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Neurosciences, Loeb Research Institute, Ottawa Civic Hospital, and University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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To examine ANG II receptors in rat median
preoptic (MnPO) neurons, we used patch-clamp whole cell recordings in a
parasagittal brain slice preparation. Lucifer yellow-filled neurons
displayed a simple morphology with two to three aspiny dendrites.
Bath-applied ANG II (1-2,000 nM for 30 s) induced a response in 37 of 70 cells. In current-clamp recordings, cells displayed a prolonged
(10- to 30-min) depolarizing plateau with action potential discharges and an associated reduction in postburst afterhyperpolarization and
spike frequency adaptation. In voltage-clamp recordings (holding potential 
65 mV), cells displayed tetrodotoxin-resistant inward currents of 7.6 ± 1.9 (n = 5), 9.9 ± 1.9 (n = 9), and 9.2 ± 2.2 pA (n = 6) at 10, 200, and 2,000 nM, respectively. Responses were blockable by pretreatment
with losartan (2 µM; n = 6) but not by PD-123177 (20 µM; n = 3). Net ANG
II-induced current revealed a 7.8 ± 0.9% reduction in membrane
conductance, decreasing but not reversing at hyperpolarized levels.
Neurons expressing a strong hyperpolarization-activated,
time-independent inward rectification were more likely to respond to
ANG II. There was no correlation between the response of a neuron to
ANG II and its response to norepinephrine.
patch-clamp recording; lamina terminalis; morphology; membrane conductance; angiotensin
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE RENIN-ANGIOTENSIN SYSTEM (RAS), an integral component of the peripheral cardiovascular regulatory system, also participates in central nervous system control of cardiovascular and autonomic function (25). Accumulating evidence points to ANG II and other derivatives of a central RAS as possible neurotransmitters and/or neuromodulators in specific pathways that connect major cardiovascular and autonomic regulatory centers in the brain stem, hypothalamus, and forebrain. One region of particular interest is the lamina terminalis, which forms the anterior wall of the third cerebral ventricle in the mammalian brain. The lamina terminalis is richly endowed with angiotensin-binding sites and receptors, almost exclusively of the AT1 subtype, and is particularly dense within the three neuronal cell groups localized to this region, i.e., the subfornical organ (SFO) and the organum vasculosum lamina terminalis (OVLT), both circumventricular organs, and the median preoptic (MnPO) nucleus (8). The SFO and OVLT are recognized as receptor and transduction sites for blood-borne angiotensin, whereas the MnPO nucleus is regarded as a target for a central angiotensinergic input arising from SFO neurons (12, 13). Additionally, lesion and microinjection studies have identified the MnPO nucleus as critically important for the behavioral and pressor responses to circulating ANG II or to a hyperosmotic stimulus (2, 12, 16), leading to the notion that this is the principal forebrain site for the neural integration of information of a sensory, circulating, and/or osmotic nature and its transduction into an appropriate hormonal, cardiovascular, and/or behavioral response (4, 18).
Whereas the dipsogenic behavior and cardiovascular effects attributed to the functions of a central RAS have been frequently reported, there is a paucity of detailed information related to the neuronal actions of angiotensin within the lamina terminalis. Investigations with extracellular recordings have indicated that the excitability of neurons in this region can usually be increased by exogenously applied ANG II (22, 28, 29). To define the postsynaptic nature of these responses and to explore possible mechanisms associated with the activation of ANG II receptors in MnPO neurons, we used the whole cell patch-clamp technique in parasagittal rat brain slice preparations. We have identified some intrinsic properties of rat MnPO neurons and report that a population of these cells responds to activation of postsynaptic AT1-type receptors with a prolonged membrane depolarization and inward current and an associated reduction in one or more membrane potassium conductances.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Preparation.
Adult male Long-Evans rats (50-200 g body wt) were anesthetized
with methoxyflurane and decapitated. The skull was opened, and the
brain was removed quickly, placed in cooled (4°C) gassed (95%
O2-5%
CO2) artificial cerebrospinal
fluid (aCSF), and blocked so that parasagittal brain slices could be
cut at 400 µm on a vibratome (Technical Products International, St.
Louis, MO). The midsagittal slice at the level of the third cerebral
ventricle contained the lamina terminalis, with the SFO, anterior
commissure, MnPO nucleus, and OVLT in the same section. This slice was
transferred to a submerged recording chamber, where it was continuously
superfused (flow rate 6-7 ml/min) with gassed aCSF at room
temperature (23-25°C). Standard aCSF contained (in mM) 127 NaCl, 3.0 KCl, 26 NaHCO3, 1.3 MgCl2, 2.4 CaCl2, and 10 D-glucose, pH 7.4 (295-305
mosmol). Recordings were commenced 
1.5 h after tissue
sectioning.
Electrophysiology.
