Excessive Leukotriene B4 in Nucleus Tractus Solitarii Is Prohypertensive in Spontaneously Hypertensive RatsNovelty and Significance
Inflammation within the brain stem microvasculature has been associated with chronic cardiovascular diseases. We found that the expression of several enzymes involved in arachidonic acid-leukotriene B4 (LTB4) production was altered in nucleus tractus solitarii (NTS) of spontaneously hypertensive rat (SHR). LTB4 produced from arachidonic acid by 5-lipoxygenase is a potent chemoattractant of leukocytes. Leukotriene B4-12-hydroxydehydrogenase (LTB4-12-HD), which degrades LTB4, was downregulated in SHR rats compared with that in Wistar-Kyoto rats. Quantitative real-time PCR revealed that LTB4-12-HD was reduced by 63% and 58% in the NTS of adult SHR and prehypertensive SHR, respectively, compared with that in age-matched Wistar-Kyoto rats (n=6). 5-lipoxygenase gene expression was upregulated in the NTS of SHR (≈50%; n=6). LTB4 levels were increased in the NTS of the SHR, (17%; n=10, P<0.05). LTB4 receptors BLT1 (but not BLT2) were expressed on astroglia in the NTS but not neurons or vessels. Microinjection of LTB4 into the NTS of Wistar-Kyoto rats increased both leukocyte adherence and arterial pressure for over 4 days (peak: +15 mm Hg; P<0.01). In contrast, blockade of NTS BLT1 receptors lowered blood pressure in the SHR (peak: −13 mm Hg; P<0.05) but not in Wistar-Kyoto rats. Thus, excessive amounts of LTB4 in NTS of SHR, possibly as a result of upregulation of 5-lipoxygenase and downregulation of LTB4-12-HD, can induce inflammation. Because blockade of NTS BLT1 receptors lowered arterial pressure in the SHR, their endogenous activity may contribute to the hypertensive state of this rodent model. Thus, inflammatory reactions in the brain stem are causally associated with neurogenic hypertension.
High blood pressure (hypertension) is a major contributor to stroke, heart attacks, and kidney disease. It has escalated to pandemic proportions (0.9 billion currently) and is expected to rise further to 1.4 billion by 2025.1 The most common form of human hypertension is neurogenic hypertension characterized by excessive sympathetic activity that not only increases vascular resistance and cardiac output, which raises blood pressure, but also damages end organs, causing stiffening of arteries and the chambers of the heart.2 The finding that this pathological rise in sympathetic activity precedes the onset of hypertension in humans3 suggests that it is an early event in the disease process, therefore making it an important therapeutic target. However, the remarkable statistic that ≈23% of hypertensive patients who take multiple antihypertensive (polypill) medication are resistant to therapy4 emphasizes the need to discover new ways to control excessive sympathetic nerve activity to bring blood pressure under control.
It is likely that immune cells communicate with the brain across the blood-brain barrier and vagal afferents and that the autonomic nervous system modulates the immune system.2–7 Such cross-talk occurs during systemic infection, stress, and cardiovascular disease and results in alterations in animal behavior, autonomic vasomotor tone, and ventilation, for example. Evidence is accumulating for immune-to-brain signaling in a number of pathophysiological conditions including hypertension.2,5 In this regard, leukocyte counts in spontaneously hypertensive rat (SHR) are 50% to 100% higher than that in controls, and leukocyte–endothelial interactions are abundant in the SHR.8 Vascular inflammation in the SHR was associated with elevated expression of interleukin-1β, IL-6, and TNF-α.9–12 Angiotensin II promotes leukocyte–endothelial interactions contributing to vascular inflammation,13 whereas candesartan decreases inflammatory cytokines.13,14 T cells play an important role in vascular inflammation in hypertension,15 angiotensin II infusion– and DOCA salt–induced hypertension, whereas the T-cell modulating agent, mycophenolate mofetil, can prevent hypertension.16,17 Immune-to-brain signaling involves the release of proinflammatory cytokines from intraluminar and extravasated leukocytes and from microglial cells activated by leukocytes.2 It is speculated that inflammatory molecules may also diffuse across the blood-brain barrier to effect neuronal activity and synaptic function. At the level of the nucleus