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Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
Submitted 10 September 2004 ; accepted in final form 5 January 2005
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ABSTRACT |
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baroreflex; renal sympathetic nerve activity; free radicals; angiotensin II type 1 receptor; rostral ventrolateral medulla; reactive oxygen species
Recent evidence indicates that NAD(P)H oxidase-derived reactive oxygen species (ROS) are important mediators of ANG II signaling (22, 61). ANG II not only augments ROS formation and increases oxidase activity but also upregulates mRNA and protein expression of most NAD(P)H oxidase subunits both in vitro (44) and in vivo (38). In addition, ROS have been shown to play an important role in various physiological and pathophysiological processes (25, 47) in the central nervous system. ROS have been linked to regulation of sympathetic nerve activity. For example, treatment with the cell membrane-permeable superoxide dismutase (SOD) mimetic tempol decreased renal sympathetic nerve activity (RSNA) in both normotensive and hypertensive rats (58, 59). Conversely, the SOD inhibitor diethyldithiocarbamate has the opposite effect (48).
AT1 receptors are widely distributed in the central nervous system from the forebrain to the brain stem (28). The rostral ventrolateral medulla (RVLM) contains a high density of these receptors (1) and is a major site of sympathoexcitation in response to ANG II administration into the cerebrospinal fluid (23). The RVLM not only plays a critical role in the generation and maintenance of sympathetic nerve activity (11, 12) but also is an essential part of the central baroreflex pathway (10, 18).
Therefore, we hypothesized that centrally administered ANG II may act via an AT1 receptor mechanism to activate sympathetic outflow and impair arterial baroreflex function by stimulation of NAD(P)H oxidase and ROS in the RVLM. The purpose of this study was to determine whether central subchronic infusion of ANG II stimulates O2– production and expression of NAD(P)H oxidase subunits and AT1 receptors in the RVLM. Second, we identified the effects on sympathetic nerve activity and arterial baroreflex function and determined whether these central effects of ANG II are mediated by AT1 receptors.
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METHODS |
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Subchronic lateral cerebral ventricle infusion. The skull was exposed through an incision on the midline of the scalp. After the bregma was identified, a 19-gauge stainless steel cerebroventricular cannula was implanted into the right lateral cerebral ventricle, 4 mm lateral to the bregma and 6 mm below the cerebral surface, and fixed tightly to the skull with super-glue adhesive and dental cement. 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. An osmotic minipump (model 2001; Durect; Cupertino, CA) filled with isotonic saline (1 µl/h), ANG II (80 ng·µl–1·h–1), ANG II (80 ng·µl–1·h–1) plus losartan (20 µg·µl–1·h–1), or losartan alone (20 µg·µl–1·h–1) was implanted subcutaneously in the back of neck and connected to the cerebroventricular cannula. The infusion was continued for 7 days.
Arterial pressure and HR recording. While animals were under anesthesia and aseptic conditions, a catheter connected to a radio-telemetry unit (Data Sciences International; St. Paul, MN) was inserted into the descending aorta via a branch of the right femoral artery for direct measurement of arterial pressure (AP) with rabbits in the conscious state. HR was derived from the AP pulse using a PowerLab (model 8S; ADInstruments; Colorado Springs, CO) data-acquisition system.
RSNA recording. RSNA-recording electrodes were implanted as described previously (32). In brief, while animals were under anesthesia and under sterile conditions, the left kidney was exposed retroperitoneally, and a branch of renal nerve was separated from the renal plexus and the surrounding connective tissues. A pair of stainless steel, stranded Teflon-coated recording electrodes were placed around the nerve branch. The nerve-electrode junction was insulated electrically from the surrounding tissues and covered with fast-setting silicone (Kwik-Sil; World Precision Instruments; Sarasota, FL). A ground wire was secured to a nearby muscle. The recording electrodes and ground wire were tunneled under the skin and exteriorized in the midscapular area. During the experiment, the electrical signal from the electrode was amplified with a Grass P55 preamplifier (Grass Instruments; West Warwick, RI) with high- and low-frequency cutoffs of 1,000 and 100 Hz, respectively. The output from the Grass amplifier was directed to the PowerLab system, which sampled at 1,000 samples/s. The signal was also full-wave rectified and integrated. The average rectified signal (RC filtered; time constant, 0.5 s) was then recorded and stored for later analysis. The frequency of nerve discharge was counted by using a window discriminator and rate meter. The cursor of the window discriminator was set just above the electrical noise. Both frequency and integrated nerve activity were recorded continuously along with the raw nerve activity. The units of RSNA used in this experiment are percent of maximum (% max) and represent the maximum RSNA induced by nasopharyngeal stimulation with cigarette smoke, which has been shown to be a suitable and reliable method of comparing RSNA baroreflex curves under a variety of different conditions (5).