Current- and voltage-clamp recordings were obtained in the whole cell
recording mode. A Brown-Flaming puller (model P-87, Sutter Instrument)
was used to make patch pipettes, which were then backfilled with a
pipette solution containing (in mM) 120 potassium gluconate, 10 KCl, 10 NaCl, 10 HEPES, 0.5 EGTA, 4 MgATP, and 0.2 GTP; pH was adjusted to 7.2 with 1 M NaOH (285-295 mosmol). Lucifer yellow (2 mM) was included
in the pipette solution to facilitate identification of cell location
and to generate a profile of cell morphology using a camera lucida.
Pipettes had resistances of 4-8 M
. Signals were amplified using
an Axopatch-1D amplifier (Axon Instruments), recorded on a chart
recorder, and taped for off-line analysis. DMA Interface and pClamp-6
software (Axon Instruments) were used to generate current-voltage
(I-V) pulses and to record the
induced V-I plots. Input
resistance was determined from the slope (60 to 80 mV) of
I-V plots obtained from membrane
voltage deflections after delivery of a series of 500-ms depolarizing and hyperpolarizing current pulses. Cells with a series resistance <40 M were selected, and the series resistance was compensated through bridge balance under current-clamp mode. In voltage-clamp experiments the series resistance was not compensated, since the series
resistance (<40 M) was much smaller than the cell input resistance
(~1.1 G). Liquid junction potential was measured for each solution
used and corrected from the results presented. Values are means ± SE.
Drugs.
ANG II and tetrodotoxin (TTX) were products of Sigma Chemical (St.
Louis, MO). Losartan and PD-123177,
AT1 and
AT2 receptor antagonists,
respectively, were generously donated by Dupont (Wilmington, DE). ANG
II and norepinephrine (RBI) were supplied via a syringe pump (Harvard
Apparatus) into the perfusion line. The final concentration (CF) was estimated on the basis
of flow rates of the perfusion media and syringe pump speed
according to the following formula: CF = C1
* 
1/(1 + 2), where
C1 is drug concentration
in the syringe,
1 is flow rate
of the syringe pump, and
2 is flow rate
of the bath perfusion. The actual amount of the drug reaching the
neuron under study was likely an overestimate, since we did not take
into consideration the amount of drug lost as a result of diffusion
barriers and binding to various surfaces, an issue that would likely
affect peptide molecules. Other drugs were applied by bath perfusion.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Properties of MnPO neurons. A total of 70 MnPO neurons were included in the present study. MnPO neurons, when visualized after intracellular injection of Lucifer yellow, were characterized by relatively small (9-20 µm) ovoid somata with two to three 200- to 400-µm-long main aspiny dendrites, with sparse branching (Fig. 1A). Most cells displayed an axon that originated from the soma or the main dendrite and extended for several hundred micrometers, often with one or more collaterals, before coursing (usually in the ventral direction) out of the plane of section. Although we did not attempt to label MnPO neurons with retrograde tracers, anatomic and electrophysiological data indicate that major targets for MnPO efferents include SFO and OVLT as well as hypothalamic paraventricular and supraoptic nuclei (21, 23).
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60 ± 0.9 mV and membrane resistance of 1,125 ± 60 M. With a
chloride reversal potential estimated at almost 70
mV, spontaneous excitatory and/or inhibitory postsynaptic
potentials were common, the former often reaching threshold and
triggering spontaneous (
3.5-Hz) action potentials with amplitudes
>70 mV (measured from threshold) and a duration of 1.2 ± 0.1 ms
(measured at one-half amplitude). Action potentials were followed by a
prominent fast afterhyperpolarization measuring 29 ± 2 mV from
threshold. Additional features included a "rebound" low threshold
potential and spike discharge when the membrane potential was returned
from a hyperpolarizing level (Fig. 1B), a postburst
afterhyperpolarization, and adaptation in action potential discharge
frequency during a depolarizing current-induced burst (see Fig.
3B). Despite relatively similar
morphological properties, MnPO neurons demonstrated heterogeneity in
their response to intracellular current pulses, such that we could
recognize three categories of neurons on the basis of their rectifying
properties. We designated these neurons as type 1 if they revealed a
hyperpolarization-activated, time-dependent inward rectification (IR;
Fig. 1B1) and
type 2 if they lacked the time-dependent IR; the latter were further subdivided into type 2a if they displayed no IR or a mild IR (Fig. 1B2) and type
2b if they demonstrated a strong IR (Fig.
1B3). The
strong IR in type 2b cells had the capacity of inducing a "ceiling" effect close to the potassium reversal
potential on the voltage traces induced by current
injections; whereas type 2a neurons could be easily hyperpolarized
beyond 110 mV (Fig. 1B2), under
our experimental conditions the maximum current-induced membrane
hyperpolarizations in type 2b neurons never exceeded 110 mV
(Fig. 1B3).
