Published online before print November 10, 2008, doi: 10.1161/HYPERTENSIONAHA.108.118224
(Hypertension. 2008;52:1127.)
© 2008 American Heart Association, Inc.
Original Articles |
Somatostatin 2A Receptor-Expressing Presympathetic Neurons in the Rostral Ventrolateral Medulla Maintain Blood Pressure
From the Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
Correspondence to Ann K. Goodchild, Australian School of Advanced Medicine, Dow Corning Building, Level 1, 3 Innovation Rd, Macquarie University, 2109 NSW, Australia. E-mail: ann.goodchild{at}vc.mq.edu.au
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Abstract |
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Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are critical for the maintenance of sympathetic vasomotor tone and normal cardiovascular reflex function. So far, selectively eliminating/inhibiting distinct subpopulations of RVLM neurons has not significantly altered arterial pressure. Here we show that RVLM presympathetic neurons that express somatostatin 2A receptors are essential for maintaining and potentially generating sympathetic vasomotor tone. Combined immunocytochemistry and in situ hybridization were used to map the expression of somatostatin receptors 1, 2A, 2B, 3, and 4 (sst1 through 4, respectively) in the rat RVLM. sst1 and sst2B were absent; sst3 and sst4 were sparse. However, sst2A was found postsynaptically and detected in 35±5% of bulbospinal RVLM neurons a population that included 54±4% of catecholaminergic and 30±3% of enkephalinergic neurons. Bilateral microinjection into the RVLM of either somatostatin or the receptor-selective agonist lanreotide evoked dramatic, dose-dependent sympathoinhibition, hypotension, and bradycardia that were blocked by the sst2 receptor antagonist BIM-23627 in anesthetized rats. Bilateral RVLM microinjection of somatostatin also attenuated chemoreceptor and somatosympathetic reflex function. Somatostatin only eliminated the first sympathoexcitatory peak evoked by somatosympathetic reflex activation, whereas muscimol abolished both excitatory peaks providing functional evidence that the activity of only a subpopulation of RVLM presympathetic neurons is inhibited by somatostatin. We suggest that the subpopulation of bulbospinal RVLM neurons that expresses the sst2A receptor sets sympathetic vasomotor output. These neurons are essential for maintaining resting blood pressure under anesthesia and contribute to adaptive reflexes mediated through the RVLM.
Key Words: cardiovascular • sympathetic vasomotor tone • catecholamine • enkephalin • respiration
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Introduction |
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Presympathetic neurons within the rostral ventrolateral medulla (RVLM) contain catecholamines and/or preproenkephalin (PPE) and are critical for the tonic and reflex control of arterial pressure (AP).1–3 Inputs regulating RVLM presympathetic neuronal activity release amino acids and/or a range of modulatory neurochemicals, including peptides.2–6 These underlie the ability to provide a differentiated sympathetic drive to the various vascular beds,6 alter the responses to reflex activation,5 and set the level of AP.1,3,5 Identification of neurons responsible for generating and maintaining sympathetic vasomotor tone and, therefore, setting the level of AP would be a major breakthrough in understanding circulatory control.
The inhibitory neuropeptide somatostatin (SST) is distributed widely in regions of the central nervous system involved in motor, cognitive, autonomic, and neuroendocrine processes.7,8 Two biologically active forms of SST, SST 14 and SST 28, are cleaved from preprosomatostatin and bind to all of the SST receptors with similar affinity.8 Six G protein-coupled SST receptors (sstRs) have been identified (sst1 through 5), including 2 splice variants, sst2A and sst2B.7,8 All of the sstRs are negatively coupled to adenylate cyclase, activate phosphotyrosine phosphatases, and modulate mitogen-activated protein (MAP) kinases, whereas subtype-specific actions are also evident.7,8
sstR and SST-containing cell bodies and terminals are present in the ventral medulla.9–11 Little is known about their functional roles, except that microinjection of SST evokes apnea.12,13 Furthermore, quantitative analysis of sstR-containing neurons and their colocalization with other functional neuronal markers in the ventral medulla is lacking.
