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1Department of Anesthesiology and Pain Medicine; The University of Texas M. D. Anderson Cancer Center; Houston, Texas; and 2Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
Submitted 18 December 2006; accepted in final form 2 February 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). Previous studies indicate that the PVN is an important source of excitatory drive for sympathetic vasomotor tone (Allen 2002; Coote et al. 1998; Martin and Haywood 1993; Swanson and Sawchenko 1983). PVN parvocellular neurons predominantly project to the rostral ventrolateral medulla (RVLM) and to the preganglionic sympathetic neurons in the intermediolateral cell column (IML) of the spinal cord (Pyner and Coote 2000; Strack et al. 1989). The PVN presympathetic neurons are critically involved in the regulation of sympathetic outflow and blood pressure, especially in hypertension and heart failure (Allen 2002; Li and Pan 2006, 2007; Zhang et al. 2002). Because the firing activity of PVN presympathetic neurons is controlled by the inhibitory and excitatory synaptic inputs, it is important to study the cellular mechanisms regulating the synaptic transmission in the PVN.
The rennin–angiotensin system is an enzymatic cascade by which angiotensinogen is cleaved by renin and then by angiotensin-converting enzyme to produce angiotensin II (Ang II) and subsequently other angiotensins. All of the components of the rennin–angiotensin system, including angiotensin-converting enzyme and angiotensin receptors, exist in the PVN (Gehlert et al. 1991; Mendelsohn et al. 1984; Oldfield et al. 2001). Through activation of AT1 receptors, Ang II contributes to the stimulation of water and sodium intake, vasopressin secretion, increased blood pressure, and modulations of baroreflexes (Averill and Diz 2000; Jensen et al. 1992). Ang II acts both as a circulating signal through receptors in the circumventricular organs and as a neurotransmitter in several areas of the hypothalamus and medulla known to be involved in autonomic and endocrine regulation. In this regard, circulating Ang II can influence the excitability of PVN neurons through synaptic connections with circumventricular organs that lack a normal blood–brain barrier (Bains and Ferguson 1995; Miyakubo et al. 2002). PVN neurons that project to the spinal IML receive the excitatory input from the subfornical organ mediated by Ang II (Bains and Ferguson 1995). We previously showed that Ang II excites PVN neurons projecting to the brain stem and spinal cord through selective inhibition of GABAergic input (Li and Pan 2005; Li et al. 2003). However, little is known about the underlying signaling mechanism for the presynaptic inhibition of synaptic 
-aminobutyric acid (GABA) release by Ang II in the brain. Therefore in this study, using in vivo retrograde labeling and in vitro whole cell recording in rat brain slices, we explored the possible downstream mechanisms involved in the effect of Ang II on GABAergic input to spinally projecting PVN neurons. The most salient finding of this study is that reactive oxygen species (ROS) are the key signaling mechanism responsible for the control of GABAergic synaptic transmission by Ang II in the PVN.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Retrograde labeling of spinally projecting PVN neurons
The procedures used for microinjecion of fluorescent dye into the spinal IML were the same as previously described (Chen et al. 2006; Li et al. 2003). Briefly, dorsal laminectomy was performed at the T1–T4 level under halothane (2% in O2) anesthesia. A glass micropipette (20- to 30-µm tip diameter) was filled with rhodamine-labeled fluorescence microsphere suspension (FluoSpheres, 0.04 µm; Molecular Probes, Eugene, OR) and inserted into the spinal cord. The contents were then pressure-ejected (Nanojector II, Drummond Scientificy, Broomall, PA) into the IML region of the spinal cord bilaterally in three or four separate 50-nl injections. After dye injection, animals were allowed to recover for 3–7 days to permit retrograde transport of the fluorescence microspheres to the PVN.
