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1
* University Research Centre for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK; and
Department of Physiology, University of Bristol, Bristol BS8 1TD, UK
1Correspondence: Department of Physiology, University of Bristol, University Walk, Bristol BS8 1TD, UK. E-mail: sergey.kasparov{at}bristol.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: hypertension • nucleus of the solitary tract • adenoviral gene transfer • calcium signaling
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. ANG II produced locally in the brain can contribute to blood pressure regulation independently of circulating ANG II. This is demonstrated in several hypertensive animal models where the development of hypertension is accompanied by an increase in brain ANG II activity (3
4
5
6)
. Although circulating ANG II has a direct vasopressor effect, the central effects of ANG II can contribute to hypertension by disabling feedback mechanisms. For example, ANG II microinjected into the nucleus of the solitary tract (NTS), the central termination of cardiorespiratory afferents, reversibly depresses the cardiac component of the baroreceptor reflex via AT1 receptors (7
8
9
10)
. We have previously shown that this ANG II-mediated inhibition of the baroreflex is dependent on release of nitric oxide (NO) by the endothelial isoform of nitric oxide synthase (eNOS; 11
). However, the transduction mechanism by which ANG II activates eNOS within the NTS remains unknown.
The NTS contains a high density of AT1 receptors (12)
. Binding of ANG II to the AT1 receptor can initiate a wide range of intracellular signaling events; therefore, ANG II can activate eNOS in more than one way. In one scenario, AT1 receptors via Gq protein activate phospholipase C (PLC) to stimulate production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), leading to release of Ca2+ from intracellular stores (13
, 14)
. Ca2+ ions then activate calmodulin (CaM), and the resultant Ca2+-CaM complex initiates eNOS dimerization, leading to formation of the enzymatically active molecule (reviewed in ref 15
). An alternative mechanism has been suggested in vascular smooth muscle and endothelial cells whereby reactive oxygen species (ROS) generated by the NADP/NADH oxidase system link AT1 receptors to a variety of cellular responses (16)
. One of these responses may include ROS-mediated activation of phosphatidylinositol-3-OH-kinase (PI3K), which subsequently activates the serine/threonine kinase Akt. Consequently, phosphorylation of eNOS on residue serine 1177 by Akt increases eNOS activity even at resting levels of intracellular Ca2+. This mechanism is thought to underlie eNOS activation in endothelial cells in vitro and in vivo in response to shear stress and vascular endothelial growth factor (17
, 18)
. Finally, interactions with other proteins that regulate eNOS activity, such as heat shock protein 90 (Hsp90; 19
) and calveolin-1 (15)
, have also been reported.
We sought to determine the transduction mechanism responsible for the ANG II-evoked baroreflex depression in the NTS. A combination of pharmacological and genetic tools was used in an unanesthetized decerebrate rat model to determine whether PLC-mediated Ca2+ release or ROS/PI3K/Akt pathways are essential for inhibition of the baroreflex by ANG II. Preliminary reports of parts of this study have been presented (20)
.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 22)
. Male Wistar rats (80–120 g) were terminally anesthetized with halothane, bisected below the diaphragm, decerebrated precollicularly, and cerebellectomized to expose the fourth ventricle in ice-chilled Ringer’s solution. The thorax and head were perfused with Ringer’s solution containing 1.25% ficoll at 31°C gassed with carbogen (95% O2-5% CO2). The perfusate was pumped at a constant flow via a double lumen catheter inserted into the descending aorta whereas the second lumen was connected to a pressure transducer to measure the aortic pressure directly. The left phrenic nerve was isolated and its activity continuously monitored together with the electrocardiogram (ECG). Phrenic nerve activity gave an index of preparation viability as indexed by its augmenting eupneic discharge pattern. Pulses triggered by the R wave of the ECG together with the digitized arterial pressure signal were acquired by a CED 1404 plus interface using Spike2 software (CED, Cambridge, UK), which calculated on-line the heart rate in beats per minute (bpm).
Reflex measurements
The baroreflex was evoked by raising perfusion pressure for 2–3 s to different levels above baseline (10–40 mmHg). Peak changes (
) in perfusion pressure and heart rate were measured on-line and baroreflex gain was calculated as the ratio of change in heart rate to the change in perfusion pressure (heart rate/perfusion pressure; expressed as bpm/mmHg). Baroreceptor reflex function curves were also plotted. Subsequent pressure ramps were generated that fell on the linear part of this curve.
