Published online before print September 30, 2004, doi: 10.1161/01.RES.0000146676.04359.64
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Superoxide Mediates Sympathoexcitation in Heart Failure
Roles of Angiotensin II and NAD(P)H Oxidase
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Correspondence to Irving H. Zucker, PhD, Department of Cellular and Integrative Physiology, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail izucker{at}unmc.edu
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Abstract |
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Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase-derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5±13.3% of control) and CHF (193.6±11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (P<0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPH-dependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT1) receptor and subunits of NAD(P)H oxidase (p40phox, p47phox, and gp91phox) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF.
Key Words: free radicals • angiotensin receptors • RVLM • ventricular pacing
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Introduction |
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It is now well accepted that neural and humoral excitation are two of the primary and most reproducible sequelae of the chronic heart failure (CHF) syndrome.1 Excessive sympathetic activation not only exacerbates the heart failure state but also is prognostic of death and complications.2 A variety of humoral substances have been shown to be elevated in the CHF state,1,3 of which angiotensin II (Ang II) has been considered a prime candidate for a substance that modulates sympathetic outflow because it has been known for some time that Ang II can alter sympathetic function at several sites from the central nervous system to the periphery.4 Indeed, many of the current therapeutic targets in the treatment of CHF relate to reducing Ang II generation or blocking the effects of Ang II at its receptor sites. Despite its importance in central regulation of sympathetic outflow and cardiovascular homeostasis in the CHF state, the precise pathways and signaling mechanisms used by Ang II are still incompletely understood.
A growing body of evidence now indicates NAD(P)H oxidase-derived reactive oxygen species (ROS) as important mediators of Ang II signaling.5 Ang II not only augments ROS formation and increases the oxidase activity, but it also upregulates mRNA and protein expression of most NAD(P)H oxidase subunits in vitro6 and in vivo.7 The degree of oxidative stress and ROS is determined by the balance between ROS generation and oxidant scavenging. Several studies have documented reductions in superoxide dismutation in peripheral tissues in the CHF state.8,9 Unfortunately, there has been a lack of studies that focus on the central nervous system in this regard. Interestingly, in a recent study by Lindley et al,10 it was clearly shown that central transfection with an adenovirus coding for Cu/Zn superoxide dismutase (SOD) reduced sympathoexcitation in mice with chronic myocardial infarctions. Considering that ROS play an important role in the development and progression of heart failure,11 we hypothesized that central Ang II via an AT1 receptor mechanism activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. Therefore, the present study was performed, in conscious sham and CHF rabbits, to: (1) determine the effects of altered levels of central ROS using intracerebroventricular infusions of the SOD mimetic tempol, the inhibitor of NAD(P)H oxidase apocynin, and the inhibitor of SOD, diethyldithio-carbamic acid (DETC), on resting or Ang II-induced sympathetic nerve activity; and (2) evaluate mRNA and protein expression of the AT1 receptor and NAD(P)H oxidase subunits as well as the superoxide anion (O2–) in the rostral ventrolateral medulla (RVLM), a major site of sympathoexcitation in response to Ang II administered into the cerebrospinal fluid.12
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Materials and Methods |
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Animals
Experiments were performed on 49 male New Zealand White rabbits weighing between 3.2 and 4.3 kg. These experiments were reviewed and approved by the University of Nebraska Medical Center institutional animal care and use committee and conformed to the Guidelines for the Care and Use of Experimental Animals of the American Physiological Society and the National Institutes of Health. Rabbits were assigned to sham-operated (n=24) and CHF (n=25) groups. They were housed in individual cages under controlled temperature and humidity and a 12-hour light/dark cycle, and fed standard rabbit chow (Harlan Techlab) with water available ad libitum. All the following surgeries were performed under anesthesia and aseptic conditions.
Induction of CHF
Rabbits underwent sterile thoracic instrumentation and then were paced to induce CHF, as described previously.13 Details of instrumentation and echocardiographic analysis are available in the online data supplement at http://circres.ahajournals.org.
