Published online before print March 5, 2007, doi: 10.1161/HYPERTENSIONAHA.106.086322
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(Hypertension. 2007;49:1170.)
© 2007 American Heart Association, Inc.
Original Articles |
Fos-Related Antigen Immunoreactivity After Acute and Chronic Angiotensin II–Induced Hypertension in the Rabbit Brain
From the Neuropharmacology Laboratory, Baker Heart Research Institute, Melbourne, Australia.
Correspondence to Pamela J. Davern, Baker Heart Research Institute, Commercial Road, Prahran, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail pamela.davern{at}baker.edu.au
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Abstract |
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Several brain regions are proposed as contributing to chronic sympatho-excitatory effects of elevated circulating angiotensin II. However, earlier c-Fos studies have been limited to acute angiotensin II exposure. This study aims to determine brain regions responding with chronic elevated angiotensin II. Rabbits were administered angiotensin II (50 ng/kg per minute) or saline for 3 hours, 3 days, or 14 days. Basal mean arterial pressure was 71±2 mm Hg and increased 23±2 mm Hg, 32±4 mm Hg, and 22±2 mm Hg for 3 hours, 3 days, and 14 days, respectively, with angiotensin II infusion. Neuronal activation was detected using Fos-related antigens, which recognizes all of the known members of the Fos family. Neurons located in the amygdala and area postrema were activated transiently after acute infusion of angiotensin II but were not responsive by days 3 or 14. Neurons located in the nucleus of the solitary tract, caudal ventrolateral medulla, and lateral parabrachial nucleus were activated for
3 days after infusion of angiotensin II but were not responsive by day 14, which is consistent with their role in response to baroreceptor pathways that reset with sustained hypertension. The vascular organ of the lamina terminalis and subfornical organ showed sustained but diminishing activation over the 14-day period. However, the downstream hypothalamic nuclei that receive inputs from these nuclei, the paraventricular, supraoptic, and arcuate nuclei, showed marked sustained activation. These findings suggest that there is desensitization of circumventricular organs but sensitization of neurons in hypothalamic regions to long-term angiotensin II infusion.
Key Words: angiotensin II • chronic hypertension • Fos-related antigen • immunohistochemistry • rabbit brain
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Introduction |
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Although renal hypertension is thought to be largely volume dependent, there is growing evidence to suggest that sympathetic nerve activity in hypertensive animals and also in human forms of the disease is likely to be increased.1 A greater depressor response to ganglion blockade has been observed in angiotensin II (Ang II)–infused hypertensive rats2 and renal wrap hypertensive rabbits.3 In renovascular hypertensive patients, noradrenaline spillover is elevated.4 Thus, it has been suggested that there are 2 distinct phases of Ang II–induced hypertension, an initial hypertension because of Ang II–mediated vasoconstriction that is replaced by a longer-term, neurogenic component.2,3,5 Even so, the expected greater sympathetic activity in renovascular hypertension has been surprisingly difficult to confirm because of the use of indirect measures, which have yielded conflicting findings.6,7 Moreover, recent studies have suggested that baroreceptor mechanisms inhibit sympathetic activity not only acutely but over several days, preventing sympathetic activation.8,9 This hypothesis questions whether baroreceptors reset completely and suggests that, if they do not, then they may contribute to blood pressure regulation in the long term. These studies are limited by the relatively short term (several days) over which experiments were performed, and clearly there is strong evidence to suggest that baroreceptor mechanisms do adjust to pressure in the very long term (several weeks to months).10 Thus, there appear to be
3 major mechanisms contributing to renovascular hypertension: (1) acute vasoconstriction produced by circulating Ang II, (2) baroreceptor feedback produced by the hypertension, and (3) central nervous system (CNS) activation via angiotensin II type 1 (AT1) receptors in circumventricular organs. The key issue remaining is to identify the pathways in the CNS that drive the humoral and sympathetic contribution to renovascular hypertension.