Microinjections
Calamus scriptorius (CS) was used as a landmark for positioning of micropipettes as described in ref 10
. Drugs were applied bilaterally using pressure injection from a 3-barreled micropipette (tip diameter 
35 µm) driven by a micromanipulator to 400–500 µm ventral to the dorsal surface, ±400 µm rostrocaudal relative to the CS, and between 250 and 500 µm from midline, with the most medial injections being the most caudal. The injected volume (50 nL) was measured by observing the movement of the meniscus through a binocular microscope fitted with a calibrated eyepiece graticule.
Adenoviral gene transfer in the NTS
Male Wistar rats (60–90 g) were deeply anesthetized with an injection of a mixture of ketamine (60 mg/kg) and medetomidine (250 µg/kg) intraperitoneally. They were placed into a stereotaxic head holder; after making a midline incision in the dorsal neck, the caudal dorsal medulla was exposed. Bilateral microinjections of adenoviral vectors (total volume of 100 nL over 1 min) were made into three or four sites within 400 µm of the CS rostrocaudally, 150–250 µm lateral to the midline and 300–500 µm below the dorsal surface. The wound was sutured and treated with neomycin powder, and the rats were allowed to recover. After 5–6 days, the rats were used for WHBP experiments (see below). After the experiment, the transfected brains were fixed with 4% paraformaldehyde, cryoprotected in 30% sucrose, and sectioned using a cryostat (Leica, Cambridge, UK). Transfected regions were visualized using a conventional fluorescent microscope and microinjection sites were plotted on representative transverse sections as from ref 22
.
To detect catalase activity introduced by Ad-CAT, a histochemical reaction was performed on sections from the rats pretransfected with this construct essentially as described in ref 23
. After fixation with 4% paraformaldehyde and 1% CaCl2 in phosphate buffer (pH 7.4), 40 µm transverse sections were cut through the caudal medulla and washed in 0.5M Tris-HCl buffer (pH 10.4; Sigma, Dorset, UK) containing 0.01M imidazole (Sigma) for 30 min at 42°C. Sections were then incubated for 35 min in the same solution with the addition of 0.2% 3, 3'-diaminobenzidine (Sigma) and 0.3% hydrogen peroxide.
Experimental protocol
At least three stable control cardiac baroreflexes were obtained before a bilateral NTS microinjection of ANG II. Sequential bilateral microinjections were made, with the second injection completed within 45 s of the first. Baroreflexes were retested within 60–90 s of the bilateral microinjection; further reflex testing was performed at 5 min intervals until reflex sensitivity returned to control levels, which was achieved within 10–15 min. In cases where a pharmacological inhibitor was used, the effects of ANG II were tested first, after which the inhibitor was either microinjected into the NTS or administered into the perfusate. In the former case, the baroreflex was tested after bilateral NTS microinjection of the inhibitor alone or inhibitor with ANG II. In the latter case, the inhibitor was added to the perfusate, and at least three control reflexes were obtained in the presence of the inhibitor before and after ANG II was microinjected into the NTS. To control against possible volume-related effects, bilateral NTS microinjection of 0.9% NaCl was performed but produced no measurable effect on either basal cardiorespiratory parameters or baroreflex sensitivity. At the end of the experiment, the locations of the microinjections were marked by injecting 50 nL of 2% Pontamine sky blue. The brains were then fixed, sectioned (50 µm), and counterstained with neutral red. Microinjection sites were documented and plotted on transverse sections as from ref 22
.
Solutions, drugs, and adenoviral vectors
The composition of the Ringer’s solution was as follows (mM): 10 dextrose, 125 NaCl, 24 NaHCO3, 5 KCl, 2.5 CaCl2, 1.25 MgSO4, 1.25 KH2PO4. Chemicals were obtained from Sigma-Aldrich unless stated otherwise. ANG II (500 fmol) was microinjected into the NTS to achieve a consistently significant, reversible attenuation of the cardiac baroreflex (10)
. PLC inhibitor U73122 (24)
was administered to the perfusate at a final concentration of 15 µM, whereas the protein kinase C (PKC) inhibitor bisindolylmaleimide I (Calbiochem, UK) was used at 500 nM in perfusate. Other antagonists were microinjected into NTS directly. Those include xestospongin C (5 pmol; Calbiochem, UK), the calmodulin antagonist W7-HCl (25 pmol; Tocris, Bristol, UK), the phosphatidylinositol-3-OH-kinase (PI3K) inhibitors LY-294002 (2(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 25 pmol), and wortmannin (100 pmol). The microinjections were used for the antagonists with sufficient solubility in water and lack of observable nonspecific depressant actions when microinjected into the NTS directly.