Evaluation of arterial baroreflex function.
Evaluation of the arterial baroreflex was carried out as previously described (31). In brief, rabbits were studied in a quiet, dimly lit room while they stood in a Plexiglas box. AP, HR, and RSNA values were recorded using a PowerLab system. Intravenous infusions were administered via a lateral ear vein. After the animal had adjusted to the environment and all hemodynamics were stable, an intravenous infusion of sodium nitroprusside (SNP) was started at a rate of 100 µg·kg–1·min–1 at 0.5 ml/min. When AP reached its nadir (usually 40–50 mmHg), the SNP infusion was stopped, and a phenylephrine (PE) infusion was started at a rate of 80 µg·kg–1·min–1 at 0.5 ml/min. The PE infusion continued until AP reached 
110 mmHg. The baroreflex was analyzed over the pressure range from lowest to highest pressure. This infusion rate increased AP at a rate of 1 mmHg/s.
The HR, MAP, and RSNA data were acquired every 2 s from the thresholds to the saturation points. A sigmoid logistic function was fit to the data using a nonlinear regression program (SigmaPlot 8.0; Jandel). Four parameters can be derived from the following equation: HR or RSNA = A/{1 + exp[B(MAP – C)]} + D, where A is the HR or RSNA range, B is the slope coefficient, C is the pressure at the midpoint of the range (BP50), and D is the minimum HR or RSNA. The peak slope (or maximum gain) was determined by taking the first derivative of the baroreflex curve and was calculated using the equation Gainmax = A1 x A2 x, where A1 is the range and A2 is the average slope.
O2– production in RVLM. O2– production was measured by the lucigenin enhanced chemiluminescence (ECL) method (TD-20/20 luminometer; Turner Designs; Sunnyvale, CA). Total protein concentration was determined using a bicinchoninic acid protein-assay kit (Pierce; Rockford, IL). NADPH (100 µM) and dark-adapted lucigenin (5 µM) were added into 0.5-ml microcentrifugal tubes just before reading. Light emission was recorded over 10 min, and values are expressed as mean light units per minute per milligram of protein.
Preparation of RVLM tissue. At the end of the experiment, each rabbit was euthanized with pentobarbital sodium. The brain was removed and immediately frozen on dry ice, blocked in the coronal plane, and sectioned into 300-µm-thick slices using a cryostat. The RVLM was punched according to the method of Palkovits and Brownstein (42) for the analysis of O2– production and mRNA and protein of AT1 receptor and NAD(P)H subunits.
RT-PCR analysis of AT1 receptor and NAD(P)H subunit mRNA in RVLM.
