 32). Thus restoration of NOS activity and NO level within the PVN may represent a new avenue for treatment of these diseases.
In conclusion, our study demonstrates that NO modulates AT1 receptor-mediated increases in renal sympathetic nerve activity. This indicates a short-loop inhibition by NO of excitation by AT1 receptor activation within the PVN to increase renal sympathetic nerve activity. This interaction may be important in dictating overall sympathetic outflow in disease states known to have altered nNOS activity in the PVN with a concomitant increase in basal sympathetic tone, such as heart failure (25, 32) and hypertension (11).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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, Sites of termination of microinjections, which were confirmed to be within the PVN region; *sites of termination of push-pull probe, which were confirmed to be within the PVN region; #sites of microinjection, which were confirmed to be outside the PVN. AH, anterior hypothalamic nucleus; f, fornix; 3V, 3rd ventricle.
, Baseline (before drug perfusion), ANG II (1.0 nmol) perfusion, and recovery period; 
, time control. Values are means ± SE. *P < 0.05 vs. time control.