Pertussis toxin (PTX) treatment
In some rats, we injected PTX into the PVN area 2 days after microinjection of fluorescence microspheres. Under halothane anesthesia, the rat was placed in a stereotaxic frame (Kopf Instruments, Tujunga, CA) and a small hole was drilled on the dorsal surface of the skull to expose the brain. The stereotaxic coordinates for the PVN were 1.6–1.9 mm caudal from bregma, 0.4–0.5 mm lateral to the midline, and 7.0–7.5 mm to the dura (Zahner and Pan 2005). A glass microinjection pipette (tip diameter 20–30 µm) was filled with PTX dissolved in saline containing 2% Chicago blue and advanced into the PVN. The PTX (0.5 µg/µl, 50 nl) or vehicle solution was pressure-ejected (Nanojector II) into the PVN region bilaterally. To ensure that neurons in the PVN were maximally exposed to PTX, two to three injections were performed in each side of the PVN. The glass pipette was left in place for 3–5 min to ensure adequate diffusion of the drug after each injection. After PTX or vehicle injection, animals were sent back to their cage for recovery for 2–3 days.
Brain slice preparation
The rat was rapidly decapitated under 2% halothane anesthesia after 3–7 days after the IML injection or 2–3 days after PTX treatment. The brain was gently removed and placed into ice-cold artificial cerebrospinal fluid (aCSF) for 1–2 min. Then the hypothalamus containing the PVN was quickly trimmed and the coronal slices (300 µm in thickness) were cut using a vibratome (Technical Product International, St. Louis, MO). The slices were allowed to equilibrate in the aCSF continuously gassed with 95% O2-5% CO2 at 34°C for 
1 h before recording. The aCSF perfusion solution contained (in mM): 124.0 NaCl, 3.0 KCl, 1.3 MgSO4, 2.4 CaCl2, 1.4 NaH2PO4, 10.0 glucose, and 26.0 NaHCO3.
Recording of miniature postsynaptic inhibitory currents (mIPSCs) in PVN neurons
After equilibration, the brain slice was transferred to a glass-bottom chamber (Warner Instrument, Hamden, CT) and continuously perfused with aCSF at 3.0 ml/min. All recordings were performed at 34°C maintained by an in-line solution heater and a temperature controller (model TC-324, Warner Instruments). The labeled neurons were briefly identified with the aid of epifluorescence illumination and differential interference contrast (DIC) optics on an upright microscope (BX51WI, Olympus, Tokyo, Japan). The recording electrode was pulled (P-97, Sutter Instrument, Novato, CA) from borosilicate capillaries (1.2 mm OD, 0.86 mm ID; World Precision Instruments, Sarasota, FL). The resistance of the electrode filled with the pipette solution was 3–7 M
. The mIPSCs were recorded using whole cell voltage-clamp techniques at the holding potential of 0 mV (Chen et al. 2006; Li et al. 2003). The internal solution was composed of 110.0 Cs2SO4, 2.0 MgCl2, 0.1 CaCl2, 1.1 EGTA, 10.0 HEPES, 2.0 Na2ATP, 0.3 Na2GTP (in mM) and adjusted to pH 7.25 with 1 M CsOH (280–300 mOsm). A glutamate non–N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 µM), was bath perfused to block excitatory postsynpatic currents. Also, 1 µM tetrodotoxin (TTX) was continuously perfused to block action potential-dependent IPSCs. To block the postsynaptic action mediated by AT1 receptors, a general G-protein inhibitor, guanosine 5'-O-(2-thiodiphosphate) (GDP-
-s, 1 mM), was added into the internal pipette solution (Li and Pan 2005; Li et al. 2003). A sodium channel blocker, lidocaine N-ethyl bromide (QX-314, 10 mM), was included in the pipette solution to suppress action potential generation. The recordings usually began 5–7 min after forming the whole cell configuration and the current reached a steady state. Signals were processed using an Axopatch 700B amplifier (Axon Instruments, Foster City, CA), filtered at 1–2 kHz, digitized at 20 kHz using Digidata 1322 (Axon Instruments), and saved to a hard drive of a computer.