Arterial Pressure and Heart Rate Recording
A catheter connected to a radio telemetry unit (Data Sciences International) was inserted into the descending aorta via a branch of the right femoral artery for direct measurement of arterial pressure (AP) in the conscious state. Heart rate (HR) was derived from the AP pulse using a PowerLab (Model 8S; AD Instruments Inc.) data acquisition system.
Brain Guide Cannula Implantation
The skull was exposed through an incision on the midline of the scalp. After the bregma was identified, a 19-gauge stainless-steel guide cannula was implanted into the right lateral cerebral ventricle 4 mm lateral to the bregma and 6 mm below the cerebral surface. The position of the cannula in the lateral cerebral ventricle was confirmed by the staining of all four ventricles after injection of 0.1 mL of Evans Blue dye at the end of the experiments. The cannula was fixed to the skull with dental cement and was sealed by a 21-gauge obturator.
Renal Sympathetic Nerve Recording
Renal sympathetic nerve recording electrodes were implanted as we have described previously.14 Experiments were performed 3 to 14 days after nerve electrodes were implanted (see online data supplement for details).
Measuring Superoxide Anion Production in the RVLM
Homogenates were prepared from RVLM samples. Total protein concentration was determined using a bicinchoninic acid protein assay kit (Pierce). Superoxide anion production was measured using lucigenin chemiluminescence method15–17 (TD-20/20 Luminometer; Turner Designs; see online data supplement for details).
In Situ Detection of O2– Production in RVLM
Dihydroethidim (DHE), an oxidative fluorescent dye, was used to detect in situ superoxide in the RVLM of rabbits as described,18 with minor modification (see online data supplement for details).
RT-PCR Analysis of AT1 Receptor and NAD(P)H Subunit mRNA in the RVLM
Tissue punches were taken from the RVLM as described below. Total RNA of RVLM was isolated by means of the RNeasy Mini Kit Total RNA Isolation System (Qiagen), after which cDNA was synthesized by means of Moloney murine leukemia virus reverse transcriptase (Invitrogen Life Technologies). PCR amplification was performed by means of a PTC-100 Programmable Thermal Controller (MJ Research) as follows: 1 cycle at 95°C for 15 minutes, followed by 35 cycles of 94°C for 45 seconds, 55°C for 45 seconds, and 72°C for 1 minute. PCR products for the subunits gp91phox, p67phox, p47phox, p40phox, and p22phox were visualized on 2% agarose gels by use of ethidium bromide and sequenced so their identity could be confirmed. The bands were analyzed using UVP BioImaging Systems. Specific methodologies and gene sequences are available in the online data supplement.
Western Blot Analysis of AT1 Receptor and NAD(P)H Subunits Protein in the RVLM
The RVLM was homogenized with the homogenizer in radioimmunoprecipitation assay buffer. Protein extraction from homogenates was used for Western blot analysis for the rabbit AT1 receptor, gp91phox, p67phox, p47phox, and p40phox (see online data supplement for details).
Experimental Protocols
On the day of the experiment, the conscious rabbit was placed in a Plexiglas box in a dimly lit, quiet laboratory. After a 30-minute stabilization period, baseline renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and HR were recorded, and then the rabbit was treated with an intracerebroventricular infusion (30 minutes) of the following agents: Ang II (50 pM per 5 µL/min) alone, losartan (100 nM per 5 µL/min) alone, Ang II+losartan, tempol (10 µg per 5 µL/min) alone, Ang II+tempol, apocynin (8 µg per 5 µL/min) alone, Ang II+apocynin, or DETC (10 µg per 5 µL/min) in seven separate experiments one day apart.