By using c-Fos immunohistochemistry, acutely activated neurons can be readily detected within the CNS.11 This methodology has been used to determine the pattern of neuronal activation in response to acute administration of Ang II in the rabbit12–14 and in the rat.15,16 However, downregulation of c-Fos renders this method ineffective in detecting the sustained influence of circulating Ang II in the CNS. More recently, studies have used an antibody that detects all of the known members of the Fos family, including c-Fos, Fos B, Fos-related antigen (Fra) 1, and Fra 2, and these Fras show prolonged induction, which persists for chronic periods after a single stimulus.17–20 Therefore, an antibody that cross-reacts with multiple Fras may be a useful tool for detecting long-term neuronal activation and is likely more effective than a specific c-Fos antibody. Nevertheless, further clarification of a specific relationship between Fra expression and neuronal activation is a consideration. Lohmeier et al19 measured Fra in brain stem and hypothalamic nuclei after Ang II infusion for 5 days in dogs, at which time there was clear evidence for continued baroreceptor activation through the nucleus of the solitary tract (NTS) and caudal ventrolateral medulla (CVLM), with no evidence of activation of the rostral ventrolateral medulla (RVLM). We hypothesize that, given sufficient time, baroreceptor mechanisms will reset, and differential patterns of neuronal activation in response to acute and chronic Ang II–induced hypertension will be revealed. Thus, in the present experiment, we examined brain regions responding to acute (3-hour), short-term (3-day), and longer-term (2-week) infusion of Ang II using Fra immunoreactivity.
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Methods |
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Animals
Experiments were conducted in 18 conscious male New Zealand White rabbits weighing between 2.45 and 2.75 kg. These rabbits were housed at the Baker Heart Research Institute and were meal fed (Glen Forrest Stock Feeders) and given ad libitum access to water. The experiments were approved previously by the Alfred Medical Research Education Precinct Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for Scientific Use of Animals.
Experimental Protocol
On the day of the experiment, rabbits were housed in a standard single rabbit holding box (15x40x18 cm), and basal mean arterial blood pressure (MAP) and heart rate (HR) were measured from the central ear artery. These were recorded for 1 hour after a minimum 30-minute settlement period. These were derived from the pulse pressure using an algorithm and digitized and averaged over 2-second periods. Rabbits were randomized into 3 experimental groups: (1) 3-hour intravenous infusions (n=4), (2) 3-day subcutaneous infusions (n=4), or (3) 14-day subcutaneous infusions (n=4). Although treatments were delivered via 2 separate methods, earlier experiments identified no differences in MAP in rabbits administered Ang II delivered either subcutaneously or intravenously (S. Malpas, personal communication, 2006). In group 1, Ang II (50 ng/kg per minute, Auspep) or vehicle (saline, n=2) was infused into the marginal ear vein for 3 hours. In groups 2 and 3, basal responses were determined initially before 7-day (Model 2ML1) and 14-day (Model 2ML3) osmotic minipumps (Alzet), respectively, were implanted in the interscapular space under local anesthetic (lignocaine HCl 1%, Delta West). Minipumps delivered Ang II (50 ng/kg per minute) or vehicle (saline, n=2) subcutaneously for 3 days or 14 days. After treatment, MAP and HR were again measured to confirm hypertension before rabbits were perfused and their brains removed for immunohistochemical analysis.
Perfusion
Rabbits were deeply anesthetized with sodium pentobarbitone (100 mg/kg) administered intravenously either immediately after intravenous infusions (3 hours) or 1-hour pressure recordings (3 and 14 day). The animals were perfused transcardially with 1 L of PBS and 1 L of 4% paraformaldehyde dissolved in 0.1 mol/L of phosphate buffer (pH 7.2; PB). Subsequently, the brain was removed and postfixed for 3 hours in 20% sucrose in paraformaldehyde and placed in 20% sucrose in PB and refrigerated overnight at 4°C.
