Abstract
Activation of the sympathetic nervous system has an important role in the pathogenesis of hypertension. However, the precise mechanisms involved are not fully understood. Oxidative stress may be important in hypertension as well as in other cardiovascular disorders. We investigated the role of oxidative stress, particularly in the rostral ventrolateral medulla (RVLM), which is known as the cardiovascular center in the brainstem, in the activation of the sympathetic nervous system in hypertension. We observed that the reactive oxygen species (ROS) production increases in the RVLM in hypertensive rats, thereby enhancing the central sympathetic outflow, which leads to hypertension. Furthermore, the environmental factors of high salt intake and a high-calorie diet may also increase the ROS production in the RVLM, thereby activating the central sympathetic outflow and increasing the risk of hypertension. The activation of the nicotinamide adenine dinucleotide phosphate oxidase via the angiotensin type 1 (AT1) receptors is suggested to be the major source of ROS production, and an altered downstream signaling pathway is involved in the activation of the RVLM neurons, leading to enhanced central sympathetic outflow and hypertension. Thus, the brain AT1 receptors may be novel therapeutic targets, and, in fact, oral treatment with angiotensin receptor blockers has been found to inhibit the central AT1 receptors, despite the blood–brain barrier.
Similar content being viewed by others
Introduction
Recent studies in animals as well as humans support the importance of the activation of the sympathetic nervous system in the pathogenesis of hypertension, including the initial pathological events, the development of hypertension and the end-organ damage.1, 2, 3, 4, 5 The activation of the renin–angiotensin system is known to be involved in the cardiovascular continuum.2, 6
Although the kidney has an important role in the pathogenesis of hypertension, the kidney function itself is influenced by renal nerves.7, 8 This is also evidenced in humans with the development of hypertension after renal nerve ablation.9, 10
There is accumulating evidence demonstrating that oxidative stress has an important role in the various aspects of hypertension.11 However, the study of the role of brain oxidative stress in the activation of the sympathetic nervous system and hypertension has been limited.12, 13, 14, 15, 16, 17 We investigated the role of oxidative stress in the brain, particularly in the rostral ventrolateral medulla (RVLM) in the brainstem, which is known as the cardiovascular center, in the pathogenesis of hypertension.2, 13, 16, 18, 19, 20, 21 The RVLM neurons determine the basal central sympathetic outflow and integrate the inputs from baroreceptors, chemoreceptors and visceral receptors via the nucleus of the solitary tract (NTS).22, 23, 24, 25, 26, 27 Importantly, it also receives the inputs from the paraventricular nucleus of the hypothalamus, which is known as a key nucleus of the central cardiovascular regulation.22, 28, 29 Therefore, we focused on the RVLM in our studies. Other investigators have also confirmed our initial observations, and other details have been further investigated. In this review, we describe the importance of oxidative stress in the brainstem, particularly in the RVLM, on the neural regulation of the sympathetic activity and its contribution to the pathophysiology of hypertension based on the findings of our studies and those of others.
Role of the reactive oxygen species (ROS) in the RVLM in hypertensive rats
We found that oxidative stress in the RVLM is increased and contributes to the neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs).16 Oxidative stress was evaluated by two methods. The levels of the thiobarbituric acid-reactive substances, an end product of lipid peroxidation, were increased in the whole brain, NTS and RVLM of the SHRSP compared with normotensive control Wistar–Kyoto (WKY) rats. Another method used the electron spin resonance spectroscopy with the nitroxide radical 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl as a spin probe. The intensity of the electron spin resonance signals decreased more rapidly in the RVLM of the SHRSP than in the WKY rats. Functionally, we performed a microinjection of tempol, a membrane-permeable superoxide dismutase (SOD) mimetic, into the RVLM and measured blood pressure and heart rate. Microinjection of tempol into the RVLM decreased the blood pressure and heart rate in the SHRSP, but not in the WKY rats. To confirm the role of ROS production in the RVLM in hypertension in the awake state, we transfected adenovirus vectors encoding the Mn-SOD gene into the bilateral RVLM in SHRSP. MnSOD overexpression in the RVLM decreased blood pressure, heart rate and urinary norepinephrine excretion in the SHRSP, but not in WKY rats. We also found reduced SOD activity in the RVLM of the SHRSP compared with the WKY rats, which led to a decreased capability of scavenging superoxide anions. Together, these findings indicated that oxidative stress in the RVLM increased the blood pressure, which may have occurred via an increase in sympathetic nerve activity, and this mechanism was involved in the neural pathophysiology of hypertension in the SHRSP. Consistent with our observations, it was reported that increased superoxide anion in the RVLM contributed to hypertension in spontaneously hypertensive rats (SHRs).17 There was an increase in the intensities and numbers of cells in the RVLM with red fluorescent ethidium bromide, which reflected the superoxide level, in SHR compared with WKY rats. Microinjection of