Five days after the last experiment, the rabbit was euthanized with pentobarbital sodium. The brain was removed and immediately frozen on dry ice, blocked in the coronal plane, and sectioned at 300-µm thickness in a cryostat. The RVLM was punched according to the method of Palkovits and Brownstein19 for analysis of O2– production, mRNA, and protein of AT1 receptor and NAD(P)H subunits.
Data and Statistical Analysis
Because the effects of intracerebroventricular infusion of Ang II on MAP and RSNA usually started at 
10 minutes, reached the peak in 15 minutes, and then maintained that level until the end of the infusion, data were taken usually between 20 and 30 minutes after Ang II infusion. Changes in RSNA were similar when quantified using either voltage integration or spike discharge rate. The RSNA discharge data in the present study are presented using the rate meter method. All measurements were averaged every 30 seconds.
Data are expressed as the mean±SE. The differences between groups were determined with a two-way ANOVA followed by the Newman-Keuls test for post hoc analysis of significance. Hemodynamic and echocardiographic differences between sham and CHF rabbits were determined with Student t test. Differences before and after intracerebroventricular infusion treatment in each group were analyzed with a paired t test. A P value of <0.05 was considered statistically significant.
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Results |
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Baseline Hemodynamics, Left Ventricular Function, RSNA, and Body and Organ Weights
Rabbits with CHF showed significant decreases in ventricular function and increases in heart weight. In addition, baseline RSNA was significantly elevated (supplemental Table I and text in the online data supplement).
Effects of Intracerebroventricular Infusion of Ang II
In sham and CHF rabbits, intracerebroventricular infusion of Ang II (50 pM per 5 µL/min in artificial cerebrospinal fluid [aCSF]x30 minutes) significantly increased MAP (
12.4±3.1 mm Hg in sham, P<0.05; 25.5±3.7 mm Hg in CHF, P<0.01), and at the same time, lowered the RSNA (–85.4±9.7% of control in sham, P<0.01; –74.9±6.1% of control in CHF, P<0.01) starting at 10 minutes, reaching a peak effect in 15 minutes, and then maintaining that level until the end of infusion. However, when the MAP was prevented from raising by intravenous infusion of sodium nitroprusside (25 µg/kg per minute) during intracerebroventricular infusion of Ang II, the RSNA was significantly increased (131.5±13.3% of control in sham, P<0.001; 193.6±11.9% of control in CHF, P<0.001), which was significantly greater in CHF than in sham rabbits (P<0.05; Figures 1 and 2
). In contrast, intracerebroventricular administration of aCSF caused no change in MAP or RSNA (data not shown).
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Effects of Intracerebroventricular Losartan on Basal and Ang II-Induced RSNA
In CHF but not in sham rabbits, intracerebroventricular infusion of losartan significantly decreased basal RSNA (38.5±4.9% of control; P<0.05). However, in sham and CHF rabbits, when losartan was infused intracerebroventricularly 30 minutes before infusion of Ang II, the effect of Ang II on RSNA was completely abolished (Figure 3). Although there was a tendency for central administration of losartan to lower MAP (sham 76.1±6.3 to 72.8±4.6 mm Hg; CHF 67.9±4.4 to 60.7±6.1 mm Hg) and raise HR (sham 201.6±15.7 to 206.9±14.8 bpm; CHF 240.1±21.7 to 245.4±19.3 bpm), these changes did not reach statistical significance.
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Effects of Intracerebroventricular Tempol, Apocynin, and DETC on Basal and Ang II-Induced RSNA
In CHF rabbits, intracerebroventricular infusion of tempol or apocynin significantly decreased the basal RSNA (49.7±8.9% of control for tempol, P<0.01; 39.6±9.6% of control for apocynin, P<0.01.), and in sham rabbits, although the RSNA tended to be lowered during intracerebroventricular treatment of tempol or apocynin, the differences did not reach statistical significance. However, pretreatment with intracerebroventricular infusion of tempol or apocynin blocked the effect of Ang II on RSNA in the two groups. On the other hand, in sham and CHF rabbits, intracerebroventricular infusion of the SOD inhibitor DETC (8 µg per 5 µL/min in aCSFx30 minutes) significantly increased the RSNA (219.7±12.2% of control in sham, P<0.001; 155.8±12.8% of control in CHF, P<0.001). The increase in sham rabbits was significantly greater than in CHF rabbits (P<0.05; Figure 4).