Immunohistochemistry
Forty-micrometer coronal brain sections were cut on a cryostat and placed in PB. Free-floating sections were incubated in 10% normal horse serum in PB at room temperature for 1 hour. Sections were then incubated in primary antibody, goat anti-c-Fos (K-25; Santa Cruz Biotechnology) diluted 1:400 in a solution of 2% normal horse serum and 0.3% Triton X-100 (Sigma-Aldrich) in PB at room temperature overnight. Sections were washed in PB before incubation in biotinylated donkey anti-goat immunoglobins (1:200, Vector Laboratories) in PB containing 2% normal horse serum for 1 hour. Thereafter, the sections were washed and incubated in avidin–biotin peroxidase complex (1:100, Vector Laboratories) in PB for 1 hour. After washes in 0.05 mol/L of Tris buffer (pH 7.6), sections were incubated in a solution of 80 mg of nickel ammonium sulfate (Sigma-Aldrich) and 100 mg 3 to 3' diaminobenzidine hydrochloride (Sigma-Aldrich) per 200 mL of Tris buffer for 10 minutes; 30 µL of 30% hydrogen peroxide was added for a further 6 minutes. After final washes, sections were mounted on gelatin-coated microscope slides.
Analysis
Bright-field illumination using a Motic BA400 microscope and Motic images plus 2.0 were used to assess sections that exhibited Fra immunoreactivity as detected by black-stained nuclei. Brain sites determined previously as responsive to increased circulating Ang II were examined as a whole region. These included the vascular organ of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), bed nucleus of the stria terminalis (BST), subfornical organ (SFO), paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON), amygdala, arcuate nucleus, lateral parabrachial nucleus (LPBN) and RVLM, CVLM, NTS, and area postrema (AP). The atlas of Annunziato et al21 and hindbrain regions described previously by Potts et al12 were used in a blind analysis of 4 to 5 sections per animal for each brain site. Statistical evaluation of Fra counts was performed by 1-way ANOVA and Bonferroni posthoc t tests. Because no significant difference in neuronal activation as detected by Fra immunoreactivity was observed between vehicle-infused controls, counts were combined for each of the 3 groups (n=6). Results are expressed as mean±SEM and, with the exception of midline structures, represent a unilateral brain region. Cardiovascular values were expressed as mean±SEM or mean difference±SE of the difference.
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Results |
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Effects on MAP and HR After Ang II Administration
Figure 1 illustrates the resting values for MAP and HR during the basal and experimental periods. Resting MAP was higher in all of the rabbits treated with either intravenous or subcutaneous Ang II (50 ng/kg per minute) compared with basal levels at 3 hours, 3 days, and 14 days (P<0.001). Average basal MAP was 70.5±2.1 mm Hg and increased by 22.7±2.2 mm Hg, 31.7±3.9 mm Hg, and 21.5±1.8 mm Hg for 3 hours, 3 days, and 14 days, respectively. There was no significant difference in MAP between 3-hour, 3-day, and 14-day Ang II infusions. There was also no significant effect between basal levels and MAP after vehicle infusion in any group.
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Fra Immunoreactivity
After Ang II infusion, all of the regions examined except the BST showed an increase in Fra-positive neurons when compared with vehicle-infused rabbits. However, differences in the pattern of activation among 3 hours, 3 days, and 14 days of infusion were observed.
Three-Hour Infusion
Ang II infused intravenously for 3 hours induced significant increases in Fos-related antigen-like immunoreactivity (Fra-IR) in the SON (Figure 2), arcuate nucleus, LPBN, CVLM, NTS (Figure 3), and the AP compared with absent or sparse labeling in these structures after control infusions of isotonic saline (P<0.001; Table and Figures 4 and 5
). Similarly, the OVLT, SFO, PVN (P<0.01), and amygdala (P<0.05; Table and Figure 4) had elevated numbers of neurons exhibiting Fra-IR. No difference was observed in neuronal labeling in the MnPO, BST, and RVLM between Ang II–treated rabbits and controls after the 3-hour infusion.