We obtained Ang II, 4-aminopyridine (4-AP), CdCl2, CNQX, bicuculline, deferoxamine, and GDP--s from Sigma (St. Louis, MO); TTX and QX-314 from Alomone Labs (Jerusalem, Israel); Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) and superoxide dismutase (SOD) from Calbiochem (La Jolla, CA); and PTX from List Biological Laboratories (Campbell, CA). All the drug solutions were freshly prepared before the experiments. Drugs were delivered at the final concentration using syringe pumps.
Data analysis
Data are presented as means ± SE. The amplitude and frequency of mIPSCs were analyzed off-line using a peak detection program (MiniAnalysis; Synaptosoft, Leonia, NJ). Detection of events was accomplished by setting an amplitude threshold (typically 6–10 pA) above the background noise (Chen and Pan 2006; Li et al. 2003). The original recording records were also visually inspected and artifacts were removed manually. The cumulative probability of the amplitude and interevent interval of mIPSCs was compared using the Kolmogorov–Smirnov test, which estimates the probability that two cumulative distributions are similar. Each analysis used 100 mIPSCs. The effect of drugs on the amplitude and frequency of mIPSCs was determined by repeated-measures ANOVA with Dunnett's post hoc test. P < 0.05 was considered to be statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). These sites were primarily located in and around the IML of the spinal cord. The labeled PVN neurons displayed a membrane potential between –55 and –75 mV and an input resistance ranging from 500 to 800 M. Effect of Ang II on GABAergic mIPSCs in labeled PVN neurons
Bath application of 2 µM Ang II significantly decreased the frequency of mIPSCs without changing the amplitude of mIPSCs in 12 labeled PVN neurons (Fig. 1, A–C). The cumulative probability analysis of mIPSCs revealed that the distribution pattern of the interevent interval of mIPSCs was shifted toward the right in response to Ang II (Fig. 1B). To determine whether the inhibitory effect of Ang II on the frequency of mIPSCs was reproducible, 2 µM Ang II was bath applied again 20 min after washout of the initial effect of Ang II. Repeated application of Ang II produced a similar effect on the frequency of mIPSCs of these neurons tested (Fig. 1, A–C). The frequency of mIPSCs returned to 95 ± 3% of the control level 20–25 min after washout of Ang II. The mIPSCs were completely blocked by 20 µM bicuculline (Fig. 1A).
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Previously we showed that AT1 receptors mediate the effect of Ang II on synaptic GABA release (Li and Pan 2005; Li et al. 2003). Because AT1 receptors are G-protein–coupled receptors (Crawford et al. 1992), we determined the role of Gi/o proteins in this presynaptic action of Ang II in the PVN. PTX selectively inactivates Gi/o proteins by ADP-ribosylation, thereby disrupting the receptor–Gi/o protein interaction (Fields and Casey 1997). To further determine whether PTX-sensitive Gi/o proteins are involved in the presynaptic effect of Ang II on synaptic GABA release to spinally projecting PVN neurons, we examined the effect of Ang II on labeled PVN neurons 2 or 3 days after microinjection of PTX (0.5 µg in 50 nl) (Brown et al. 2000) into the PVN. The dye-stained region of the PVN was first verified in the PVN slice under the light microscope and fluorescent-labeled PVN neurons in this area were then identified for whole cell recording. In rats that received the vehicle injection (Chicago blue solution only), bath application of 2 µM Ang II reduced the frequency (from 3.17 ± 0.26 to 2.73 ± 0.22 Hz, P < 0.05) but not the amplitude (from 18.52 ± 2.64 to 18.49 ± 2.57 pA, P > 0.05) of mIPSCs in 12 labeled PVN neurons tested. However, in labeled neurons recorded from PTX-treated rats, 2 µM Ang II failed to significantly change the frequency and amplitude of mIPSCs in 27 labeled PVN neurons examined (Fig. 2, A–C). The baseline frequency of mIPSCs in PVN neurons recorded from PTX-treated rats was not significantly different from that in vehicle-treated animals.