a membrane-permeable SOD mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin, into the RVLM elicited an enhanced depressor response in the SHR compared with the WKY rats. The expression of Mn-SOD, but not Cu/Zn-SOD, in the RVLM was reduced in the SHR. Chan et al.30 demonstrated that the Cu/Zn-SOD, Mn-SOD and catalase expression levels (both protein and mRNA) and their activities in the RVLM were reduced in the SHR compared with the WKY rats, and this was also associated with the increased superoxide and hydrogen peroxide production in the SHR. In fact, overexpression of Cu/ZnSOD, MnSOD or catalase into the RVLM reduced blood pressure and heart rate in the SHR. It is interesting to note that every intervention tested led to a similar extent of reduction of blood pressure and superoxide production in the SHR, although it remains unknown whether the reduced expression and activity of hydrogen peroxide is a major factor for stimulating ROS production by a feed-forward mechanism. In addition, recent studies suggest that hypertension and sympathoexcitation in renovascular (two-kidney one-clip) hypertensive rats are associated with oxidative stress in the RVLM and paraventricular nucleus of the hypothalamus and with systemic oxidative stress.31, 32 Because the two-kidney and one-clip model is an angiotensin II-dependent hypertension model, it is not surprising that oxidative stress was increased in this model. However, it is important that the increased oxidative stress in the autonomic brain regions, such as the RVLM and paraventricular nucleus of the hypothalamus, was involved in the activation of the sympathetic nervous system as one of the mechanisms of hypertension in this model. The nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits and angiotensin type 1 (AT1) receptor mRNA expression levels in the RVLM were increased in this model, and the microinjection of tempol or vitamin C into the RVLM reduced the blood pressure and renal sympathetic nerve activity, supporting this notion. Importantly, a recent study found that ROS signaling in the RVLM had a major role in the enhanced central sympathetic outflow in the two-kidney one-clip hypertensive rats.33 In that study, transfection of an adenovirus vector encoding the Cu/ZnSOD gene into the RVLM neurons was confirmed by costaining with tyrosine hydroxylase and neuronal nuclei. Regarding angiotensin II, the peripheral slow-pressor dose of angiotensin II (600 ng kg−1 min−1 for 2 weeks) in mice led to a gradual development of hypertension that was correlated with marked elevations in superoxide production.34 In this case, the authors emphasized the importance of the sub-fornical organ, in which the blood–brain barrier is lacking and the AT1 receptors are rich. Angiotensinergic inputs in the sub-fornical organ are delivered to the paraventricular nucleus of the hypothalamus, and then it sends the neural information to the RVLM neurons. Thus, the functional responses of the sub-fornical organ to angiotensin II are the increases in drinking behavior and blood pressure via the activation of the sympathetic nervous system and vasopressin release.
Sources of ROS production in the RVLM in hypertension
For the sources of ROS production, there are several candidates, such as NAD(P)H oxidase, xanthine oxidase, uncoupled nitric oxide synthase and mitochondria. Among them, we demonstrated that the activation of the NAD(P)H oxidase through AT1 receptors had a major role in the ROS production in the brainstem including the RVLM of the SHRSP (Figure 1).19 Regional expression of the NAD(P)H oxidase and SOD has been demonstrated in the brain including the NTS and RVLM.35, 36, 37 In addition, we showed that Rac1 activation occurs in this process. Rac1 is a small G protein involved in integrating the intracellular transduction pathways toward NAD(P)H activation and requires lipid modifications to migrate from the cytosol to the cell membrane. The inhibition of Rac1 caused by the transfection of the adenovirus vectors encoding a dominant-negative Rac1 into the RVLM or NTS decreased the blood pressure, heart rate and urinary norepinephrine excretion in the SHRSP, but not in the WKY rats.12, 38 It was demonstrated that Nox2-containing NAD(P)H oxidase followed by an influx of Ca2+ via the L-type Ca channels was the source of the angiotensin II-induced ROS production in the NTS neurons that were anterograde labeled from the vagal afferents using DiA.39, 40 Because azelnidipine could reduce oxidative stress in the RVLM of SHRSP associated with sympathoinhibition, the inhibition of the Ca2+ channel in the RVLM may have reduced oxidative stress.21 Inhibition of Rac1 also reduced the NAD(P)H oxidase activity and ROS production in the brainstem of SHRSP. Thus, our findings indicate that the activation of the Rac1 in the RVLM or NTS produces ROS via the NAD(P)H oxidase in SHRSP. In fact, it was demonstrated that the activation of the Rac1/NAD(P)H oxidase was required in the pressor and dipsogenic actions of angiotensin II in the brain.41