Total RNA of the RVLM was isolated using the RNeasy Mini Kit Total RNA Isolation System (Qiagen; Valencia, CA), after which cDNA was synthesized by means of Moloney murine leukemia virus (MMLV) reverse transcriptase (Invitrogen Life Technologies; Carlsbad, CA) according to the manufacturers' instructions. RNA was treated in parallel in the presence or absence of reverse transcriptase. PCR amplification was performed by means of a PTC-100 programmable thermal controller (MJ Research; Watertown, MA) as follows: 1 cycle at 95°C for 15 min, followed by 35 cycles of 94°C for 45 s, 55°C for 45 s, and 72°C for 1 min. The primer pairs were based on the cDNA sequences of rabbit AT1 receptor (GenBank accession no. S59041), gp91phox (GenBank accession no. AF323788), p67phox (GenBank accession no. AF323789), p47phox (GenBank accession no. AF324409), p40phox (GenBank accession no. AF323790), and p22phox (GenBank accession no. AF323787) with 
-actin (GenBank accession no. AF309819) as an internal control. The primer pairs were as follows: AT1 receptor, 5'-TTTGGGAACAGCTTGGCGGT-3' and 5'-GCCAGCCAGCAGCCAAATAA-3'; gp91phox, 5'-gcttgtggctgtgataagca-3' and 5'-ctcctgcatctgtgtctcca-3'; p67phox, 5'-aactcagtgggtgaccaagg-3' and 5'-gttcttccacgaaggctctg-3'; p47phox, 5'-acgagagtggttggtggttc-3' and 5'-tagccagtgacgtcctcctt-3'; p40phox, 5'-tcactgggaacagcaaactg-3' and 5'-ctgctgaggtcttcctccac-3'; p22phox, 5'-cgcttcacccagtggtactt-3' and 5'-gcagccagcaggtagatgat-3'; and -actin, 5'-GATCGCTGACCGTATGCAG-3' and 5'-GTCGTACTCCTGCTTGGTG-3'. The amplification products were visualized on 2% agarose gels by the use of ethidium bromide and were sequenced so that their identities could be confirmed. The bands were analyzed using UVP BioImaging Systems.
Western Blot analysis of AT1 receptor and NAD(P)H subunit protein in RVLM. The RVLM was homogenized with the homogenizer in RIPA buffer. Protein extraction from homogenates was used for Western blot analysis for rabbit AT1 receptor, gp91phox, p67phox, p47phox, and p40phox. Protein concentration was measured using a protein assay kit (Pierce). Samples were adjusted to the same concentrations of protein, mixed with equal volumes of 2x 4% SDS sample buffer, boiled for 5 min, and then loaded onto a 7.5% SDS-PAGE gel (5 µg protein/30 µl per well) for electrophoresis using a Bio-Rad minigel apparatus at 40 mA (for each gel) for 45 min. The fractionized proteins on the gel were electrophoretically transferred onto the polyvinylidene difluoride membrane (Millipore) at 300 mA for 90 min. The membrane was probed with primary antibody (1:1,000 dilutions of rabbit anti-human AT1 receptor polyclonal antibody and goat anti-human gp91phox, p67phox, p47phox, and p40phox polyclonal antibodies; Santa Cruz) and secondary antibody (1:2,500 dilutions of goat anti-rabbit IgG-horseradish peroxidase and rabbit anti-goat IgG-horseradish peroxidase; Santa Cruz) and then treated with enhanced chemiluminescence substrate (Pierce) for 5 min at room temperature. The bands in the membrane were visualized and analyzed using UVP BioImaging Systems.
Data and statistical analysis. Data are expressed as means ± SE. Differences between groups were determined with a two-way ANOVA followed by a Newman-Keuls test for post hoc analysis of significance. The 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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mRNA expression of AT1 receptor and NAD(P)H oxidase subunits in RVLM after ANG II and losartan infusions. The mRNA expression of AT1 receptor and NAD(P)H oxidase subunits in the RVLM was assessed by RT-PCR. As shown in Fig. 4B, intracerebroventricular infusion of ANG II for 7 days significantly increased AT1 receptor expression by 66.7%, p40phox expression by 120.0%, p47phox and p67phox expression by 200.0%, and gp91phox expression by 175.0%. We failed to detect mRNA expression for p22phox in the RVLM of either the saline- or ANG II-treated group. However, as a positive control, we observed mRNA expression of p22phox in liver and kidney of these rabbits (data not shown). In the rabbits treated with ANG II plus losartan, mRNA expression of AT1 receptor and NAD(P)H oxidase subunits in the RVLM was significantly decreased compared with the ANG II group and almost the same as the saline group (Fig. 4B). In addition, mRNA expression of AT1 receptor and NAD(P)H oxidase subunits in the RVLM of losartan-treated rabbits was not significantly different from saline-treated rabbits (Fig. 4B). Figure 4A is a representative RT-PCR image that shows the upregulation of AT1 receptor, p40phox, p47phox, p67phox, and gp91phox mRNA expression in RVLM of ANG II-treated rabbits (Fig. 4A) compared with saline-treated animals (controls, Fig. 4C).