Adenoviral vector expressing a dominant negative mutant of the 
subunit of Gq protein Ad.GqDN was obtained from D. Cook (University of Sydney, Australia). Ad.Cat, a kind gift from X. Fang and B. Davidson (University of Iowa), overexpresses human catalase (25)
. Ad.HA-Akt[AA] encoding mouse Akt with 2 alanine mutations in the regulatory site (Thr308 and Ser-473) fused to the hemagglutinin (HA) epitope (26)
was generously donated by K. Walsh (Division of Cardiovascular Research, St. Elizabeth’s Medical Center and Tufts University School of Medicine, Boston). The above vectors were microinjected with small amounts of Ad.eGFP (1:10 mixture), which encodes the enhanced green fluorescent protein (eGFP; gift from J. Uney, University of Bristol) to mark the site of transfection. In the control group of animals, only Ad.eGFP was used. The viral titers of Ad.GqDN, Ad.Cat, Ad.HA-Akt[AA], and Ad.eGFP were 1 x 1010, 4 x 109, 5 x 109, and 9 x 1010 plaque-forming units/mL, respectively.
Data analysis
All data were analyzed using Spike2 software with custom-written scripts. Baroreflex input-output curves were fitted using Excel (Microsoft) as described previously (10)
. An averaged value for the baroreflex gain for each test was calculated for each animal. The effect of each drug or adenoviral vector was expressed as a percentage of the control values. The significance of effects was assessed by applying paired two-tailed Students’ t test to the raw data. All values are quoted as mean ± SE and n is the number of preparations. Absolute values are tabulated and percent changes are quoted in the text. Differences were taken as significant at the 95% confidence limit.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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qDN, Ad.Cat, Ad.HA-Akt[AA], and Ad.eGFP, were not significantly different (Table 1
). Bilateral NTS microinjection of 500 fmol ANG II consistently, significantly, and reversibly attenuated the baroreflex gain; the effect of this dose of ANG II was in accordance with our previous report (10)
. Concentrations of antagonists used in this study were adjusted so as to avoid any changes in baroreceptor reflex and any other measurable parameter.
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Role of PLC-Ca2+ calmodulin pathway in mediating ANG II-induced depression of baroreflex in NTS
The coupling of AT1 receptors to PLC is likely to be mediated by Gq protein. We used an Ad vector expressing a dominant negative inhibitor of the subunit of the Gq protein Ad.GqDN to block Gq protein function in the NTS. In the control group of Ad.eGFP-transfected animals, ANG II attenuated the baroreflex gain by -57.2 ± 5.9% (Fig. 1
and Fig. 3
; n=8, P<0.001). In contrast, in the Ad.GqDN-transfected animals, bilateral microinjection of ANG II in the NTS only marginally reduced baroreflex gain by -15.0 ± 6.2% (Fig. 1b
and Fig. 3
; n=8, P=0.04). This suggests that Gq protein is involved in the signaling pathway under study. Post hoc histological analysis was performed to demonstrate the exact sites of microinjection as revealed by Pontamine sky blue staining. The sites of microinjection were found to be dorsomedial and medial to the solitary tract at levels corresponding to the area postrema and extending 0.6 mm more caudal. Representative sites for these experiments are shown in Fig. 1c
. Expression of eGFP was observed in the caudal regions of the NTS extending into the commissural NTS (representative section shown in Fig. 1d
).
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To investigate the role of the PLC in ANG II-mediated attenuation of the baroreflex, a specific inhibitor (U73122) was used (Fig. 2
; n=6). In control animals, NTS microinjection of ANG II depressed the baroreflex by -58.1 ± 7.4%. Application of 15 µM U73122 into the perfusate did not significantly change the baroreflex gain. However, microinjection of ANG II into the NTS in the presence of U73122 completely failed to depress baroreflex gain (Fig. 2
and Fig. 3
; n=6, P=0.46), indicating a pivotal role for PLC. IP3 released due to PLC activation may be expected to release Ca2+ from the intracellular stores. Consistent with this idea, a blocker of the IP3 receptors, xestospongin C, totally abolished ANG II-induced baroreflex attenuation (0.8±11%; n=6, Fig. 3
) although it did not affect the reflex when microinjected alone (P>0.1). In another group of animals, a CaM antagonist (W7-HCl) was used to target Ca2+-CaM formation, an event downstream of Ca2+ release. Microinjection of W7-HCl into NTS did not change the gain of the baroreflex (W7-Cl alone vs. preinjection: -7±4%, P>0.05), but ANG II microinjected in the presence of W7-Cl caused no reflex inhibition (Fig. 3
; -8.6±4.1%; n=8, P>0.05). This is indicative of a major role for calmodulin. The biochemical cascades mentioned above can also lead to PKC activation. However, in the presence of 500 nM of a PKC inhibitor, bisindolylmaleimide I, ANG II still significantly attenuated the baroreflex gain (-34.9±7.5%, Fig. 3
; n=6, P<0.05) although the attenuation seemed to be somewhat less than in control groups. This suggested that PKC was at least not crucial for mediating ANG II-induced baroreflex depression in the NTS. It is unlikely that the inhibition of PKC by the concentration of bisindolylmaleimide I used was incomplete given that its Ki is only 14 nM (27)
. Higher concentrations could not be tested because of detrimental effects on the preparation.