tractus solitarii (NTS), a major region that governs both the sensitivity of the baroreceptor reflex and the set point of arterial pressure and the structure studied in this study, we described a unique pattern of expression of cytokines and chemokines within the NTS of the SHR relative to the normotensive rat.18 Subsequently, we have found functional roles for the chemokine (C-C motif) ligand 5 (Ccl5 or Regulated on activation, normal T-cell expressed and secreted) and interleukin 6 in the NTS in modulating arterial pressure and baroreceptor reflex function, respectively.19,20 Further, we reported an increase in a chemoattractant protein in the NTS of the SHR, which is called junctional adhesion molecule-A.21 When overexpressed in normotensive rats, junctional adhesion molecule-A induced leukocyte adhesion in the brain stem microvasculature and induced mild hypertension in a normotensive animal.21
Given these previous findings and the importance and power of immune-to-brain signaling, this study has sought to determine whether other molecules are involved in mediating leukocyte adhesion in the brain stem of hypertensive human and SHR. Here, we used microarray screening of the NTS from SHR and Wistar-Kyoto (WKY) rats and identified a major difference in arachidonic acid metabolism in the SHR, including a downregulation of leukotriene B4 12-hydroxydehydrogenase (LTB4-12-HD), the enzyme that degrades leukotriene B4 (a powerful chemoattractant of leukocytes).22 We further demonstrate that the NTS of the SHR has elevated levels of LTB4 and that this has functional consequences for its hypertensive state.
Procedures were carried out according to the UK Home Office guidelines on animals (Scientific Procedures) Act 1986. They were also approved by the University of Bristol’s Animal Ethic Committee. All animals were housed individually, given normal rat chow and drinking water ad libitum, and kept on a 12-hour light/12-hour dark cycle. Human brain tissue studies were approved by Frenchay Hospital (Bristol) ethics committee.
NTS Transcriptomic Analysis and Data Handling
Affymetrix 230 2.0 Gene chips were used. Tissue from NTS was microdissected from brain slices from 11- to 13-week-old age-matched adult male inbred WKY rats and SHR. Five replicates were made for each rat strain. For further details, see the online-only Data Supplement.
Quantitative RT-PCR of Whole NTS and Primer Sequences
See the online-only Data Supplement.
Isolation of Microvasculature from the Medulla Oblongata and Quantitative RT-PCR
See the online-only Data Supplement.
Quantitative RT-PCR of Human Brain Stem
Fresh frozen brain stem tissue was thawed and transected coronally at the level of the NTS, which was identified as a distinct translucent structure in the dorsomedial medulla. At the level of the area postrema, a 2- to 3-mm-diameter (1- to 2-mm-thick) piece of NTS was cut out using a scapel under a binocular microscope. Subjects were male, and either had a medical history of uncomplicated essential hypertension (>140/90 mm Hg; n=3) or were normotensive (n=4). For RNA extraction and primer sequences used, see the online-only Data Supplement.
LTB4 Content in Medulla Oblongata of WKY and SHR
See the online-only Data Supplement.
NTS Microinjection and Immunohistochemistry for Leukocytes
See the online-only Data Supplement.
BLT1 Receptor Immuncytochemistry in SHR
See the online-only Data Supplement.
Blood Pressure Responses to NTS Microinjections in (1) Anaesthetized and (2) Conscious Rats
Group data were expressed as mean±SEM. To evaluate time-dependent changes of cardiovascular variables by injecting LTB4 or the BLT1 receptor antagonist into the NTS, we used repeated-measures ANOVA and the Bonferroni post hoc test. An unpaired t test was also used for comparisons between 2 groups (eg, comparison of gene expression levels). Differences were considered significant if P<0.05.
Catalogue of Gene Expression in the NTS
We present here lists of genes that, with a high degree of statistical confidence, represent comprehensive descriptions of the RNA populations expressed in the NTS of WKY (15 402 probesets, S1) and SHR (13 618 probesets, S2); see http://www.vasopressin.org/#/data-bank/3755442 for full details. Our genetic data were also submitted to the NCBI gene expression and hybridization array data repository (GEO); the GEO accession number is: Series GSE8796.