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DISCUSSION |
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Strong evidence is accumulating to suggest that central ROS are involved in the action of ANG II in the regulation of cardiovascular activity and function of central autonomic networks. For example, the adenoviral vector-mediated overexpression of SOD abolishes the cardiovascular effects of intracerebroventricular-injected ANG II in mice (61), and chronic systemic infusion of ANG II in mice causes a gradually developing hypertension that is correlated with marked elevations in O2– production specifically in the subfornical organ (62). Moreover, in the nucleus of the solitary tract, the essential NAD(P)H oxidase subunit gp91phox is present in somatodendritic and axonal profiles that contain AT1 receptors, and both the SOD scavenger Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and NAD(P)H oxidase assembly inhibitor apocynin blocked the potentiation of ANG II on L-type Ca2+ currents (53). In the present study, we found that subchronic intracerebroventricular infusion of ANG II increases O2– production in the RVLM concomitant with elevation in basal RSNA and impaired arterial baroreflex function, which suggests that O2– is involved in the modulation of RSNA and arterial baroreflex function by long-term central ANG II treatment. In this regard, in a recent study by Mayorov et al. (35), it was nicely demonstrated that bilateral microinjections of tempol or tiron into the RVLM attenuated the pressor, sympathetic, and tachycardic responses to stress or microinjection of ANG II into the RVLM. The studies by Zanzinger and Czachurski (60) showed that SOD injected into the RVLM of pigs caused sympathoinhibition to a greater extent when the animals were under conditions of chronic overproduction of ROS, which further supports our hypothesis that ROS in the RVLM plays an important role in modulation of central autonomic nervous system activity and cardiovascular function by central ANG II. However, the mechanisms by which ROS excites the RVLM neurons are still unknown. Some studies (2, 29) indicate that ROS may directly activate Ca2+ channels to enhance Ca2+ currents and therefore might depolarize neurons and increase excitability and spontaneous activity.
The main source of ANG II-derived ROS is NAD(P)H oxidase (20, 37), an enzyme first described in phagocytes. NAD(P)H oxidase is composed of two membrane-bound subunits (gp91phox and p22phox), several cytoplasmic subunits (p40phox, p47phox, and p67phox), and the small G protein Rac 1a (26). After stimulation of AT1 receptors by ANG II, the cytoplasmic subunits bind to the membrane subunits and activate the enzyme, which results in production of O2– (21, 30, 49). In the present study, RT-PCR and Western blots showed a significant enhancement of most NAD(P)H oxidase subunit mRNA and protein in the RVLM from ANG II-infused vs. vehicle-infused and ANG II plus losartan-treated rabbits that correlated positively with changes in O2– production. This would be expected to contribute to higher NAD(P)H oxidase O2–-generating activity, because increases in even individual components have been shown to enhance NAD(P)H oxidase activity in cell-free assays (13). Previous reports by other groups have shown that prolonged subcutaneous or intraperitoneal infusion of ANG II significantly increased renal cortical (6) or aortic (7, 38) NAD(P)H oxidase subunit expression. The data reported here extend those findings to rabbit RVLM, which is a specific central region that not only maintains sympathetic vasomotor outflow and plays a key role in controlling the baroreceptor reflex (9) but also has a high density of AT1 receptors (1) and is a major site of sympathoexcitation in response to ANG II administered into the cerebrospinal fluid (23). This suggests close relationships between the brain renin-ANG II system, central redox signaling, and the regulation of cardiovascular function and autonomic nerve activity.