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) can be seen throughout many nuclei in experimental groups (B through D); alternatively, little activation is demonstrated in the vehicle-infused control (A). BV indicates blood vessel; OC, optic chiasm. Scale bar=100 µm.
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Three-Day Infusion
Subcutaneous administration of Ang II for 3 days induced a significant increase in Fra-IR in cells located in the SON (P<0.001; Figure 2), OVLT, arcuate nucleus, NTS (Figure 3;P<0.01), MnPO, SFO, PVN, LPBN, and CVLM (P<0.05) compared with rabbits infused with vehicle (Table and Figures 4 and 5
). By contrast, neuronal activation was no longer visible in the amygdala and AP after 3-day Ang II infusions.
Fourteen-Day Infusion
Chronic Ang II treatment via subcutaneous infusion in animals over a 14-day period resulted in significant increases in the expression of Fra-IR in the SON (P<0.001; Figure 2); the arcuate nucleus (P<0.01); and the OVLT, MnPO, SFO, and PVN (P<0.05) compared with rabbits infused with vehicle (Table and Figure 4). There were no significant differences in neuronal activation identified in the BST, amygdala, LPBN, RVLM, CVLM, NTS (Figure 3), and AP after chronic Ang II–induced hypertension compared with vehicle-infused controls. Analysis of the time-dependent changes indicated that diminishing activation occurred in the OVLT and SFO but not in the PVN, SON, or arcuate nucleus (refer to the Table).
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Discussion |
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In the present study, the timeframes chosen revealed clear patterns of activation, as indicated by Fra-IR, for acute and chronic Ang II infusion–induced hypertension in rabbits. The AP was observed as active only during the 3-hour infusion, whereas the NTS, CVLM, and LPBN appeared to remain activated for several days but not at 14 days. The known role of these nuclei in the integration of baroreceptor input and previous work showing that c-Fos activation in NTS, CVLM, and AP is abolished by sinoaortic denervation12 suggests that the primary mechanism is activation by baroreceptor afferents. In addition, the LPBN has also been described as playing an integrative role in relaying baroreceptor information to forebrain regions, and bilateral ablation of the LPBN in rats has also prevented the development of sustained Ang II–induced hypertension.22 Although further investigation is required, these data suggest that neurons located within brain stem regions and in the LPBN may play a role in regulating acute but not chronic Ang II–induced hypertension via an ascending baroreceptive pathway.
The transient nature of the activation of the brain stem nuclei, which are associated with baroreflex integration, indicates that complete baroreceptor resetting does occur in Ang II–induced hypertension, which supports our initial hypothesis. This is in agreement with indirect evidence provided by the recent work of Thrasher23 and previous studies of Brooks and colleagues24,25 in the rabbit, as well as our own studies showing complete resetting of cardiac and renal sympathetic baroreflexes.26 In support of this, the distribution of Fra-IR within the NTS was observed in subnuclei that receive baroreceptor inputs, and the concept that baroreceptors undergo rapid adaptation and resetting is well established.27 Our studies are also consistent with a contribution from central resetting of baroreceptor pathways that may occur within the NTS itself. These findings contradict the view that baroreceptor mechanisms do not completely reset in hypertension, a notion based on the recent studies examining Ang II–induced hypertension.8,28 The latter view is limited by the relatively short timeframe of these experiments. Thus, given sufficient duration of hypertension, cardiac baroreflexes do indeed completely reset to the higher BP level.10 Furthermore, the arterial baroreceptor contributions to the HR reflex are additive, whereas for the renal sympathetic baroreflex they are redundant.29 Thus, because the majority of the baroreceptors reset, there is still enough raised activity to keep the RSNA baroreflex affected, whereas the HR reflex shows clear resetting. Thus, one cannot use the RSNA baroreflex as an indication of the baroreflex resetting.