Combination of these lists provides a basis from which statistical testing was conducted. Of 15 870 probesets that were considered to be present in all the independent microarrays from both SHR and WKY NTS, 85 were significantly regulated differentially by greater than 1.5-fold (54 downregulated and 31 upregulated). We identified a clear downregulation of LTB4-12-DH (or prostaglandin reductase 1) in the NTS of SHR. This drove the hypothesis that this pathway may contribute to the hypertensive phenotype of SHR. Hence, first we validated the array result using RT-PCR, second we investigated the expression of other components of this pathway, and third, we proceeded to establish its functional significance to blood pressure control.
RT-PCR Analysis of Expression of the Components of the Arachidonic Acid Signaling Cascade in SHR and WKY Rats
We confirmed the array data by showing that LTB4-12-HD gene expression level was significantly lower in both young and adult SHR than in age-matched WKY (adult WKY and SHR: 1.13±0.25 versus 0.42±0.04, respectively, n=6 for each strain, P<0.05; young WKY and SHR, 1.07±0.20 versus 0.45±0.10, respectively, n=6 for each strain, P<0.05; Table and Figure 1A). The level of 5LOX (5 lipoxygenase) gene was significantly higher in the NTS of both young and adult SHR compared with age-matched WKY rats (adult WKY and SHR: 1.02±0.08 versus 1.52±0.23, respectively, n=6 for each strain, P<0.05; young WKY and SHR, 1.02±0.10 versus 1.47±0.09, respectively, n=6 for each strain, P<0.05; Figure 1A). The level of LTA4H (leukotriene A4 hydrolase) gene expression was not different between SHR and WKY (adult WKY and SHR: 1.01±0.07 versus 1.09±0.05, respectively, n=6 for each strain, P<0.05; young WKY and SHR, 1.05±0.14 versus 0.98±0.15, respectively, n=6 for each strain; Figure 1A). Note that both the rostral ventrolateral medulla and hypothalamic paraventricular nucleus also exhibited lower levels of LTB4-12-HD in SHR versus WKY rats (Table).
Brain Stem Blood Vessels
Consistent with brain stem tissue, there was also a reduction of LTB4-12-HD gene in isolated microvessels extracted from the brain stem of 3-week-old rat strains (SHR, 0.49±0.08 versus WKY 1.01±0.05; n=4, P<0.05; Table).
Human Hypertensive NTS Tissue.
As with the SHR:WKY rat difference, a similar difference was found in human NTS where hypertensive subjects had lowered expression levels of LTB4-12-HD compared with controls (hypertensives: 0.42±0.05 versus control: 1.02±0.10, n=4; P<0.01).
Levels of LTB4 in the Medulla Oblongata of SHR and WKY Rats
When the LTB4 quantity was normalized to the total protein concentration, the concentration of LTB4 was higher in the SHR versus WKY rats (WKY: 7.95 pg LTB4/mg protein, SHR: 9.94 pg LTB4/mg protein, n=10, P<0.01; Figure 1B and the online-only Data Supplement). Thus, either the production of LTB4 is increased or its degradation decreased in the NTS of SHR relative to WKY rats.
BLT1 and BLT2 Receptor Expression in the NTS
mRNA expression of LTB4 receptors indicated the presence of BLT1 receptors in the NTS of both SHR and WKY rats (Figure 2). BLT2 receptor expression was hardly detectable (Figure 2A). At the protein level, BLT1 receptors were detected immunocytochemically in the NTS of SHR and found to be colocalized with cells that were immunopositive for GFAP but not NeuN or RECA (Figure 2B). Colocalization with GFAP was relatively dense and supports substantial numbers of BLT1 receptors on astrocytes.