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Voltage-gated Ca2+ channels are typically involved in neurotransmitter release and play an important role in the downstream signaling of many G-protein–coupled receptors such as the opioid and GABAB receptors (Rusin and Moises 1998; Wu et al. 2004). We next assessed the role of voltage-gated Ca2+ channels in the inhibitory effect of Ang II on GABA release in the PVN neurons. In 11 separate PVN neurons, bath application of 100 µM CdCl2, a general voltage-gated Ca2+ channel blocker (Wu and Pan 2004), alone did not appreciably affect the basal frequency and amplitude of mIPSCs. In the presence of 100 µM CdCl2, 2 µM Ang II still caused a significant reduction in the frequency of mIPSCs in all 11 cells examined (Fig. 3, A–C).
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Voltage-gated K+ channels are located on the presynaptic terminals and modulate neurotransmitter release in the brain (Cooper et al. 1998; Ishikawa et al. 2003). Voltage-gated K+ channels also mediate the inhibitory effect of several G-protein–coupled receptors on synaptic GABA release (Finnegan et al. 2006; Yang et al. 2004). We thus examined the role of voltage-gated K+ channels in the presynaptic effect of Ang II on GABA release. In another 11 labeled PVN neurons, bath application of 2 mM 4-AP, a broad voltage-gated K+ channel blocker (Mathie et al. 1998; Vydyanathan et al. 2005), did not significantly alter the frequency and amplitude of mIPSCs. The effective concentration of 4-AP was shown in our previous studies (Finnegan et al. 2006; Vydyanathan et al. 2005). In the presence of 2 mM 4-AP, 2 µM Ang II still significantly decreased the frequency of mIPSCs in all 11 cells tested (Fig. 4, A–C).
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Recent studies suggest that the ROS constitute an important mediator for the Ang II action in the brain stem (Wang et al. 2006; Zimmerman et al. 2002, 2005). Overexpression of SOD in the brain blocks the central effect of Ang II (Zimmerman et al. 2002). We subsequently determined whether the ROS play a role in the inhibitory effect of Ang II on GABA release to spinally projecting PVN neurons. Bath application of 50 µM MnTBAP, a cell-permeable ROS scavenger (Batinic-Haberle et al. 1998; Wang et al. 2004), alone had no significant effect on the baseline frequency and amplitude of mIPSCs. In the presence of 50 µM MnTBAP, 2 µM Ang II failed to reduce the frequency of mIPSCs in all 10 labeled PVN neurons tested (Fig. 5, A–C).
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). Bath application of 200 U/ml SOD alone had no significant effect on the frequency and amplitude of mIPSCs in another 11 PVN neurons. The inhibitory effect of 2 µM Ang II on the frequency of mIPSCs was completed blocked by 200 U/ml SOD in all 11 neurons examined (Fig. 5D).
Additionally, to assess whether hydroxyl radicals are involved in the effect of Ang II on synaptic GABA release in the PVN, we tested the effect of the ion chelator deferoxamine (DEF, 100 µM), which effectively inhibits hydroxyl radical formation (Stahl et al. 1993; Yamamoto and Zhu 1998). In 13 labeled PVN neurons, bath application of 100 µM DEF alone for 4–6 min had no significant effect on the basal frequency and amplitude of mIPSCs. Furthermore, DEF did not significantly alter the effect of Ang II on the frequency of mIPSCs (Fig. 6, A–C).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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GABAergic synaptic input tonically inhibits the firing activity of PVN presympathetic neurons (Allen 2002; Li and Pan 2007; Martin and Haywood 1993). Ang II, a potent effector in the renin–angiotensin system, can regulate GABAergic tone in the PVN. For instance, Ang II activates presynaptic AT1 receptors to increase the firing of PVN outputs neurons projecting to the spinal cord and RVLM through inhibition of GABA release (disinhibition) (Li and Pan 2005; Li et al. 2003). On the other hand, Ang II does not affect synaptic glutamate release to PVN neurons (Li and Pan 2005; Li et al. 2003). Although AT1 receptors are G-protein–coupled receptors (Crawford et al. 1992), the types of G proteins and downstream signaling mechanisms for the GABAergic modulation by Ang II in the PVN remain largely unknown. It was previously shown that stimulation of AT1 receptors also affects area postrema neurons and nodose ganglion neurons through PTX-sensitive Gi/o proteins (Bacal and Kunze 1994; Consolim-Colombo et al. 1996). In this study, we found that Ang II–induced inhibition of GABAergic mIPSCs was abolished in labeled PVN neurons treated with PTX. Therefore our data suggest that PTX-sensitive Gi/o proteins are critically involved in the presynaptic effect of Ang II on GABAergic input to spinally projecting PVN neurons.