Our aims were, first, to comprehensively describe the cellular distribution of SST receptors in the sympathoexcitatory region of the RVLM, and, second, to determine the cardiovascular responses elicited by SST and sstR ligands microinjected into the RVLM. Finally, we sought to determine whether SST receptors modulate the effectiveness of excitatory or inhibitory inputs into the RVLM.
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Materials and Methods |
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An expanded Materials and Methods section is provided (please see http://hyper.ahajournals.org). Experiments were carried out on male Sprague-Dawley rats (n=47) with the approval of the animal care and ethics committees of Royal North Shore Hospital/University of Technology Sydney and Macquarie University, in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.
Immunohistochemical and In Situ Hybridization Experiments
Cholera toxin B subunit (CTB; 1%, 200 nL, List Biological Laboratories) was bilaterally microinjected into the T1 spinal cord in sodium pentobarbitone (60 mg/kg, IP) anesthetized rats (n=10). After 24 hours of recovery, rats were reanesthetized, transcardially perfused, and brain stem and spinal cord sections were processed for light or fluorescence immunohistochemistry or combined in situ hybridization and immunohistochemistry, as described previously.6,14
mRNA for PPE, glutamic acid decarboxylase (GAD67), vesicular glutamate transporter 2 (VGluT2), or preprosomatostatin was revealed by in situ hybridization using digoxigenin-labeled antisense riboprobes. After hybridization, or for immunohistochemistry alone, sections were incubated with species-specific primary antibodies for digoxigenin (DAKO), tyrosine hydroxylase (TH, Sigma-Aldrich), SST receptors (Gramsch Laboratories), CTB, and/or synaptophysin (Synaptic Systems GmbH) and then washed and incubated with fluorophore/peroxidase-conjugated secondary antisera.6
The RVLM was defined as the area ventral to the nucleus ambiguus, medial to the spinal trigeminal tract, and lateral to the inferior olive. Labeled RVLM neurons were counted from 4 hemisections, each separated by 200 µm (n=4).
Electrophysiological Experiments
Electrophysiological experiments were conducted as described previously.4,6,15 Urethane anesthetized (10% wt/vol in saline, 1.3 g/kg, IP, Sigma-Aldrich), vagotomized, paralyzed (pancuronium bromide, 0.4 mg/h, IV, Astra Pharmaceuticals), and artificially ventilated (end-tidal CO2 4% to 5%) rats with body temperature maintained at 36.5±0.5°C (heating blanket, Harvard Apparatus) were used.
A tracheotomy was performed, and the jugular vein and carotid artery were cannulated to permit drug administration and record AP. Heart rate (HR) was derived from AP. The left greater splanchnic preganglionic and phrenic nerves were isolated and recorded using bipolar silver hook electrodes. All of the signals were acquired online using Spike2 software (CED Ltd). Animals were placed in a stereotaxic frame, and the dorsal medullary surface was exposed.