The brain renin–angiotensin system is upregulated in chronic disease states such as hypertension and heart failure with enhanced central sympathetic outflow.42, 43, 44, 45, 46, 47 We also determined whether mitochondria-derived ROS mediates sympathoexcitation induced by angiotensin II in the RVLM.19 It is well established that exogenously administered angiotensin II into the RVLM elicits the pressor response via the activation of the sympathetic nervous system.48, 49 In contrast, the inhibition of AT1 receptors in the RVLM by an AT1 receptor blocker does not reduce blood pressure in normotensive rats.48, 49 However, it reduces blood pressure with sympathoinhibition in hypertensive rats such as SHR.18, 48 We found that the overexpression of MnSOD attenuated the angiotensin II-induced pressor response and also suppressed the angiotensin II-induced ROS production in the RVLM.19 In that study, we showed that angiotensin II increased mitochondrial ROS production in vitro. Overexpression of MnSOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed the angiotensin II-induced ROS production. The depletion of extracellular Ca2+ with ethylene glycol bis-N,N,N′,N′-tetraacetate and the administration of p-trifluomethoxycarbonylcyanyde phenylhydrazone, which prevents Ca2+ uptake into the mitochondria, blocked the angiotensin II-elicited mitochondrial ROS production. Together, our findings indicate that angiotensin II increases mitochondrial ROS production in the RVLM, leading to sympathoexcitation. Furthermore, NAD(P)H oxidase-derived ROS may trigger a Ca2+ influx, and the mitochondrial Ca2+ accumulation would lead to mitochondrial ROS production. A recent study also demonstrated that the ROS-induced impairment of the mitochondrial electron transport chain complexes in the RVLM contribute to further chronic oxidative stress, thereby leading to augmented central sympathetic outflow and hypertension.50 In addition, it was demonstrated that superoxide mediates the angiotensin II-induced influx of extracellular Ca2+ in cultured neural cells.51 It should be noted that angiotensin II regulates neuronal activity by reducing the potassium current, and the increased superoxide production in neurons closes the potassium channels to inhibit a delayed rectifying potassium current resulting in membrane depolarization.52
When discussing the role of ROS in the regulation of sympathetic activity, we need to consider the role of nitric oxide (NO) because NO and ROS interact. In general, NO in the brain, including the RVLM, inhibits sympathetic activity.53, 54 In fact, we found that an increase in NO in the RVLM reduces blood pressure, heart rate, and sympathetic activity in the WKY rats and SHRSP.55 Moreover, the magnitude of the decreases in these variables were greater in the SHRSP than in the WKY rats, suggesting a deficiency in the NO bioavailability in SHRSP. Our important finding was that overexpression of the inducible NO synthase (iNOS) in the RVLM elicited blood pressure elevation and sympathoexcitation in the WKY rats and that this was caused by an increase in oxidative stress.56 This may have been caused by the so-called uncoupling of the NO synthase function because of the deficiency of the precursor of L-arginine and/or the cofactor tetrahydrobiopterin. We found that the micoinjection of the L-arginine reversed the blood pressure elevation elicited by the overexpression of iNOS in the RVLM. Importantly, we have found that the iNOS expression in the RVLM is enhanced in the SHR compared with the WKY rats, and the micoinjection of the iNOS blockers into the RVLM reduced the blood pressure only in the SHR.57 A recent study also suggested that the upregulation of AT1 receptors and iNOS in the RVLM was important for the maintenance of high blood pressure and renal sympathetic activation in the two-kidney one-clip hypertensive rats.58
Signaling pathways of AT1 receptor activation and ROS production in the brain
Recently, we found that the AT1 receptor activates caspase-3 through the Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in the rostral ventrolateral medulla, which is involved in the sympathoexcitation in SHRSP.20 The activities of Ras, p38 mitogen-activated protein kinase, ERK and caspase-3 in the RVLM were elevated in the SHRSP compared with those in the WKY rats. The phosphorylation of the proapoptotic protein Bax and Bad, which releases cytochrome c in the mitochondria, leads to caspase-3 activation.20 In contrast, the phosphorylation of the antiapoptotic protein Bcl-2 inhibits the caspase-3 activation. Intracerebroventricular infusion of a caspase-3 inhibitor reduces blood pressure, heart rate and sympathetic activity in the SHRSP, but not in the WKY rats. Intracerebroventricular infusion of an AT1 receptor blocker also reduced the blood pressure, heart rate, and sympathetic activity and also reduced the activities of Ras, p38 mitogen-activated protein kinase, ERK and caspase-3 in the RVLM of SHRSP, suggesting that these pathways exist downstream to the AT1 receptor activation in the RVLM of SHRSP and are related to blood pressure elevation and sympathoexcitation of SHRSP. In that study, we did not examine the effect of ROS reduction in the RVLM on caspase-3 activity in SHRSP. In support of our findings, it was reported that the NAD(P)H oxidase-derived superoxide anion mediates the activation of p38 mitogen-activated protein kinase or ERK but not the stress-activated protein kinase/Jun N-terminal kinase by angiotensin II in the RVLM and pressor response.59 Furthermore, in a later study, the authors suggested that the activation of the NAD(P)H oxidase/ERK in the RVLM induced the phosphorylation of the transcriptional factor cyclic adenosine monophosphate response element-binding protein and c-fos induction, thereby contributing to the long-term pressor response triggered by angiotensin II.60 It is also important to note that the activation of the activator protein 1 and the Jun N-terminal kinase may occur in rabbits with rapid pacing-induced heart failure.61 Thus, the signaling pathway followed by the activation of the ROS production may differ between hypertension and heart failure because of the advancement of the disease state. Further studies are required to clarify the mechanisms involved.