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ROS/PI3K/Akt pathway and ANG II-mediated attenuation of baroreflex
To investigate the role of ROS in linking ANG II-activation of AT1 receptors to activation of eNOS, we used the vector Ad.Cat. Ad.Cat reduces intracellular ROS levels and blocks redox signaling downstream of NADH/NADPH oxidase (25)
. High catalase activity in Ad.Cat transfected areas could be readily demonstrated cytochemically (Fig. 1e
). However, bilateral microinjection of ANG II into the Ad.Cat-transfected NTS still attenuated significantly the baroreflex by 53.0 ± 6.7% (Fig. 3
; n=6, P<0.05). Inhibition of PI3K in the NTS by LY294002 also failed to prevent the attenuation of the baroreflex by ANG II: microinjection of ANG II together with LY294002 into the NTS caused a significant depression of the baroreflex by -38.9 ± 12.6% (Fig. 3
; n=6, P<0.05). There were no observable effects of LY294002 alone on baseline baroreflex gain (-1±2% of control). Similar results were obtained with another PI3K inhibitor, wortmannin (-84±6.0% reduction by ANG II in the presence of wortmannin, n=3, not shown). To examine a role for Akt, a vector expressing a dominant negative inhibitor of Akt was used. ANG II microinjection into the Ad.HA-Akt[AA]-transfected NTS attenuated the baroreflex by -47.9 ± 6.0% (Fig. 3
; n=7, P<0.01). Thus, the ROS-PI3K-Akt pathway does not appear to mediate the ANG II depressant effect on the baroreflex pathway in the NTS.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These findings extend our previous results that in NTS the inhibitory effect of microinjected ANG II on the baroreflex-evoked bradycardia depended on activation of eNOS and release of NO (11)
. Here we show that this effect depends on the integrity of the PLC-Ca2+-calmodulin signaling pathway.
Activation of the PLC-Ca2+ pathway by AT1 receptors apparently is mediated by the subunit of Gq protein. Functional disruption of the Gq protein by an adenoviral vector expressing a dominant negative mutant nearly abolished the ANG II-mediated attenuation of the baroreflex, suggesting a major role for Gq signaling. However, activation of multiple G proteins is an established feature of AT1 receptors (28)
and could in an indirect way contribute to the residual effect of ANG II. This effect may also be explained by incomplete suppression of Gq protein function, so-called ‘leakage’ of the dominant negative action (29)
, or by incomplete transduction of all cellular targets for ANG II or compensatory up-regulation of endogenous Gq. In any case, the efficacy of ANG II was drastically reduced in transfected animals. These results illustrate the fact that the expression of a dominant negative protein was an adequate approach to detect the relevant signaling pathways under our experimental conditions, consistent with our previous results (11)
.
According to our results, the next step involves activation of PLC, which hydrolyzes phosphatidylinositide bis-4,5-phosphate to IP3 and DAG. IP3 causes the release of intracellular Ca2+ and DAG activates PKC. A similar signaling cascade revolving around the AT1 receptor/Gq/11 protein/PLC and an increase in intracellular Ca2+ concentration has been implemented in the inhibition of neuronal delayed rectifier K+ (Kv) current by ANG II in cultured neurones (30)
.
Xestospongin C, an IP13 receptor blocker, and W7-Cl, a CaM blocker, abolished ANG II action antagonist, and these results reveal the next steps of the process under study. Thus, PLC activation leads to release of Ca2+ from the IP13-sensitive stores, formation of the Ca2+-CaM complex, which in turn binds to and activates eNOS, hence mediating NO release.