The third pattern of Fra expression that we observed was associated with forebrain circumventricular organs, such as the OVLT and SFO, which showed sustained expression, but 1 that is very high initially and reduces with time. The fourth pattern, and perhaps the most important, is the hypothalamic nuclei inside the blood–brain barrier, such as the PVN, SON, and arcuate nucleus that show a marked and consistent level of Fra expression over the 14-day period. These nuclei are likely responding to signals arising from angiotensinergic synapses relayed from the OVLT, MnPO, and SFO, because colocalization of c-Fos and AT1 receptor expression in these neurons has been well established.30 Although additional projections may arise from other brain regions and influence these sites, the OVLT and SFO are directly influenced by changes in circulating Ang II because of their unique lack of a blood–brain barrier. Furthermore, efferent neural pathways arising from these regions have been identified as innervating the PVN, SON, and arcuate nucleus.31 Thus, it is somewhat surprising that the known drive for the activation for these nuclei coming from the OVLT and SFO is diminishing with time, but Fra expression in the PVN and SON is marked and well sustained over the 14-day period. This is a major finding, because it suggests that there is sensitization of the PVN and SON over time to chronic high levels of Ang II. These regions, therefore, form prime candidates for mediating the suggested greater role of the sympathetic nervous system in renovascular hypertension.32,33 They are also recognized as playing a major role in the brain Ang II system regulating body fluid homeostasis and blood pressure.34
Given that the PVN projects not only to the spinal cord but also to the RVLM,35 it is surprising that we did not see any consistent activation of this nucleus. However, there was an trend for activation to be greater at 3 hours (P=0.09) consistent with the previously reported small degree of activation of RVLM neurons observed acutely in rabbits12 and rats.5 However, by 14 days there was clearly no Fra expression in RVLM neurons. Thus, the PVN at 2 weeks does not appear to be driving sympathoexcitation through the RVLM. Indeed, in a conscious rabbit, the PVN may activate or inhibit the RVLM depending on the circumstances, but this is normally tonically sympathoinhibitory.36 Although the technique of using Fra as an indication of long-term activation of neurons is receiving increasing attention and interest, there has not been, to date, any in-depth analysis of the relationship between Fra and neuronal activation. Whether the technique detects all of the active neurons over the longer term has not been validated, and the possible limitations of interpreting negative findings is also a consideration. Thus, whereas it is important to be cautious about interpreting the presence of Fra in neurons, the studies, such as those from Sharp et al,37 are consistent with the view that, as long as the stimulus persists, the appropriate neurons remain activated, which differs from the transient nature of c-Fos.
Decreasing Fra-IR over time within the OVLT and SFO is not likely to be because of diminishing baroreceptor inputs, because previous studies have shown that sinoaortic denervation did not affect the number of activated neurons in the OVLT and SFO during Ang II–induced hypertension.38 In the case of the MnPO, numbers of activated neurons actually increased after denervation. Thus, other factors, such as the downregulation or internalization of the AT1 receptors themselves,39 may be responsible for the diminished activation over time. In support of this, in vitro studies have demonstrated the rapid desensitization of the AT1 receptor located in rat circumventricular organs.40 Furthermore, 4 weeks of 2-kidney 1-clip hypertension downregulates the AT1 receptor message in the forebrain of rats.41 It is unlikely that changes to plasma Ang II have occurred, because osmotic minipumps provide very stable levels of infusions over specified periods.