Influence of salt and obesity on oxidative stress in the brain and sympathetic function in hypertension
A high salt intake is an important environmental factor for the development of hypertension.62 Increasing evidence suggests that central nervous system mechanisms are involved in salt-induced hypertension, although the kidney also has a key role in salt-induced hypertension.63, 64, 65, 66 We sought to determine whether high salt intake increases hypertension in the SHR and whether the increased ROS production in the RVLM contributes to this mechanism.18 High salt intake augmented the development of hypertension in the SHR beginning at the age of 6–12 weeks. There was greater ROS production in the RVLM of the SHR with high salt intake than in those with a regular salt intake. The scavenging of the produced ROS by tempol injected into the RVLM elicited a greater reduction of blood pressure in the SHR with a high salt intake than in those with a regular salt intake. We suggested that the increased AT1 receptors and NAD(P)H oxidase expression levels in the RVLM were responsible for the increased ROS production and blood pressure in SHR with a high salt intake compared with those with a regular salt intake. The enhanced depressor response to an AT1 receptor supported this suggestion. Consistent with our findings, increased oxidative stress was involved in the blood pressure elevation through an enhanced central sympathetic outflow in Dahl salt-sensitive rats.67 In that study, the activation of the NAD(P)H oxidase in the brain, particularly in the hypothalamus, was also suggested to be a source of ROS production. It is possible that the enhanced neuronal activity in the hypothalamus, such as the paraventricular nucleus, conveyed the input to the RVLM, thereby augmenting the RVLM neuronal activity. It is interesting that the RVLM neuronal activity was enhanced in rats with a high-salt diet. However, on the basis of our findings, oxidative stress in the RVLM itself causes the increased central sympathetic outflow, thereby contributing to the development of hypertension with a high-salt diet.
It has also been demonstrated that the sympathetic activation has an important role in obesity-related hypertension, including the metabolic syndrome.68, 69, 70, 71, 72, 73 Insulin or leptin increases the sympathetic activity, thereby causing increased blood pressure; however, with obesity or metabolic syndrome, there is insulin or leptin resistance. In addition, it has been demonstrated that the RVLM neurons are activated in obesity-induced rats.73 A recent study suggested that oxidative stress, particularly in the hypothalamus, was involved in the activation of the sympathetic nervous system in obesity-induced rats.74 The importance of the RVLM is also suggested in this regard.75
Effects of AT1 receptor blockers on oxidative stress in the brain and sympathetic function in hypertension
As described above, the upregulation of AT1 receptors in the brain has an important role in the pathophysiology of hypertension.22, 24, 42 It is interesting to note that AT1 receptors are rich in the specific brain nuclei that regulate the sympathetic activity such as the anteroventral third ventricle, paraventricular nucleus of the hypothalamus, NTS and the RVLM in the brainstem.46, 47, 76 It has been demonstrated that the peripheral administration of the AT1 receptor blockers penetrate the blood–brain barrier and blocks the AT1 receptors within the brain as well as outside of the brain, although the extent of the blocking action within the brain varies among the AT1 receptor blockers when they are administered peripherally.77 There are two important observations in this regard. First, the peripheral treatment with AT1 blockers attenuates or nearly blocks the pressor response to centrally administered angiotensin II.78, 79, 80 This is also observed with the microinjection of angiotensin II into the RVLM in SHR that are orally treated with olmesartan.81 Second, the central nervous system blockade by the peripheral administration of AT1 receptor blockers has been documented by autoradiographic binding studies.77 It should be noted that the high density of AT1 receptors is present in brain regions that are involved in the regulation of the autonomic nervous system such as the circumventricular organs (for example, the sub-fornical organ, the organum vasculosum laminae terminalis and area postrema) outside of the blood–brain barrier where peripherally administered AT1 receptor blockers are able to access without considering the existence of the blood–brain barrier as well as inside of the blood–brain barrier (paraventricular nucleus of the hypothalamus, NTS and the RVLM).76 Recent studies suggest that the systemic administration of the AT1 receptor blockers also act on the AT1 receptors within the brain, thereby reducing blood pressure in hypertensive rats.80, 81, 82 The extent of the actions of the AT1 receptor blockers within the brain depends partly on the lipophilicity and pharmacokinetics.77, 78 However, even the hydrophilic AT1 receptor blockers are able to block the AT1 receptors within the blood–brain barrier.79 The mechanism(s) involved remain unknown. It is an important question because the brain AT1 receptors are now considered to be novel and pleiotropic therapeutic targets for hypertension and related cardiovascular diseases. Thus, it is conceivable that oral treatment with an angiotensin receptor blocker may block the AT1 receptors in the brain, particularly in the RVLM, thereby reducing the ROS production