LTB4 in the NTS of WKY Rats: Acute and Chronic Effects on Cardiovascular Control
In normotensive anesthetized WKY rats, a depressor site was located in the NTS as determined by glutamate microinjection (range: −30 to −60 mm Hg drop in arterial pressure). Within a 1-hour observation period, neither arterial pressure nor HR changed after LTB4 microinjection into this NTS depressor site (SBP, before: 105±7 and after: 107±8 mm Hg; HR, before: 323±23 and after: 322±25 bpm; n=6). After 1 hour, glutamate still produced a quantitatively similar fall in arterial pressure, suggesting that the structure had maintained its viability.
In conscious telemetered WKY rats, baseline levels of SBP, HR, and sBRG were 113±3 mm Hg, 365±6 bpm, and 0.92±0.08 ms/mm Hg, respectively. After NTS microinjection of LTB4, the maximum increment of SBP was +15±3 mm Hg relative to preinjection levels; this occurred 2 days after the injection (P<0.001, Figure 3A) and remained above baseline levels for postinjection days 3 (P<0.05) and 4 (P<0.05). The peak mean arterial pressure response increased from 93±3 to 107±4 mm Hg (P<0.05). In contrast, HR and sBRG did not change (P>0.1). Three days post LTB4 injection, the low frequency+very low frequency (LF+VLF) power of SBP variability increased from 7.40±0.34 to 10.69±1.29 mm Hg (P<0.05) and the change in the LTB4 injection group was higher than that in the control group (3.30±0.99 versus 0.22±0.74 mm Hg,2 P<0.05; Figure3B), indirectly suggesting raised sympathetic vasomotor activity. Consistently, LF SBP increased from 0.20±0.3 to 0.87±0.3 mm Hg (P<0.05). Both the changes in LF:HF and HF power of HR variability were not different between LTB4 injection and control groups (P>0.1). Post hoc analysis at the conclusion of the experiment (ie, day 6 postinjection) failed to find leukocyte adhesion (ie, CD4 immunoreactivity) in the NTS, suggesting that any inflammatory response was either undetectable or transient and resolved by the time arterial pressure had returned to control levels.
Chronic Blockade of BLT1R in the NTS of WKY and SHR on Cardiovascular Control
In conscious rats fitted with radio transmitters, resting SBP was 171±8 (SHR, U75 group), 179±5 (SHR, acsf), and 121±4 mm Hg (Wistar, U75302). SBP decreased maximally by −13±5 mm Hg (n=5; P=0.05) after NTS microinjection of U75302 in SHR. This reduction in SBP persisted for up to 6 days relative to baseline and SHR treated with acsf (Figure 3C; P<0.05). Mean arterial pressure fell from 134±5 to 115±3 mm Hg (P<0.05). In SHR treated with BLT1 receptor blocker, LF+VLF power of SBP decreased significantly relative to baseline (from 4±0.2 to 3.3±0.2 mm Hg, P<0.05; Figure 3D). This reduction remained significant for up to 6 days, thereby accompanying the pressure fall. LF SBP also fell (4.0±0.2 to 3.3±0.2 mm Hg; P<0.05). No such changes were observed in the SHR acsf and Wistar rat groups (Figure 3D). None of the 3 rat groups showed any significant change in heart rate, heart rate spectra, or sBRG. In control SHR microinjected with acsf, a rise of 12±1 mm Hg was noted (n=4; P<0.05), whereas no change was observed in Wistar rats receiving U75302.
BLT1 Receptor Modulation of Inflammation in the NTS
We found that LTB4 microinjection into the NTS of WKY rats produced inflammation as detected from elevated CD4 immunoreactivity after 2 days (Figure 4A; n=4). We confirmed our original finding of high endogenous CD4 immunoreactivity in the NTS of the SHR,21 which was minimal in WKY rats (Figure 4B). However, blocking BLT1 receptors in the SHR failed to reduce endogenous CD4 immunoreactivity in the NTS of the SHR (Figure 4C; n=4), suggesting that maintaining inflammation is not dependent on continuous BLT1 receptor activation. Thus, these data indicate a potential role for LTB4 in evoking inflammation in the NTS of WKY rats, but that blockade of endogenous BLT1 receptor activity is insufficient to reduce CD4 immunoreactivity in the SHR.