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Expression of AT1 Receptor in RVLM
As shown in Figure 5, mRNA and protein expression of AT1 receptor in the RVLM were significantly upregulated in CHF rabbits compared with sham rabbits (mRNA 2.15±0.31 versus 0.66±0.22; protein 0.85±0.08 versus 0.38±0.09 arbitrary units, respectively).
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Expression of NAD(P)H Subunits of RVLM
As is shown in Figure 6, mRNA and protein expression for p40phox, p47phox, and gp91phox were significantly increased in CHF rabbits compared with sham rabbits. There were no differences in mRNA or protein expression for p67phox in RVLM of sham and CHF rabbits. Because rabbit p67phox is 16 to 17 amino acids longer than any other (human, bovine, murine, and dolphin) known p67phox homolog,20 it migrated as a band of 73 kDa. In addition, we failed to detect mRNA expression for p22phox in RVLM of either sham or CHF rabbits. However, as a positive control, we observed mRNA expression of p22phox in liver and kidney of sham and CHF rabbit (data not shown).
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Measurements of O2– Production in RVLM
NADPH-dependent superoxide production was significantly increased in the RLVM homogenates from CHF rabbits compared with that from sham rabbits (1.59±0.03 versus 0.53±0.01; P<0.05). The enhanced superoxide production in CHF rabbits was markedly inhibited by SOD, Tiron, apocynin, or phenylarsine oxide but was unaltered by oxypurinol, rotenone, or NG-nitro-L-arginine methyl ester (Figure 7).
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In Situ Detection of O2– Production in RVLM
To provide in situ evidence that the O2– levels in the RVLM in CHF rabbits, confocal analysis of DHE fluorescence was used to estimate O2– levels in brain sections of sham and CHF rabbits. As shown in Figure 8, DHE fluorescence was increased in the RVLM of CHF rabbits (B and D) compared with sham rabbits (A and C).
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Discussion |
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The mechanism by which sympathetic function is enhanced in the CHF state has been a topic of intense investigation for many years. The precise cause of the sympathoexcitatory state in CHF has eluded investigators most likely because of its multifactorial nature. Recent studies from our and other laboratories have suggested that Ang II is a prime candidate for a substance that modulates sympathetic outflow in this disease because blockade of the Ang II type 1 (AT1) receptors reduces the enhanced sympathetic tone in the CHF state.21,22 In this study, we found that intracerebroventricular administration of Ang II evoked a significant increase in AP and a significant decrease in RSNA in sham and CHF conscious rabbits. This finding is similar to that observed by Jin et al in anesthetized normal rats.23 We believe that the decreased RSNA was caused by an increase in AP via a baroreceptor reflex mechanism that overcame and blunted the direct effects of Ang II on RSNA. Indeed, when AP was clamped at the baseline level, the sympathoexcitatory effect of intracerebroventricular Ang II emerged (Figures 1 and 2
). This is first time, to our knowledge, the direct excitatory effects of central administration of Ang II on sympathetic activity in conscious rabbits with CHF have been demonstrated. These data suggest that the initial pressor response of central Ang II is mediated by increases in sympathetic outflow to vascular beds other than the kidney. In addition, we showed that this effect of Ang II is mediated by central AT1 receptors because pretreatment with intracerebroventricular losartan completely abolished the pressor response to central treatment of Ang II (Figure 3). An important finding in this study was that the increase in RSNA induced by Ang II in CHF rabbits was significantly greater than that in sham rabbits (Figure 1). This enhanced response to intracerebroventricular Ang II may be mediated by an upregulation in the expression of AT1 receptor mRNA and protein in RVLM of CHF rabbits (see below). In this regard, in a recent study by Lazartigues et al,24 it was nicely demonstrated that intracerebroventricular