and reducing the blood pressure via inhibiting the sympathetic activity. Treatment with telmisartan orally reduced the blood pressure and urinary norepinephrine excretion in SHRSP, and it was associated with a reduction of ROS production in the brainstem including the RVLM.12 The reduction of oxidative stress was evaluated with thiobarbituric acid-reactive substance levels, electron spin resonance spectroscopy and 2,3-dihydroxybenzoic acid measurements. In another study, treatment with olmesartan was carried out in SHRSP, and brain oxidative stress was evaluated by using the in vivo electron spin resonance spectroscopy method.83 It did not induce reflex-mediated sympathoexcitation, despite the fact that blood pressure reduction was >50 mm Hg. In contrast, treatment with hydralazine or a combination of hydralazine and hydrochlorthiazide elicited a reflex-mediated sympathoexcitation and a blood pressure reduction that was similar in extent to the reduction observed with the treatment with telmisartan or olmesartan. Importantly, the antihypertensive treatment with hydralazine or a combination of hydralazine and hydrochlorthiazide did not reduce oxidative stress in the brain including the RVLM.12, 83
Perspectives
Considering the importance of the AT1 receptors in the brain, particularly in the autonomic regulatory regions, such as the RVLM, NTS and paraventricular nucleus of the hypothalamus, it should be noted that these areas contain a high density of AT1 receptors in human.84 The AT1 receptor blockers are widely used in the treatment of hypertension.85 The inhibition of the brain AT1 receptors may have a significant role in the sympathoinhibitory effect via the reduction of oxidative stress in humans. It is also suggested that AT1 blockers may have neuroprotective effects, reducing the incidence of stroke and improving cognition function.85, 86 In addition, renal afferent nerves may also contribute to the blood pressure elevation according to the recent findings of the renal nerve ablation in patients with resistant hypertension.8, 10 Renal afferent nerves project directly to many areas in the central nervous system controlling the sympathetic nervous system activity such as the NTS and hypothalamus.87, 88, 89 It is demonstrated that oxidative stress mediates the stimulation of the sympathetic nerve activity in the phenol renal injury model of hypertension in which the renal afferent nerves are stimulated.90 In this model, the brain AT1 receptor and NAD(P)H oxidase are activated. It is suggested that the increased ROS production and reduced neuronal NOS expression may be involved in this mechanism(s), which leads to the alteration of cytokines in the brain.90, 91 It is interesting and important to consider AT1 receptors and the related ROS production in the brain as novel therapeutic targets for the treatment of hypertension, which are focused on the aspects of sympathetic activation.
References
Grassi G . Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension 2009; 54: 690–697.
Grassi G . Sympathetic neural activity in human hypertension and related diseases. Am J Hypertens 2010; 23: 1052–1060.
Grassi G, Seravalle G, Quarti-Trevano F . The ‘neurogenic hypothesis’ in hypertension: current evidence. Exp Physiol 2010; 95: 581–586.
Esler M . The 2009 Carl Ludwig lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol 2010; 108: 227–237.
Mauo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP . The role of sympathetic nervous system activity in renal injury and end-stage renal disease. Hypertens Res 2010; 33: 521–528.
Dzau VJ . The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens 2005; 23 (suppl 1): S9–S17.
DiBona GF . The Walter B Cannon Memorial Award Lectures: physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol 2005; 289: R633–R641.
DiBona GF, Esler M . Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010; 298: R245–R253.
Krum H, Schlaich MP, Whitbourn R, Sobotka P, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M . Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of principle cohort study. Lancet 2009; 373: 1275–1281.
Simplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Simplicity HTN-2 Trail): a randomised controlled trial. Lancet 2010; 376: 1903–1909.
Briones AM, Touyz RM . Oxidative stress and hypertension: current concepts. Curr Hypertens Rep 2010; 12: 135–142.
Hirooka Y, Sagara Y, Kishi T, Sunagawa K . Oxidative stress and central cardiovascular regulation: pathogenesis of hypertension and therapeutic aspects. Circ J 2010; 74: 827–835.
Hirooka Y . Role of reactive oxygen species in brainstem in neural mechanisms of hypertension. Auton Neurosci 2008; 142: 20–24.
Peterson JR, Sharma RV, Davisson RL . Reactive oxygen species in the neuropathogenesis of hypertension. Curr Hypertens Rep 2006; 8: 232–241.
Campos RR . Oxidative stress in the brain and arterial hypertension. Hypertens Res 2009; 32: 1047–1048.
Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A . Increased reactive oxygen species in rostral ventrolateral medulla contributes to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 2004; 109: 2357–2362.
Tai M-H, Wang L-L, Wu KLH, Chan JYH . Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Rad Biol Med 2005; 38: 450–462.
Koga Y, Hirooka Y, Araki S, Nozoe M, Kishi T, Sunagawa K . High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertens Res 2008; 31: 2075–2083.
Nozoe M, Hirooka Y, Koga Y, Araki S, Konno S, Kishi T, Ide T, Sunagawa K . Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla. J Hypertens 2008; 26: 2176–2184.