The novel findings of this study are that in both adult and young prehypertensive SHR, LTB4-12-HD gene was downregulated in the NTS, whereas 5LOX gene was upregulated compared with age-matched WKY rats. Based on this, we predicted excessive amounts of the arachidonic acid metabolite LTB4 in the NTS of the SHR, which we have confirmed. We also described the presence of BLT1 receptors on glial cells in the NTS. We found that a single injection of LTB4 in NTS produced hypertension in normotensive rats, whereas BLT1 receptor antagonism lowered arterial pressure in the SHR but not in normotensive rats. Although BLT1 receptor blockade was unable to reduce CD4 immunoreactivity in the NTS of SHR, LTB4 could induce inflammation in this brain stem region of normotensive rats. Our findings indicated that a high level of LTB4 in the NTS may have roles in both the development and maintenance of the hypertension in the SHR and that this is likely mediated via a BLT1 receptor signaling process involving astrocytes.
Altered Arachidonic Acid-LTB4 Metabolic System in the NTS of SHR
5-lipoxygenase is a lipoxygenase present in the central nervous system.24 Both its upregulation in the NTS of the SHR and downregulation of LTB4-12-HD, the enzyme that causes dehydrogenation of LTB4 to 12-oxo-LTB4, could cause the elevated levels of LTB4 that we found. Because this imbalance was seen in PHSHR, these changes are not secondary to the hypertension but occur early in the pathology and could therefore be involved in the establishment of hypertension. Although our sample number was low, the observation that LTB4-12-HD was lower in the NTS of human hypertensives lends both credence to the relevance of our rat transcriptomic data to human essential hypertension and the applicability of the animal model for understanding human neurogenic hypertension. These changes are unlikely to be unique to the NTS because LTB4-12-HD was also downregulated in the rostral ventrolateral medulla and hypothalamic paraventricular nucleus (Table). Thus, the magnitude of the blood pressure responses reported herein may well be amplified if the LTB4 signaling pathways are modulated in this additional brain stem site simultaneously.
Potential Sources of LTB4 in the NTS of the SHR
Generally, LTB4 synthesis is increased by inflammatory mediators including endotoxin, complement fragments, tumor necrosis factor, and interleukins.25 In the brain, astrocytes26 and oligodendrocytes27 are both potential sources of LTB4. However, because our data indicate reduced levels of LTB4-12-HD in isolated brain stem vessels, LTB4 may also be released from the endothelium and vascular muscle cells in the SHR. This is consistent with the evidence that both these cell types have been shown to synthesize this leukotriene.28,29 If of endothelial origin, LTB4 could be released into the blood stream to attract leukocytes (and into the brain to activate glial cells). As confirmed in this study, and found previously,21 there is leukocyte accumulation in the NTS capillaries of SHR but not in that of WKY rats. This may, in part, be attributable to the greater adhesiveness of leukocytes in the SHR than in normotensive rats.30 It may also be accentuated by the high level of endothelial junctional adhesion molecule-A expression in the NTS,21 which has a binding site for leukocytes31–33 but also attributable to the high level of LTB4 as detected in this study. The types of leukocytes will need to be identified in future studies. Because leukocytes can synthesize LTB4,22 we cannot rule out their contribution to the raised levels of this LTB4 in the medulla oblongata of the SHR described herein. Given these multiple mechanisms for attracting leukocytes to the NTS in the SHR and that LTB4 production may be a product of an inflammatory process, it is perhaps unsurprising that blocking BLT1 receptors was ineffective in reducing CD4 immunoreactivity.