administration of Ang II to conscious mice with specific overexpression of brain AT1 receptors exhibited greater pressor responses compared with wild-type mice. In addition, we also found in the current experiment that intracerebroventricular infusion of losartan lowered RSNA in CHF rabbits but not in sham rabbits (Figure 3), suggesting a tonic excitatory effect of elevated endogenous Ang II in the heart failure state. Because the change of RSNA induced by losartan was not accompanied by a significant alteration in MAP, we believe the sympathetic tone modulated by central endogenous Ang II may be limited to the kidney alone. Growing evidence indicates that ROS are key mediators of Ang II signaling and that several important physiological functions of Ang II are directly mediated by ROS, including growth of vascular smooth muscle, induction of a vascular inflammatory responses, impairment of endothelium-dependent relaxation, and cardiac hypertrophy.25 On the other hand, there is extensive experimental evidence from in vitro and animal experiments that CHF is a state of oxidative stress.26 Moreover, recent data from animal studies8 as well as from patients27 support the role of increased oxidative stress in pathogenesis of CHF. On the basis of these findings, we hypothesized that ROS mediates the renal sympathoexcitatory effects of central Ang II. In the present study, we found that pretreatment with intracerebroventricular tempol or apocynin abolished the increased RSNA induced by intracerebroventricular Ang II in sham and CHF rabbits (Figure 4). These results indicate that NAD(P)H oxidase-derived ROS play an important role during Ang II-induced sympathoexcitation because the SOD mimetic tempol and the inhibitor of NAD(P)H oxidase apocynin were effective in blunting the response. Because tempol and apocynin significantly decreased basal RSNA in CHF, it is difficult to determine whether the lowered RSNA in the Ang II+tempol or Ang II+apocynin groups compared with the group given Ang II alone was attributable to either the basal effects of tempol and apocynin or to the blocking effect of these agents. However, in sham rabbits, although tempol and apocynin have no effects on basal RSNA, the RSNA in Ang II+tempol or Ang II+apocynin groups were lower than that in the Ang II group, indicating that tempol and apocynin blocked the sympathoexcitation induced by Ang II (Figure 4). Recently, Xu et al28 performed studies in anesthetized deoxycorticosterone acetate-salt hypertensive rats and found that tempol lowered blood pressure and sympathetic nerve activity but not vascular O2–, indicating a direct sympathoinhibitory effect of this SOD mimetic. However, in two sham rabbits of the present study, we did not find that tempol potentiated the inhibitory effects of apocynin on the sympathoexcitatory response to intracerebroventricular Ang II (data not shown) when combining administration of tempol with apocynin.
The third major finding of the present study was that intracerebroventricular infusion of tempol or apocynin significantly decreased the basal RSNA in conscious CHF rabbits (Figure 4), indicating that enhanced oxidative stress promotes a tonic sympathoexcitatory effect in the CHF state. In contrast, in sham rabbits, we failed to observe any change in RSNA during intracerebroventricular infusion of tempol or apocynin, indicating that in the normal state, the lower level of oxidative stress is not a necessary factor for maintaining baseline sympathetic outflow. In addition, we found that intracerebroventricular infusion of DETC, an SOD inhibitor that increases superoxide production,29 significantly increased RSNA in sham and CHF rabbits, and the extent of this increase was significantly greater in sham rabbits compared with CHF rabbits (Figure 4). This result suggests that central ROS directly excites sympathetic nerve activity, and that central SOD activity may be lower in CHF than that in the normal state. Recently, Shokoji et al30 performed studies in anesthetized normotensive and hypertensive rats and found that intravenous administration of DETC rapidly increased RSNA in both groups of rats. However, the authors did not evaluate the central or peripheral action of DETC in these experiments.