Kishi T, Hirooka Y, Konno S, Ogawa K, Sunagawa K . Angiotensin II type 1 receptor-activated caspase-3 through ras/mitogen-activated protein kinase/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats. Hypertension 2010; 55: 291–297.
Konno S, Hirooka Y, araki S, Koga Y, Kishi T, Sunagawa K . Azelnidipine decreases sympathetic nerve activity via antioxidant effect in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol 2008; 52: 555–560.
Guyenet PG . The sympathetic control of blood pressure. Nat Rev Neurosci 2006; 7: 335–346.
Pilowsky PM, Goodchild AK . Baroreceptor reflex pathways and neurotransmitters: 10 years on. J Hypertens 2002; 20: 1675–1688.
Sved AF, Ito S, Sved JC . Brainstem mechanisms of hypertension: role of the rostral ventrolateral medulla. Curr Hypertens Rep 2003; 5: 262–268.
Carlson SH, Wyss JM . Neurohormonal regulation of the sympathetic nervous system: new insights into central mechanisms of action. Curr Hypertens Rep 2008; 10: 233–240.
Dampney RAL, Polson JW, Potts PD, Hirooka Y, Horiuchi J . Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression. Cell Mol Neurobiol 2003; 23: 597–616.
Campos RR, Bergamschi CT . Neurotransmission alterations in central cardiovascular control in experimental hypertension. Curr Hypertens Rev 2006; 2: 193–198.
Dampney RAL, Horiuchi J, Killinger S, Sheriff MJ, Tan PSP, McDowall LM . Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol 2005; 32: 419–425.
Coote JH . Landmarks in understanding the central nervous control of the cardiovascular system. Exp Physiol 2007; 92: 3–18.
Chan SHH, Tai M-H, Li C-Y, Chan JYH . Reduction in molecular synthesis or enzyme activity of superoxide dismutase and catalase contributes to oxidative stress and neurogenic hypertension in spontaneously hypertensive rats. Free Rad Biol Med 2006; 40: 2028–2039.
Oliveira-Sales EB, Dugaich AP, Carillo BA, Abreu NP, Boim MA, Martins PJ, D’Ameida V, Dolnkoff MS, Bergamaschi CT, Campos RR . Oxidative stress contributes to renovascular hypertension. Am J Hypertens 2008; 21: 98–104.
Oliveira-Sales EB, Nishi EE, Carillo BA, Dolnikoff MS, Bergamaschi CT, Campos RR . Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension. Am J Hypertens 2009; 22: 484–492.
Oliveira-Sales EB, Colombari DSA, Davisson RL, Kasparov S, Hirata AE, Campos RR, Paton JFR . Kidney-induced hypertension depends on superoxide signaling in the rostral ventrolateral medulla. Hypertension 2010; 56: 290–296.
Zimmerman MC, Larzartigues E, Shrama RV, Davisson RL . Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res 2004; 95: 210–216.
Campese VM, Sindhu RK, Ye S, Bai Y, Vaziri ND, Jabbari B . Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain. Brain Res 2007; 1134: 27–32.
Bai Y, Jabbari B, Ye S, Campese VM, Vaziri ND . Regional expression of NAD(P)H oxidase and superoxide dismutase in the brain of rats with neurogenic hypertension. Am J Nephrol 2009; 29: 483–492.
Infanger DW, Shrama RV, Davisson RL . NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 2006; 8: 1583–1596.
Nozoe M, Hirooka Y, Koga Y, Sagara Y, Kishi T, Engelhardt JF, Sunagawa K . Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart arte in stroke-prone spontaneously hypertensive rats. Hypertension 2007; 50: 62–68.
Wang G, Anrather J, Huang J, Speth RC, Pickel VM, Iadecola C . NADPH oxidase contributes to angiotensin II signaling in the nucleus tarctus solitarius. J Neurosci 2004; 24: 5516–5524.
Wang G, Anrather J, Glass MJ, Tarsitano J, Zhou P, Frys KA, Pickel VM, Iadecola C . Nox2, Ca2+, and protein kinase C play a role in angiotensin II-induced free radical production in nucleus tractus solitarius. Hypertension 2006; 48: 482–489.
Zimmerman MC, Dunlay RP, Lazartigues E, Zhang Y, Sharma RV, Engelhardt JF, Davisson RL . Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ Res 2004; 95: 532–539.
Dupont AG, Brouwers S . Brain angiotensin peptides regulate sympathetic tone and blood pressure. J Hypertens 2010; 28: 1599–1610.
Leenen FHH . Brain mechanisms contributing to sympathetic hyperactivity and heart failure. Circ Res 2007; 101: 221–223.
Huang BS, Leenen FHH . The brain renin-angiotensin-aldosterone system: a major mechanism for sympathetic hyperactivity and left ventricular remodeling and dysfunction after myocardial infarction. Curr Heart Fail Rep 2009; 6: 81–88.
Zucker IH, Schultz HD, Patel KP, Wang W, Gao L . Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure. Am J Physiol Heart Circ Physiol 2009; 297: H1557–H1566.