Potential Actions of LTB4 in the NTS of the SHR
LTB4 is one of the most potent chemoattractants and activators of leukocytes, and it has a primary role in inflammatory diseases.22,34 We found that microinjection of the LTB4 into the NTS or normotensive rats induced leukocyte adherence. These data are consistent with the role of BLT1 receptor activation as a major stimulus driving leukocyte accumulation.22,34–36 Because BLT1 receptor antagonism blocks neutrophil activation,37 it may reduce the inflammatory response in the NTS. This is relevant because LTB4 stimulates the production of a number of proinflammatory cytokines that augment and prolong tissue inflammation. For example, it stimulates the release of monochemoattractant protein-138 (MCP-1) via the NF-κB pathway in human monocytes. Interestingly, we found that MCP-1 was higher in the NTS of the SHR,18 but it is unclear whether this relates causally to the high LTB4 levels in the NTS of the SHR. LTB4 can increase levels of IL-6,39 but this chemokine was downregulated in the NTS of the SHR,18 and its expression was not altered after NTS injection of LTB4.19 The latter support the notion of a specific type of inflammatory condition in the NTS of the SHR as proposed previously.18 In contrast, LTB4 decreased the expression of Ccl5 in the NTS of normotensive rats.19 Because endogenous Ccl5 was downregulated in the NTS of the SHR, it is tempting to speculate that this is triggered by the elevated levels of LTB4 in this nucleus, but this awaits confirmation. Ccl5 receptors have been associated with enhancing glutamate transmission and were previously found on NTS neurons.19 Their activation resulted in a lowering of arterial pressure that was significantly more pronounced in the SHR than in the normotensive rat.19 Because LTB4 lowers Ccl5 expression, it is suggested that the restraining effect of Ccl5 on arterial pressure may be depressed in the SHR, which could contribute to its hypertensive state. Ccl5 also contributes directly to monocyte-leukocyte activation and could further support the aforementioned actions of LTB4 and junctional adhesion molecule-A in white cell aggregation in the SHR. Because Ccl5 stimulates the production and release of specific proinflammatory arachidonic acid products, including LTB4 from monocytes,40 we suggest that leukocyte aggregation in the NTS could lead to further LTB4 production through a positive feedback/wind-up mechanism.
BLT1 Receptors and Potential Downstream Intercellular Signaling in the NTS
In this study, gene expression of BLT1 receptors predominated over BLT2 receptors in the NTS. BLT1 receptor is a G-protein–coupled receptor22,41 and previously described on leukocytes.42 Our immunofluorescence labeling suggested that BLT1 receptors were located on glial cells in the NTS. It is hypothesized that leukocyte accumulation in the NTS induced, in part, by LTB4 acting of BLT1 receptors, releases both cytokines and reactive oxygen species such as super oxide; these are established products from such cells43,44 and known to activate central neurones including brain stem cardiovascular neurones.45,46 Reactive oxygen species and some types of cytokines can cross the blood-brain barrier.47 Whether leukocytes extravasate into the NTS was not confirmed,21 and a role for LTB4 in diapedesis is controversial.35,38,48 However, it is known that astrocytes are a potential source for cytokines and reactive oxygen species production.49–51 On physical contact with leukocytes, astrocytes release MCP-1.51 MCP-1 receptors are present on central neurones52; however, its functional role has yet to be identified in the NTS. Taken together, we propose that leukocyte accumulation, even if intraluminally, may well influence central neuronal circuits via cytokines, chemokines, and reactive oxygen species activation that originates from adhered white cells or LTB activation of glial cells via BLT1 receptors. This may dramatically alter neuronal function, leading to neurogenic hypertension. Because we have found that gene expression of LTB4-12-HD was downregulated in the rostral ventrolateral medulla and hypothalamic paraventricular nucleus, it remains to be established whether LTB4 also affects these other regions of the SHR, resulting in hypertension.
Our findings raise the intriguing and novel possibility that there is a link between high levels of leukocyte adhesion in the cardiovascular control regions of the brain with excessive levels of sympathetic nerve activity. We surmise that by antagonizing either leukocyte adhesion and reducing inflammation in the brain stem of the SHR, one might predict a reduction in the proinflammatory status, thereby alleviating the symptoms of hypertension. With the demonstration that BLT1 receptor activation can itself induce leukocyte adherence in the brain stem and trigger hypertension in normotensive rats, anti-inflammatory therapy may prove an effective antihypertensive strategy. Although anti-inflammatory drugs are generally ineffective antihypertensive agents, we argue that the inflammatory status of the brain stem is relatively specific.18 Anti-inflammatory agents tested to date may be inappropriate or not cross the blood-brain barrier. However, minocycline given centrally restricts the pressor response induced by angiotensin II infusion and decreases the numbers of activated microglia and mRNAs for interleukin (IL) 1 β, IL-6, and tumor necrosis factor-α, but increase mRNA for IL-10 (anti-inflammatory) in the hypothalamus.53 Because we found that LTB4-12-HD gene is also downregulated in the NTS of humans with a history of essential hypertension, we suggest that LTB4-12-HD itself might be an effective target for therapeutic intervention as proposed previously.54 Moreover, it may also be an early diagnostic indicator to predict whether a subject is likely to develop hypertension before it has manifested itself, especially because this gene was downregulated in the prehypertensive SHR. Such early diagnosis might stimulate anti-inflammatory approaches as an effective preventive approach to hypertension.