It is well known that the RVLM plays a critical role in the generation and maintenance of sympathetic nerve activity.31 Recent studies showed that the RVLM contains high concentrations of AT1 receptors32 and is a major site of the sympathoexcitatory action of central Ang II.12 In the present study, we measured the expression of AT1 receptors in the RVLM by RT-PCR and Western Blot analysis and confirmed the upregulation of AT1 receptors in RVLM of CHF rabbits (Figure 5). In a previous study from this laboratory, we confirmed a significant increase in the cerebrospinal fluid concentration of Ang II in dogs with pacing-induced heart failure.33 These results imply that in the heart failure state, elevated central Ang II may act to upregulate AT1 receptors in the RVLM. This, in turn, may increase sympathetic outflow via stimulation of NAD(P)H oxidase-derived ROS. Recently, Yoshimura et al34 and Tan et al35 demonstrated that in the subfornical organ, the paraventricular hypothalamic nuclei, and the solitary tract nuclei of rats with heart failure, AT1 receptor expression was markedly upregulated and AT1 receptor binding density was significantly increased.
NAD(P)H oxidase is a multicomponent enzyme complex that consists of the two membrane-spanning polypeptide subunits p22phox and gp91phox (which, together, comprise flavocytochrome b558), and three cytoplasmic polypeptide subunits p40phox, p47phox, and p67phox to produce superoxide.36 NAD(P)H oxidase was first found and has been best characterized in phagocytic cells.37 However, recent studies showed that NAD(P)H oxidase proteins also have been localized in neurons.38 In this study, we provided evidence for the existence of mRNA and protein expression of all of the NAD(P)H oxidase subunits except for p22phox in the RVLM of sham and CHF rabbits (Figure 6), implying NAD(P)H oxidase-derived ROS may play a role in the central regulation of sympathetic outflow. As noted above, a variety of studies have documented that Ang II upregulates the gene expression of most NAD(P)H oxidase subunits.6,7 At the same time, Ang II concentration is significantly increased in the cerebrospinal fluid of CHF dogs, 33 and the AT1 receptor mRNA and protein expression in the RVLM is significantly upregulated in CHF rabbits (Figure 5). In the current study, we found that CHF rabbits exhibited a significant enhancement of p40phox, p47phox, and gp91phox subunits in the RVLM compared with sham rabbits. This observation correlated positively with changes in NADPH-dependent O2– production (Figures 7 and 8), supporting the view of a functional upregulation of these components in RVLM of the CHF state. These increases would be expected to contribute to higher NAD(P)H oxidase O2–-generating activity because increases in individual components have been shown to enhance NAD(P)H oxidase activity in cell-free assays.36 The above results imply that in the CHF state, an enhanced central Ang II mechanism(s) stimulates NAD(P)H oxidase subunit gene expression in the RVLM to increase O2– formation.
In summary, we show that intracerebroventricular Ang II significantly increased RSNA in sham and CHF rabbits. These responses were abolished by intracerebroventricular losartan, tempol, and apocynin. Intracerebroventricular tempol and apocynin significantly reduced resting RSNA in CHF but not in sham rabbits. Intracerebroventricular DETC significantly increased the RSNA in CHF and sham rabbits. The mRNA and protein expression of AT1 receptor and the NAD(P)H oxidase subunits p40phox, p47phox, and gp91phox in the RVLM were significantly upregulated in CHF rabbits compared with sham rabbits. NADPH-dependent superoxide anion was increased in the RVLM in CHF rabbits. These data demonstrate intense radical stress in an important autonomic area of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to the sympathoexcitation in CHF.
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Acknowledgments |
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This study was supported by National Institutes of Health grant PO-1 HL62222. We thank Johnnie F. Hackley, Pamela Curry, and Jodi Hallgren-Golka for their expert technical assistance.
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Footnotes |
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Original received June 23, 2004; revision received September 17, 2004; accepted September 21, 2004.
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