Reja V, Goodchild AK, Phillips JK, Pilowsky PM . Upregulation of angiotensin AT1 receptor and intracellular kinase gene expression in hypertensive rats. Clin Exp Pharmacol Physiol 2006; 33: 690–695.
Hu L, Zhu D-N, Yu Z, Wang JQ, Sun Z-J, Yao T . Expression of angiotensin type 1 (AT1) receptor in the rostral ventrolateral medulla in rats. J Appl Physiol 2002; 92: 2153–2161.
Hirooka Y, Potts PD, Dampney RAL . Role of angiotensin II receptor subtypes in mediating the sympathoexcitatory effects of exogenous and endogenous angiotensin peptides in the rostral ventrolateral medulla. Brain Res 1997; 772: 107–114.
Dampney RAL, Tan PSP, Sheriff MJ, Fontes MAP, Horiuchi J . Cardiovascular effects of angiotensin II in the rostral ventrolateral medulla: the push-pull hypothesis. Curr Hypertens Rep 2007; 9: 222–227.
Chan SHH, Wu KLH, Chang AYW, Tai M-H, Chan JYH . Oxidative impairment of mitochondrial electron transport chain complexes in rostral ventrolateral medulla contributes to neurogenic hypertension. Hypertension 2009; 53: 217–227.
Zimmerman MC, Sharma RV, Davisson RL . Superoxide mediates angiotensin II-induced influx of extracellular calcium in neural cells. Hypertension 2005; 45: 717–723.
Sun C, Sellers KW, Sumners C, Raizada ML . NAD(P)H oxidase inhibition attenuates neuronal chronotropic actions of angiotensin II. Circ Res 2005; 96: 659–666.
Patel K, Li Y-F, Hirooka Y . Role of nitric oxide in central sympathetic outflow. Exp Biol Med 2001; 226: 814–824.
Hirooka Y, Kishi T, Sakai K, Shimokawa H, Takeshita A . Effects of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats. J Cardiovasc Pharmacol 2003; 41 (Suppl 1): S119–S126.
Kishi T, Hirooka Y, Ito K, Sakai K, Shimokawa H, Takeshita A . Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventroalteral medulla in stroke-prone spontaneously hypertensive rats. Hypertension 2002; 39: 264–268.
Kimura Y, Hirooka Y, Sagara Y, Ito K, Kishi T, Shimokawa H, Takeshita A, Sunagawa K . Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. Circ Res 2005; 96: 252–260.
Kimura Y, Hirooka Y, Kishi T, Ito K, Sagara Y, Sunagawa K . Role of inducible nitric oxide synthase in rostral ventrolateral medulla in blood pressure regulation in spontaneously hypertensive rats. Clin Exp Hypertens 2009; 31: 281–286.
Oliveira-Sales EB, Nishi EE, Boim MA, Dolnikoff MS, Bergamaschi CT, Campos RR . Upregulation of AT1R and iNOS in the rostral ventrolateral medulla (RVLM) is essential for the sympathetic hyperactivity and hypertension in the 2K-1C Wistar rat model. Am J Hypertens 2010; 23: 708–715.
Chan SHH, Hsu K-S, Huang C-C, Wang L-L, Ou C-C, Chan JYH . NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ Res 2005; 97: 772–780.
Chan SHH, Wang L-L, Tseng H-L, Chan JYH . Upregulation of AT1 receptor gene on activation of protein kinase Cβ/nicotinamide adenine dinucleotide disphosphate oxidase/ERK1/2/c-fos signaling cascade mediates long-term pressor effect of angiotensin II in rostral ventrolateral medulla. J Hypertens 2007; 25: 1845–1861.
Liu D, Gao L, Roy SK, Cornish KG, Zucker IH . Neuronal angiotensin II type 1 receptor upregulation in heart failure: activation of activator protein 1 and Jun N-terminal kinase. Circ Res 2006; 99: 1004–1011.
Adrogué HJ, Madias NE . Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007; 356: 1966–1978.
Brooks VL, Haywood JR, Johnson AK . Translation of salt retention to central activation of the sympathetic nervous system in hypertension. Clin Exp Pharmacol Physiol 2005; 32: 426–432.
Osborn JW, Fink GD, Sved AF, Toney GM, Raizada MK . Circulating angiotensin II and dietary salt: converging signals for neurogenic hypertension. Curr Hypertens Rep 2007; 9: 228–235.
Huang BS, Amin S, Leenen FHH . The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol 2006; 21: 295–304.
Adams JM, Madden CJ, Sved AF, Stocker SD . Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses from the rostral ventrolateral medulla. Hypertension 2007; 50: 354–359.
Fujita M, Ando K, Nagae A, Fujita T . Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension 2007; 50: 360–367.
Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E . Mechganisms of sympathetic activation in obesity-related hypertension. Hypertension 2006; 48: 787–796.
Rahmouni K, Correia ML, Haynes WG, Mark AL . Obesity-associated hypertension: new insights into mechanisms. Hypertension 2005; 45: 9–14.