One aim of our study was to determine the roles, if any, played by Ca2+ and K+ channels in Ang II–induced attenuation of GABAergic input to hypothalamic presympathetic neurons. Many receptors coupled to PTX-sensitive Gi/o proteins, such as the opioid and GABAB receptors, decrease neurotransmitter release through inhibition of presynaptic Ca2+ channels (Kohno et al. 1999; Takahashi et al. 1998; Wu et al. 2004). Also, at least some of the Ang II effect seems mediated by voltage-gated Ca2+ channels. For instance, nifidepine, an L-type Ca2+ channel blocker, attenuates Ang II–induced drinking behavior produced by microinjection of Ang II into the median preoptic nucleus (Saad et al. 2006). However, the decrease in [3H]-GABA release by Ang II in the hippocampus is Ca2+ independent (Hadjiivanova and Georgiev 1998). In the present study, we observed that blocking of voltage-gated Ca2+ channels with Cd2+ had no significant effect on Ang II–induced inhibition in the frequency of mIPSCs. Presynaptic voltage-gated K+ channels are also important in the regulation of neurotransmitter release (Ishikawa et al. 2003). In this regard, 4-AP–sensitive voltage-gated K+ channels are involved in the inhibitory effect of some G-protein–coupled receptor agonists on GABAergic mIPSCs (Finnegan et al. 2006; Yang et al. 2004). Furthermore, Ang II can activate neuronal voltage-gated K+ channels in cultured neurons (Zhu et al. 2000). Nonetheless, contrary to what we had expected, 4-AP failed to attenuate Ang II–induced decrease in the frequency of mIPSCs in labeled PVN neurons. Because we measured action potential–independent quantal release of GABA, it is not surprising that 4-AP or CdCl2 alone had no significant effect on baseline mIPSCs (Chen and Pan 2006; Finnegan et al. 2006; Li et al. 2004). Collectively, our data suggest that voltage-gated Ca2+ and K+ channels are not involved in the presynaptic inhibition of GABA release to PVN presympathetic neurons by Ang II.
The important role of the ROS in the presynaptic inhibitory effect of Ang II on synaptic GABA release in the PVN was unexpected at the outset of this study. Reactive oxygen species were not considered initially in our study because they mediate the stimulatory effect of Ang II on voltage-gated Ca2+ channels and intracellular Ca2+ in nucleus tractus solitarius neurons (Wang et al. 2004; Zimmerman et al. 2005), which could potentially increase (but not decrease) neurotransmitter release. It is well known that the primary source of Ang II–derived ROS in vascular smooth muscle cells and nucleus tractus solitarius neurons is NADPH oxidase (Griendling et al. 1994; Mohazzab et al. 1994; Taniyama and Griendling 2003; Wang et al. 2004). Activation of the AT1 receptor by Ang II results in stimulation of NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to produce superoxide anions (Groemping et al. 2003). Because Ang II increases the production of superoxide, which is NADPH oxidase dependent in the PVN, NADPH oxidase is also the key source of ROS for PVN neurons (Erdos et al. 2006). Thus we determined whether the ROS contribute to Ang II–induced presynaptic inhibition of GABA release. MnTBAP is considered a broad-spectrum ROS scavenger because it possesses both superoxide dismutase and catalase activity and scavenges superoxide anions, H2O2, ONOO–, and lipid peroxyl radicals (Batinic-Haberle et al. 1998; Day et al. 1997). We found that MnTBAP completely blocked Ang II–induced inhibition of GABAergic mIPSCs in spinally projecting PVN neurons. Furthermore, superoxide dismutase, a highly specific superoxide scavenger by accelerating the dismutation of superoxide to hydrogen peroxide (H2O2) and molecular oxygen (Klann et al. 1998; Zimmerman et al. 2002), also abolished the effect of Ang II on GABAergic mIPSCs. Interestingly, deferoxamine, an ion chelator that blocks the secondary hydroxyl radical formation from H2O2, did not alter the presynaptic effect of Ang II. These data strongly suggest that ROS contributes importantly to the presynaptic effect of Ang II on synaptic GABA release in the PVN. Also, superoxide anions probably are the principal ROS involved in the downstream signaling of the Ang II effect on GABAergic input to PVN presympathetic neurons.