Unilateral or bilateral RVLM microinjections of drugs (Sigma-Aldrich unless otherwise stated) were made as described previously.4,6,16 L-Glutamic acid (100 mmol/L), SST (SST-14, 15 µmol/L, 150 µmol/L, 450 µmol/L, and 1.5 mmol/L, Auspep), muscimol (10 mmol/L), and colloidal gold (25% v/v) were dissolved in 10 mmol/L of PBS (pH 7.4), and 50 nL were administered. The sst2 receptor antagonist BIM-23627 (500 µmol/L, Bachem) was dissolved in PBS (100 nL per microinjection), and the sst2 agonist, lanreotide (450 µmol/L and 1.5 mmol/L, Bachem), was dissolved in 5% dimethyl sulfoxide/PBS. PBS was microinjected as vehicle control. We have demonstrated previously the small transient pressor effects evoked by 5% dimethyl sulfoxide/PBS in the RVLM.17
Cardiovascular reflexes were evoked as described previously,4,6,15 with intermittent stimulation of the barosensory aortic depressor nerve (ADN; 50 pulse train at 100 Hz; 0.2-ms pulse width; 3 to 5 times threshold; n=10), somatic sciatic nerve (single 0.2-ms pulse; 50 sweeps at 0.5 Hz; 2 times threshold; n=7), and carotid chemoreceptor activation by ventilating with nitrogen for 12 seconds (isocapnic anoxia; n=10). After experimentation, injection sites were marked, and rats were euthanized with KCl (3 mol/L, 0.5 mL, IV). Brainstems were removed, fixed, and sectioned to verify injection sites.6
Data were analyzed as described previously.4,6,15 Neurograms were rectified and smoothed (sSNA; 1-second time constant; phrenic nerve activity [PNA], 50 ms). Baseline values were obtained by averaging 20 seconds of data 5 minutes before the first microinjection, and changes were expressed as a percentage of baseline activity. Reflexes were tested before and after SST/lanreotide microinjection. For details concerning data and statistical analysis, please see http://hyper.ahajournals.org.
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Results |
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SST Receptors in the RVLM
The distribution of sst1, 2A, 2B, 3, and 4 receptors in the RVLM was examined (please see Figure S1). Intense sst2A immunoreactivity (ir) was evident on somata, dendrites, and fibers throughout (Figure S1B1 and S1B2). No labeling for sst1 or sst2B was observed (Figure S1A1 and S1C1), although robust labeling was evident at other sites, including the nucleus ambiguus, dorsal and lateral horns of the thoracic spinal cord (sst1; Figure S1A2), and dorsal and lateral horn (sst2B; Figure S1C2). sst3-ir was detected within the RVLM-labeling neuronal cilia, as described in other brain sites18 (Figure S1D1 and S1D2). sst4-ir weakly labeled some somata, dendrites, and fibers in the RVLM (Figure S1E1 and S1E2) but was abundantly expressed within the nucleus ambiguus (Figure S1E1). Quantitative analysis was restricted to sst2A-ir.
RVLM neurons were examined for immunoreactivity for sst2A receptor, TH, CTB, and mRNA for PPE, GAD67, VGluT2, or preprosomatostatin. In the area containing TH-ir (Figure 1A1) and bulbospinal neurons (CTB-ir; Figure 1A2), sst2A receptor-ir perikarya and fibers (Figure 1A3) were concentrated. In the RVLM, most GAD67 neurons surrounded the most dense sst2A-ir (Figure 1A3 through 1A4). Bulbospinal neurons (TH and non-TH containing) in the RVLM expressed the sst2A receptor (Figure 1B1 through 1B4). A total of 56±5% (403 of 749 cells; , n=6) of bulbospinal neurons were TH-ir, of which 54±4% (216 of 403) were also sst2A-ir. A total of 35±5% (241 of 749) of bulbospinal neurons expressed sst2A, most of which contained TH (89±2%; 216 of 241). Almost all of the TH-ir/CTB-ir/sst2A-ir neurons in the RVLM contained VGluT2 mRNA (Figure 1C1 through 1C4). A total of 24±3% of bulbospinal TH-ir neurons also contained PPE mRNA, which made up 64±9% of bulbospinal PPE neurons. sst2A was expressed by 30±3% (24 of 79; n=3) of bulbospinal PPE neurons (Figure 1D1 through 1D4) and 34±3% of bulbospinal TH-ir/PPE mRNA-positive neurons.
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No colocalization of sst2A-ir and GAD67 mRNA was observed (Figure 1B1 through 1B4). PPS mRNA was found in very few (4±1%) bulbospinal RVLM neurons (data not shown), as described previously.10,19 Although sst2A-ir neurons were closely apposed by synaptophysin-ir terminals, sst2A-ir did not seem to colocalize with synaptophysin-ir terminals (Figure 1E1 through 1E4), suggesting that inputs to RVLM do not express sst2A.