Grassi G . Adrenergic overdrive as the link among hypertension, obesity, and impaired thermogenesis: lights and shadows. Hypertension 2007; 49: 5–6.
Grassi G . Sympathetic overdrive and cardiovascular risk in the metabolic syndrome. Hypertens Res 2006; 29: 839–847.
Landsberg L . Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). J Hypertens 2001; 19: 523–528.
Stocker SD, Meador R, Adams JM . Neurons of the rostral ventrolateral medulla contribute to obesity-induced hypertension in rats. Hypertension 2007; 49: 640–646.
Nagae A, Fujita M, Kawarazaki H, Matsui H, Ando K, Fujita T . Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension. Circulation 2009; 119: 978–986.
Konno S, Hirooka Y, Kishi T, Ito K, Koga Y, Araki S, Sunagawa K . Increased oxidative stress in cardiovascular center of brain stem causes sympatho-excitation in dietary-induced obesity rat. Circ J 2009; 73 (suppl I): 406 (abstract).
McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, Oldfield BJ, Mendelsohn FAO, Chai SY . The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003; 35: 901–918.
Wang JM, Tan J, Leenen FHH . Central nervous system blockade by peripheral administration of AT1 receptor blockers. J Cardiovasc Pharmacol 2003; 41: 593–599.
Gohlke P, Weiss S, Jansen A, Wienen W, Stangier J, Rascher W, Culman J, Unger T . AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats. J Pramacol Exp Ther 2001; 298: 62–70.
Nishimura Y, Ito T, Hoe K-L, Saavedra JM . Chronic peripheral administration of the angiotensin II AT1 receptor antagonist candesartan blocks brain AT1 receptors. Brain Res 2000; 871: 29–38.
Tsuchihashi T, Kagiyama S, Matsumura K, Abe I, Fujishima M . Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR. J Hypertens 1999; 17: 917–922.
Lin Y, Matsumura K, Kagiyama S, Fukuhara M, Fujii K, Iida M . Chronic administration of olmesartan attenuates the exaggerated pressor response to glutamate in the rostral ventrolateral medulla of SHR. Brain Res 2005; 1058: 161–166.
Leenen FHH, Yuan B . Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade. Hypertension 2001; 37: 981–984.
Araki S, Hirooka Y, Kishi T, Yasukawa K, Utsumi H, Sunagawa K . Olmesartan reduces stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method. Hypertens Res 2009; 32: 1091–1096.
Allen AM, MacGregor DP, McKinley MJ, Mendelsohn FAO . Angiotensin II receptors in the human brain. Regul Pept 1999; 79: 1–7.
Iwanami J, Mogi M, Iwai M, Horiuchi M . Inhibition of the renin-angiotensin system and target organ protection. Hypertens Res 2009; 32: 229–237.
Mogi M, Horiuchi M . Effects of angiotensin II receptor blockers on dementia. Hypertens Res 2009; 32: 738–740.
Stella A, Golin R, Genovesi S, Zanchetti A . Renal reflexes in the regulation of blood pressure and sodium excretion. Can J Physiol Pharmacol 1987; 65: 1536–1539.
Calaresu FR, Ciriello J . Renal afferent nerves affect discharge rate of medullary and hypothalamic single units in cat. J Auton Nerv Syst 1981; 3: 311–320.
Ciriello J, Calaresu FR . Central projection of afferent renal fibers in the rat: an antegrade transport study of horseradish peroxidase. J Auton Nerv Syst 1983; 8: 273–285.
Ye S, Zhong H, Campese VM . Oxidative stress mediates the sympathetic nerve activity in the phenol renal injury model of hypertension. Hypertension 2006; 48: 309–315.
Campese VM, Shaohua Y, Huiquin Z . Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 2005; 46: 533–539.
Acknowledgements
Our studies were supported by the Grants-in Aid for Scientific Research from the Japan Society for the Promotion of Science (C15590757, C17590745, B19329031), Grants from the Salt Science Research Foundation, a Grant-in-Aid of The Japan Medical Association and a Grant from the Kimura Memorial Foundation Research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no conflict of interest.
Rights and permissions
About this article
Cite this article
Hirooka, Y. Oxidative stress in the cardiovascular center has a pivotal role in the sympathetic activation in hypertension. Hypertens Res 34, 407–412 (2011). https://doi.org/10.1038/hr.2011.14
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/hr.2011.14
Keywords
This article is cited by
-
Clarification of hypertension mechanisms provided by the research of central circulatory regulation
Hypertension Research (2023)
-
Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure
Journal of Biomedical Science (2020)
-
Daily inhalation of hydrogen gas has a blood pressure-lowering effect in a rat model of hypertension
Scientific Reports (2020)
-
Inhalation of odors containing DMHF generated by the Maillard reaction affects physiological parameters in rats
Scientific Reports (2020)
-
Central blockade of the AT1 receptor attenuates pressor effects via reduction of glutamate release and downregulation of NMDA/AMPA receptors in the rostral ventrolateral medulla of rats with stress-induced hypertension
Hypertension Research (2019)