Activation of PLC results in formation of DAG that can activate PKC. In contrast to the report of Pan et al. (30)
, we found no crucial role for PKC in the intracellular signaling pathway involved in the baroreflex attenuation by ANG II. This was despite the very high concentration (500 nM) of bisindolylmaleimide I used in this study (IC50<20 nM in various cellular systems; 27
). This is consistent with previous findings that PKC-mediated eNOS phosphorylation inhibits rather than activates eNOS activity (31)
. It is possible, however, that PKC plays a more important role in longer term actions of ANG II. For example, it has recently been demonstrated that chronic exposure to ANG II causes massive up-regulation of PKC activity in vascular tissue, which then affects activity and expression of NADPH (32)
.
ANG II-induced NADH- and NADPH-driven ROS production may activate Akt in vascular smooth muscle cells via PI3K (33)
. Other stimuli such as insulin (34)
and shear stress (35)
promote NO release through a PI3K-dependent stimulation of Akt, which then phosphorylates and activates eNOS at resting levels of calcium. In our hands, neither adenoviral-mediated overexpression of human catalase, which reduces ROS concentrations, nor pharmacological inhibition of PI3K by LY294002 and wortmannin prevented the ANG II depression of the baroreflex in the NTS, although both drugs were used at relatively high concentrations (compare ref 36
). In Ad.HA-Akt[AA]-transfected rats expressing the dominant negative mutant of Akt in the NTS, attenuation of the baroreflex bradycardia by ANG II was preserved. Though it could be argued that the lack of action of Ad.HA-Akt[AA] is due to its inability to block the endogenous Akt, even strikingly high catalase activity in NTS (Fig. 1e
) conferred by Ad.Cat did not affect the action of ANG II. Thus, the ROS/PI3K/Akt signaling pathway is not involved in the ANG II depression of the baroreceptor reflex bradycardic response in the NTS, at least in an acute situation. Whether the same is true for chronic actions of ANG II remains to be established. The situation might be quite different in hypertensive animals. For example, in has been demonstrated that PI3K blockade by wortmannin antagonized ANG II actions in rostral ventrolateral medulla selectively in spontaneously hypertensive rats (36)
.
Apparently ‘the Ca2+-mediated’ pathway of ANG II signaling can also converge onto Akt via induction of calmodulin-dependent protein kinase kinase, which will activate Akt and eventually phosphorylate eNOS (37)
. Again, it is possible that activation of Akt as well as cAMP-dependent protein kinase (38)
are more important for long-term actions of ANG II.
As alluded to in our previous report (11)
, the relative importance of eNOS in NTS neurones vs. capillary endothelial cells in the mediating the ANG II effect on the baroreflex awaits clarification. Whereas others (39)
found that eNOS in the rat brain is strictly confined to the endothelium, we found eNOS colocalized with AT1 receptors in neurones and endothelial cells lining blood vessels in the NTS (11)
. Identification of the cellular source of NO could not be achieved in the present study as the adenoviral vectors used were not engineered to be cell specific and the pharmacological agents could diffuse to all cell types. Development of cell-specific adenoviral vectors will enable us to specifically target the dominant negative inhibitors to either neurones or endothelial cells, thereby revealing the source of NO.
ANG II application to the NTS can potentiate both inhibitory and excitatory synaptic transmission within different subpopulations of NTS neurones subserving distinct reflex pathways (40)
. It is thought that ANG II-mediated enhancement of evoked inhibitory postsynaptic potentials (IPSPs) predominates in the baroreflex circuitry (41)
. The NO released by ANG II in the NTS might act to enhance GABA release from local inhibitory interneurons, which shunt out incoming excitatory potentials from baroreceptor afferents. A similar mechanism has been reported in the paraventricular nucleus of the hypothalamus where NO acts on parvocellular GABAergic neurones to evoke GABA release, thus increasing IPSPs recorded in magnocellular neurones in vitro (42)
.
In summary, this study used a combination of genetic and pharmacological interventions to differentially target various components of signaling pathways that underlie the transduction mechanism by which ANG II in the NTS attenuates the baroreceptor reflex. This pathway involves the Gq-mediated activation of PLC to mediate increases in intracellular Ca2+ that ultimately result in NO release by eNOS. It is plausible that in pathological hypertension, an elevated ANG II activity in the NTS may disrupt the normal functioning of the baroreflex and contribute to hypertension via an NO-ergic mechanism.
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ACKNOWLEDGMENTS |
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Received for publication January 31, 2002.
Revision received June 5, 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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