In the present study, we failed to detect mRNA expression for p22phox in the RVLM of rabbits. This does not appear to be due to a technical problem, because as a positive control, we did observe mRNA expression of p22phox in liver and kidney of these rabbits. However, this is not to say that NAD(P)H oxidase works well even without p22phox. One possibility, we believe, for the lack of p22phox in the RVLM of rabbit is the existence of some yet-unknown p22phox homolog, similar to what is observed in smooth muscle cells that lack gp91phox; recent studies have identified the existence of several gp91phox homologs such as Nox1 and Nox4 (27).
The ANG II receptor is a central component of the renin-angiotensin system. Activation of ANG II receptors mediates a variety of effects from contraction of vascular smooth muscle to secretion of hormones including the effects on NAD(P)H oxidase and ROS. Thus regulation of their expression is important in cardiovascular and central responsiveness to ANG II. The existence of two types of ANG II receptors, AT1 and AT2, has been demonstrated. Although little is known about the function of AT2 receptors, AT1 receptors mediate many of the functions described. The other finding of the present study is that subchronic intracerebroventricular infusion of ANG II significantly increased the mRNA and protein expression of AT1 receptors in the RVLM of rabbits, which might give an explanation for our previous finding that in the chronic heart-failure animal model, elevated ANG II levels were often concomitant with overexpression of AT1 receptors. Porter (43) also found that 1 wk of intracerebroventricular ANG II infusion produced a significant increase in brain AT1 receptor protein (via Western blot) and mRNA (via relative RT-PCR) expression. Moellehoff et al. (36) showed an increase in AT1 receptor number in some brain regions in rats after repetitive intracerebroventricular injections of ANG II (by immunohistochemical staining). The exact molecular mechanisms by which the expression of AT1 receptors in brain was upregulated by its ligand are still unclear. On the one hand, a number of factors including aldosterone are suggested to modulate the expression of AT1 receptor protein and mRNA (46). Chronic ANG II infusion increases plasma aldosterone and then induces transcription factors through mineralocorticoid receptors, and this is followed by an increase in AT1 receptor expression (51). ANG II also activates various nuclear transcription factors including activator protein-1, the signal transducers and activators of transcription family of transcription factors, cAMP response-element binding protein, and nuclear factor-
B (45), some of which are involved in the transcription of AT1 receptor genes (8).
In the present study, we also found that subchronic intracerebroventricular infusion of ANG II significantly increased basal RSNA, which may be due to the stimulation of ANG II on NAD(P)H oxidase and ROS in RVLM as described above, and contributed to the impaired baroreflex control of HR and RSNA observed in the same experiments. Many studies have solidly supported the idea that sympathetic activity and/or renin-angiotensin system activity can antagonize arterial baroreflex function in both humans and experimental animals (19, 33, 52). This was in agreement with the work of Gaudet et al. (17), who described diminished sensitivity of the cardiac baroreflex in conscious normotensive rabbits after long-term central administration of ANG II at subpressor doses. Considering these data, the increased NAD(P)H oxidase expression and ROS production in RVLM is critical for the effects of intracerebroventricular ANG II infusion on basal sympathetic activity and arterial baroreflex function. In addition, we still found that subchronic intracerebroventricular infusion of the AT1 receptor antagonist losartan produced enhanced baroreflex control of both HR and RSNA concomitant with suppressed baseline sympathetic activity but without any change of AT1 receptor protein and NAD(P)H oxidase subunit expression or O2– production in RVLM, which indicates that in conscious normal rabbits, there was tonic activation of these receptors from endogenous ANG II on arterial baroreflex function and sympathetic activity but no effect on AT1 receptor and NAD(P)H oxidase subunit expression.
In summary, our results demonstrate that in normal rabbits, subchronic intracerebroventricular infusion of ANG II upregulated AT1 receptor and NAD(P)H oxidase subunit expression and increased O2– production in RVLM mediated by central AT1 receptors and contributed to the enhanced sympathetic outflow and impaired arterial baroreceptor reflex control of HR and RSNA induced by this ANG II treatment. Endogenous ANG II, however, regulates the sympathetic activity and artery baroreflex function independent of the NAD(P)H-ROS pathway in RVLM.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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