The signaling mechanisms involved in the biological effect of AT1 receptors are complex and likely differ considerably in different tissues and cells. In nucleus tractus solitarius neurons, Ang II promotes production of ROS to increase intracellular calcium and synaptic glutamate release through NADPH oxidase (Chan et al. 2005; Wang et al. 2004; Zimmerman et al. 2004). ROS produced by Ang II in PVN neurons, however, seem to inhibit synaptic GABA release. Consistent with our finding, ROS were previously shown to inhibit synaptic transmission in hippocampal slices (Avshalumov et al. 2000). It remains uncertain how ROS inhibit synaptic GABA release in the PVN. Free radicals may inhibit vesicle H+-ATPase to reduce neurotransmitter release (Wang and Floor 1998). More recent evidence indicates that SNAP25 is probably the presynaptic target for the inhibitory action of ROS on neurotransmitter release (Giniatullin et al. 2006). It should be noted that the direct link between Gi/o proteins and NADPH oxidase in the brain has not been demonstrated. Although the association between PTX-sensitive Gi/o proteins and NADPH oxidase–dependent ROS production was shown in vascular smooth muscle cells (Rodriguez-Puyol et al. 2002), further studies are warranted to determine how Gi/o proteins are linked to NADPH oxidase after activation of the presynaptic AT1 receptors in the PVN.
In summary, we demonstrated for the first time that PTX-sensitive Gi/o proteins contribute to presynaptic inhibition of GABA release to PVN presympathetic neurons by Ang II. Furthermore, ROS, especially superoxide anions, function as critical signaling molecules to mediate the effect of Ang II on synaptic GABA release in the PVN (Fig. 7). Unlike previous studies that showed that Ang II promotes production of ROS to increase intracellular calcium and synaptic glutamate release in the nucleus tractus solitarius (Chan et al. 2005; Wang et al. 2004; Zimmerman et al. 2004), our study provides new evidence that ROS are critically involved in the inhibitory action of Ang II on synaptic GABA release in the PVN. These findings are important for our understanding of the diverse downstream signaling mechanisms responsible for the presynaptic effect of Ang II in PVN presympathetic neurons. Ang II plays an important role in the potentiation of sympathetic outflow from the PVN in some pathophysiological conditions, such as heart failure and hypertension (Gutkind et al. 1988; Miyakubo et al. 2002; Zhang et al. 2002). Previously it was shown that NADPH oxidase–derived ROS mediate the stimulatory effect of Ang II on the sympathetic outflow in the RVLM in an animal model of congestive heart failure (Gao et al. 2005). It is possible that dysfunction of the downstream signaling cascade may underline the altered actions of Ang II in autonomic neurons in these disease conditions.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H.-L. Pan, Department of Anesthesiology and Pain Medicine, Unit 409, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Blvd., Houston, TX 77030 (E-mail: huilinpan{at}mdanderson.org)
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