One of the major findings of the current study was the sustained activation of the PVN, SON, and arcuate nucleus over the 14-day period. These sites give rise to vasopressin synthesizing and secreting neurons, and circulating Ang II has been shown to increase the secretion of vasopressin from these brain sites.34 Because Fra positive neurons were diffused throughout the PVN, these neurons may contribute to either hormone release or sympathetic activity. One possibility is that Ang II infusion over a 14-day period induces Fra expression within these brain regions in neurons that release vasopressin. In support, vasopressin V1 receptor message is increased in the forebrain of rats during 4 weeks of 2-kidney 1-clip hypertension in rats.41 Earlier studies have proposed that 1 effect of hypertension is an increase in vasopressin release from the hypothalamus, and, although raised levels of vasopressin plasma concentration have been observed in spontaneously hypertensive rats, Dahl salt-sensitive rats, rats administered DOCA plus salt, and in essential hypertension, these concentrations were reported as insufficient to initiate a vasopressor effect.42 Furthermore, chronic vasopressin antagonism does not alter renovascular hypertension.43 Thus, whereas raised vasopressin may not sustain the hypertension itself, it may be important in the process of altering the way in which the neuronal control mechanisms operate. For example, vasopressin activation of V1 receptors in the NTS and AP is well known to modulate baroreflex mechanisms.44
The AP is a circumventricular organ that is located in the hindbrain and has been proposed to be the site at which circulating Ang II signals the CNS to influence sympatho-excitatory effects.45 Previous studies have demonstrated activation of neurons in the AP after short-term systemic Ang II infusion in the rat46 and in the rabbit12 and after 5-day infusions in the dog.19 Earlier evidence indicates that ablation of the AP blocks the pressor effects of chronic Ang II infusion in the rat47 and in the rabbit.3,12 By contrast, lesions of this brain region did not appear to prevent acute hypertension in response to short-term intravenous Ang II infusions.48 Paradoxically, the present study provides evidence of Fra expression in the AP during the acute phase of Ang II infusion only. Little or no neuronal activation was evident with respect to Fra-IR when Ang II was administered subcutaneously for 3 or 14 days. This response may be secondary to increased arterial pressure and is likely mediated by baroreceptor activation, because earlier studies in sinoaortic denervated rabbits abolished the increase in c-Fos expression in the AP after Ang II infusion.12
The present study demonstrates that neurons located within the amygdala express Fra-IR in the acute phase of Ang II administration only. By contrast, little or no activity was observed after Ang II infusions for 3 or 14 days. The amygdala receives visceral baroafferent information from the NTS, and the NTS is no longer active after chronic Ang II–induced hypertension. Therefore, the amygdala is more likely involved in mediating arousal and stress-induced cardiovascular responses arising from auditory and visual systems.49 Neuroanatomical studies have identified a strong projection arising from efferent neurons in the amygdala that terminates in the BST.50 Nonetheless, and although earlier studies have described the BST as integral in responding to changes in blood pressure, no neuronal activation was evident in the BST in the present study.
Perspectives
Our results show distinct patterns of acute and chronic activation of CNS nuclei during systemic Ang II infusion. The differences are likely to be because of a differential response to elevated circulating Ang II and hypertension. Hindbrain nuclei associated with integrating baroreflex information (NTS, CVLM, and LPBN) are activated for several days but not at 2 weeks, which is consistent with baroreceptors resetting. The purpose of this resetting mechanism is to maintain short-term cardiovascular control at the highest gain point of the reflex curve.51 Forebrain circumventricular organs (OVLT and SFO) show a marked initial activation and a diminishing long-term activation, a pattern consistent with sensing blood-borne Ang II and downregulation of AT1 receptors. This pattern may be important in minimizing the long-term changes to fluid and sodium intake by rabbits in the presence of continuing high-circulating Ang II.52 Thus, in the longer term, it is advantageous for forebrain nuclei known for driving the sympathetic nervous system via spinal and medullary connections (eg, PVN) to remain activated. Furthermore, forebrain regions located behind the blood–brain barrier, including the PVN, SON, and arcuate nucleus, are receiving diminished input from the OVLT and SFO. Thus there appears to be an "amplification" of these pathways through an undetermined mechanism. This amplification may be important in maintaining neural support for hypertension and may explain the change from Ang II vasoconstriction to a neurogenic form, as described by Fink.32
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Acknowledgments |
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Source of Funding
This work was funded by the National Health and Medical Research Council, Australia (317821).
Disclosures
None.
Received December 20, 2006; first decision January 9, 2007; accepted February 14, 2007.
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