RVLM Injection of SST or Lanreotide Evokes Profound Sympathoinhibition and Hypotension
SST injected bilaterally at RVLM pressor sites evoked bradycardia, a large depressor response, and robust sympathoinhibition that approached levels seen after cervical spinal cord transection or death, together with small and transient effects on PNA (Figure 2A). Grouped data (n=8) are shown in Figure 2B. Figure 2C shows the responses evoked by bilateral SST followed 80 minutes later by injections of the preferentially selective sst2 receptor agonist lanreotide. Apart from the longer duration of response evoked by lanreotide (>2 hours) and smaller effects on HR, the profound sympathoinhibitory and depressor effects were identical (n=6; Figure 2B). Dose-dependent responses were evoked with both drugs (Figure 2D) with SST (75 pmol per side) and lanreotide (75 pmol per side), eliciting similar levels of hypotension (–58±6 mm Hg, n=8; –59±5 mm Hg, n=6) and sympathoinhibition (–66±4%, n=8; –73±3% baseline, n=6) that were quantitatively similar to those seen after C1 spinal cord transection (Figure 2D). Figure 2D also shows the effects of unilateral SST.
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Sympathoinhibitory Effects of SST in the RVLM Are Abolished by a Selective sst2A Receptor Antagonist
Similar magnitudes and duration of depressor and sympathoinhibitory responses were evoked by bilateral injections of SST followed >1 hour later by either injections of SST or of lanreotide, indicating that, with adequate intervals, tachyphylaxis did not occur (Figures 2C, 3A, and 3
B). Bilateral injection of the selective sst2A antagonist BIM-23627 (n=7) at RVLM sites at which SST or lanreotide had previously evoked strong sympathoinhibition abolished the effects of subsequent SST or lanreotide microinjection (Figure 3C and 3D). Bilateral injection of BIM-23627 alone evoked small transient pressor effects similar to those evoked with PBS injection.
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) or Lan (
) vs previous responses to SST in the same animals (
). C, Responses to SST were strongly attenuated by microinjection of the selective sst2 receptor antagonist BIM-23627 before SST administration. Grouped data (D) show that sympathoinhibition evoked by SST or Lan is significantly attenuated or abolished by BIM-23627.
Effects of SST in the RVLM on PNA
Bilateral microinjection of SST at RVLM pressor sites occasionally caused transient apneas and small reductions in PNA amplitude (Figure 2A). The respiratory effects of SST injection were mapped: prolonged apnea was often evoked by SST microinjection at caudal RVLM sites (12 mm caudal to bregma). More rostral (11.5 mm caudal to bregma) and medial injections evoked small transient if any effects on PNA (Figure S2A and S2B). At more caudal ventrolateral medulla sites, 75 pmol per side SST evoked inhibition of PNA with little to no effect on SNA (Figure S2B) or MAP, as described previously.12,13
Effects of SST in the RVLM on Reflex Function
Somatosympathetic Reflex
Low-intensity sciatic nerve stimulation evoked 2 distinct peaks in sSNA at 88±5 ms and 175±3 ms (n=7; Figure 4AI). Bilateral RVLM microinjection of SST (75 pmol per side) abolished the early peak but did not alter the late response (n=4; Figure 4AII). In contrast, bilateral muscimol (0.5 nmol per side; n=4) into the same region abolished both early and late peaks and unmasked the short latency (34±1 ms) spinal component of the reflex (Figure 4AIII) that was also evident after C1 spinal cord transection (n=7; Figure 4AIV).
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Chemoreceptor Reflex
Anoxia evoked reproducible sympathoexcitatory (74±11%) and pressor responses (40±7 mm Hg; n=12; Figure 4B). After bilateral SST (n=9) or lanreotide (n=3) injection into the RVLM, anoxia evoked much smaller sympathoexcitatory effects (42±7% and 29±5%; P<0.05) and no alteration in MAP (–2±2 and –2±9 mm Hg; P<0.001; Figure 4B).