Sources of Funding
The study was financially supported by the British Heart Foundation (BS/93003), the Japan Society for the Promotion Science (19-07458), the Biotechnology and Biological Science Research Council, and the National Institute of Health. J.F.R.P. was in receipt of a Royal Society Wolfson Research Merit Award. We acknowledge the generous donation from Pfizer (United States).
↵* Drs Waki and Hendy contributed equally to this work.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.112.192252/-/DC1.
- Received February 3, 2012.
- Revision received March 19, 2012.
- Accepted October 15, 2012.
- © 2012 American Heart Association, Inc.
- Zubcevic J,
- Waki H,
- Raizada MK,
- Paton JF
- Smith PA,
- Graham LN,
- Mackintosh AF,
- Stoker JB,
- Mary DA
- Rosas-Ballina M,
- Olofsson PS,
- Ochani M,
- et al
- Schmid-Schönbein GW,
- Seiffge D,
- DeLano FA,
- Shen K,
- Zweifach BW
- Sanz-Rosa D,
- Oubiña MP,
- Cediel E,
- et al
- Viel EC,
- Lemarié CA,
- Benkirane K,
- Paradis P,
- Schiffrin EL
- Ando H,
- Zhou J,
- Macova M,
- Imboden H,
- Saavedra JM
- Marvar PJ,
- Thabet SR,
- Guzik TJ,
- et al
- Takagishi M,
- Waki H,
- Bhuiyan ME,
- et al
- Waki H,
- Li B-H,
- Kasparov S,
- Murphy D,
- Paton JFR
- Manev H,
- Uz T,
- Sugaya K,
- Qu T
- Fukuda S,
- Yasu T,
- Kobayashi N,
- Ikeda N,
- Schmid-Schönbein GW
- Fraemohs L,
- Koenen RR,
- Ostermann G,
- Heinemann B,
- Weber C
- Naik UP,
- Ehrlich YH,
- Kornecki E
- Nohgawa M,
- Sasada M,
- Maeda A,
- et al
- Huang L,
- Zhao A,
- Wong F,
- et al
- Toda A,
- Yokomizo T,
- Shimizu T
- Krötz F,
- Sohn HY,
- Pohl U
- Mayorov DN,
- Head GA,
- De Matteo R
- Zimmerman MC,
- Lazartigues E,
- Sharma RV,
- Davisson RL
- Andjelkovic AV,
- Kerkovich D,
- Pachter JS
- Banisadr G,
- Gosselin RD,
- Mechighel P,
- Rostène W,
- Kitabgi P,
- Mélik Parsadaniantz S
- Shi P,
- Diez-Freire C,
- Jun JY,
- et al
Novelty and Significance
What Is New?
Leukotriene B4 (LTB4), a major chemoattractant for immune cells, is elevated in nucleus tractus solitarii of spontaneously hypertensive rats and human hypertensives.
LTB4 receptor stimulation in nucleus tractus solitarii is prohypertensive, whereas their blockade is antihypertensive.
LTB4 receptors exist on astrocytes in nucleus tractus solitarii.
What Is Relevant?
The brain stem microvasculature of the spontaneously hypertensive rat is inflamed; this occurs before the onset of hypertension and may involve LTB4.
Appropriate anti-inflammatory treatment may provide an antihypertensive strategy.
Arachidonic acid metabolism is altered in spontaneously hypertensive rat brain stem; this is associated with inflammatory reactions that seem to be causally related with neurogenic hypertension.