Baroreceptor Reflex
Tetanic ADN stimulation evoked baroreflex-mediated reductions of sSNA and MAP (Figures 2A, 2C, 3A, and 3
C). After microinjection of SST or lanreotide, ADN stimulation continued to reduce sSNA to similar levels until baseline sSNA fell maximally, at which point ADN stimulation failed to alter sSNA.
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Discussion |
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The major findings are that activation of sst2A receptors in the RVLM, located on only
35% of presympathetic neurons containing TH and/or PPE, evoked profound sympathetically mediated hypotension and bradycardia. Reflex function mediated by excitatory events in the RVLM was attenuated by SST injected into the RVLM. In contrast, muscimol inhibition of the RVLM abolished reflex function. These findings indicate that the activity of only a subpopulation of RVLM presympathetic neurons is altered by SST and shows for the first time that this cell population, or a part thereof, at least acutely, maintains sympathetic vasomotor tone, setting the baseline level of AP. Here we showed that sst2A, 3, and 4 receptors were present on neurons within the RVLM, with sst2A receptors being the most highly abundant. This pattern of expression is consistent with previous investigations at other sites20–23 and extends recent work by Spary et al,11 which colocalized sst2A with phenylethanolamine N-methyltransferase (PNMT) containing neurons in more caudal, ventral medulla. We used well-characterized sstR antibodies23 of which the specificity has been validated by controls, including incubation of primary antibodies together with immunizing peptide11,24 and adsorption controls for Western and immunoblotting.23,25 Other control experiments included tissue incubation without primary antibodies11 (present study). The sensitivity of the antibodies was appropriate, because distinct labeling for sst1 and sst2B was evident in the spinal cord, as reported previously,20 and for sst4 within the nucleus ambiguus, despite little or no labeling within the RVLM. Consistent with studies of other brain sites, sst3 receptor expression was confined to neuronal cilia in the RVLM.18,23
sst2A receptors were found on approximately one third of bulbospinal RVLM neurons. Approximately half of the bulbospinal catecholamine containing VGlut2-positive neurons and one third of bulbospinal enkephalinergic neurons but not adjacent GABAergic neurons contained sst2A, consistent with a sympathetic premotor function.11,26 The sst2A receptor was present on the soma and dendrites of bulbospinal neurons but not on terminal boutons within the RVLM, indicating that SST is involved in the postsynaptic modulation of select presympathetic output.
Bilateral SST injection into the RVLM reversibly evoked sympathoinhibition, hypotension, and sympathetically mediated bradycardia to levels akin to those produced by cervical spinal transection. The doses used here were based on previous studies that administered SST in large volumes (0.5 to 1.5 µL; 1.2 mmol/L) into the ventral12,13 or dorsal medulla or the cisterna magna (>10 µL).27 Although these studies noted mild hypotensive effects of SST administration, the striking respiratory effects (commonly apnea) were their main focus. Here we demonstrate that this SSTergic inhibition of central respiratory drive is evoked more caudally and is independent of the RVLM-mediated sympathoinhibitory effects. This suggests that SSTergic inputs control the respiratory and sympathetic outputs independently.
The effects of SST were mimicked by lanreotide, which has little effect at sst1 and 4 receptors but binds with high affinity to sst2, sst5, and, to a lesser extent, sst3 receptors.7,8 We and others have not detected significant expression of sst2B or sst5 in the medulla oblongata.20,22,23,28 Given the abundance of sst2A on RVLM presympathetic neurons and the abolition of SST-evoked cardiovascular responses by the sst2 receptor antagonist BIM-23627, it seems likely that the cardiovascular effects evoked by SST/lanreotide microinjection were mediated by sst2A. Because BIM-23627 had little effect when microinjected alone, it seems unlikely that SST is tonically released in the RVLM.
It is well established that neurons within the RVLM are essential for the tonic and reflex control of sympathetic activity. As seen previously1,29,30 and described here, bilateral inhibition of the RVLM with muscimol reduces SNA and blood pressure to levels seen after cervical spinal cord transection and eliminates reflex sympathetic function. Substantial evidence indicates that normal function is retained after elimination of a large proportion of RVLM neurons. Inhibition of 50% of bulbospinal neurons, by unilateral muscimol microinjection, has little effect on sympathetic nerve activity or blood pressure, because any effects are rapidly compensated for by baroreceptor function.31 Similarly, destruction of 84% of catecholaminergic bulbospinal neurons does not alter blood pressure (at least chronically),30,32 and subsequent inhibition of the RVLM, using muscimol, still causes blood pressure to drop to spinal levels,30 indicating that some other cell population within the RVLM is the main locus of sympathetic tone generation. Because bilateral SST or lanreotide microinjection in the RVLM reduces the levels of sSNA and blood pressure to those seen after spinal cord transaction, we conclude that the vasomotor tone supporting AP is maintained and perhaps generated by bulbospinal RVLM neurons that express sst2A receptors.
Although bilateral injection of SST reduced sympathetic nerve activity to levels that could not be reduced further by baroreflex loading, sympathoexcitation evoked by somatosympathetic reflex or peripheral chemoreceptor activation was reduced to 40% to 50% of control levels. Sympathoexcitation evoked by chemoreceptor activation is significantly attenuated when catecholaminergic bulbospinal neurons are lesioned33 but abolished when muscimol is injected into the RVLM.29 Because sst2A receptors are found on a subpopulation of catecholamine-containing bulbospinal neurons, chemoreceptor reflex attenuation was unsurprising. Activation of the somatosympathetic reflex evokes a biphasic sympathetic response that is mediated by a glutamatergic synapse in the RVLM.34 It is thought that the first peak is attributable to activation of fast-conducting presympathetic neurons and the second peak mediated by more slowly conducting catecholaminergic neurons of the RVLM.35–37 Bilateral muscimol in the RVLM acts on all of the presympathetic neurons, eliminating RVLM-mediated peaks, and unmasks the short-latency spinally mediated peak. In contrast, bilateral SST eliminated only the first RVLM peak, leaving the second largely untouched. This provides definitive functional evidence that SST inhibits a subpopulation of RVLM neurons that includes fast presympathetic presumably enkephalinergic neurons.
These data indicate that SST acts on a subpopulation of 35% of RVLM presympathetic neurons containing the sst2A receptor and includes noncatecholaminergic and some catecholaminergic neurons, causing profound sympathoinhibition. This neuronal population, or part thereof, sets the level of resting AP.
Perspectives
The RVLM neurons critical for maintaining SNA and AP contain the sst2A receptor. Because elimination of most of the catecholamine-containing population has little effect on blood pressure, the enkephalinergic sst2A-positive, presumably fast-conducting subgroup, albeit small in number, is strongly implicated. We now hypothesize that they or a subpopulation of them may be crucial for generating sympathetic tone. Furthermore, sst2A receptor-expressing RVLM neurons contribute to the elaboration of sympathoexcitatory chemoreceptor and somatosympathetic reflexes. The source and conditions under which SST is released in the RVLM are as yet unknown and demand investigation. Sympathetic activity is increased in hypertension3,38 and heart failure, and the activity of RVLM neurons is raised, at least in animal models of hypertension39 (see, however40). Future therapies that target SST transmission or sstR expression in the medulla may prove effective treatment for these diseases.
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Acknowledgments |
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We thank Elizabeth Moon for technical assistance.
Sources of Funding
This work was supported by the National Health and Medical Research Council of Australia (211023, 211196, 457068, 457069, and 457080), Garnett Passe, and Rodney Williams Memorial Foundation. P.G.R.B. is supported by a National Heart Foundation of Australia Postgraduate Scholarship.
Disclosures
None.
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Footnotes |
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The first 2 authors contributed equally to this study.
Received June 16, 2008; first decision July 8, 2008; accepted October 9, 2008.
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