Response to ANG II. A total of 37 of 70 tested neurons were observed to respond to application of 1-2,000 nM ANG II. In current-clamp recordings the typical response to a 30-s application of 100 nM ANG II was a slowly rising membrane depolarization that reached a peak within 1 min and remained as a prolonged depolarizing plateau that gradually subsided over a time course of 10-30 min (Fig. 2A). At the peak of the response, cells produced a prolonged burst of action potentials. ANG II-induced responses were often accompanied by an increase in the baseline noise level, suggesting a possible presynaptic component; this may reflect the excitation by ANG II of SFO neurons that project to MnPO cells (10, 12, 28). ANG II-induced responses were always prolonged (>10 min), even at the lowest concentrations; by contrast, responses from the same neurons to similar applications of glutamate (100 µM for 30 s) peaked within 8-9 s, triggering a brief burst of action potentials and recovering within a few seconds (Fig. 2B). At the higher concentrations of ANG II (1-2 µM), membrane depolarization often persisted beyond our ability to maintain a stable recording. For those cells where membrane potentials eventually returned to baseline after a lengthy wash (30 min), the response to a subsequent ANG II application was usually blunted or nonexistent. In view of the prolonged nature of the ANG II response and the possibility of desensitization, we used repeated trials sparingly (see Fig. 4A, low dose only) and did not attempt to establish a dose-response relationship, generally restricting tests to only a single neuron in any given slice preparation.
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Postsynaptic AT1 receptors mediate ANG
II-induced inward currents.
To characterize the ANG II-induced responses in more detail, recordings
were obtained in the voltage-clamp mode. At a holding potential of
65 mV and in aCSF containing 1 µM TTX (to block voltage-dependent sodium channels and thereby minimize any presynaptic component), ANG II induced an inward current that persisted for several
minutes beyond the period of application (Fig.
4A).
Although prolonged, the duration of these inward currents (in the
presence of TTX) was shorter than that observed in the current-clamp
mode (without TTX), implying that a presynaptic contribution was
present in the current-clamp recordings detailed above. The ANG
II-induced inward currents attained peak values of 7.6 ± 1.9 (n = 5), 9.9 ± 1.9 (n = 9), and 9.2 ± 2.2 pA
(n = 6) in response to concentrations of 10, 200, and 2,000 nM, respectively. The similarity in peak current
values over several peptide concentrations suggested that our tests
were performed near the peak of the dose-response curve. However, as
noted earlier, in view of the relatively small magnitude of the
currents and the prolonged duration of the response, we did not attempt
to define a dose-response curve and opted to test cells with a single
peptide application, usually in the 100-200 nM range.
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ANG II effects on membrane conductance.
Membrane conductances associated with these peptide-induced responses
were evaluated after analysis of I-V
relationships. In Fig. 5,
A and
B, the
I-V plot obtained during the ANG II
response indicates a reduction in membrane conductance compared with
the control. For six cells the net ANG II-induced current, obtained by
subtraction of I-V plots during
control and peptide-induced responses (Fig.
5C), indicated that the net
angiotensin-induced current was associated with a 7.8 ± 0.9% reduction in membrane conductance. In each case the net
angiotensin-induced current decreased with increasing membrane
hyperpolarization within the tested voltage range of 50 to
130 mV, although no reversal was observed. Although suggestive
of a reduction in membrane potassium conductance, we did not evaluate
the influence of changing extracellular potassium concentrations.
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Properties of ANG II-responsive neurons. Given that only a portion of MnPO neurons responded to ANG II, we considered that these cells might have a unique distribution or properties. A plot of the distribution of 27 ANG II-responsive and 25 nonresponding cells indicated that location within the MnPO nucleus was not distinct (Fig. 6A). On the other hand, when we classified 70 MnPO neurons according to their rectifying properties (Fig. 1B), we noted ANG II-responding neurons within all groups but a preferential distribution within the type 2b neurons, where 96% of cells responded to the peptide (Fig. 6B). Recognizing this association has to some extent biased recordings in favor of type 2b cells, and the voltage-clamp data as well as the current-clamp illustrations were derived from type 2b cells. Nonetheless, it seems appropriate to point out that other categories of MnPO neurons are among the ANG II-responsive population (40% for type 1 and 12% for type 2a), leading us to suggest that the inward rectification may be casually, rather than causally, related to its mechanism of action.
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Concordance of response to ANG II vs. norepinephrine.
An ability for norepinephrine to restore angiotensin-induced
drinking behavior after 6-hydroxydopamine-induced catecholamine depletion in the anteroventral third ventricle area has
fostered the notion that angiotensin-induced drinking normally requires an interaction with norepinephrine within the area of the MnPO nucleus
(4). To evaluate a possible postsynaptic interaction, 50 MnPO neurons
were tested for a response to norepinephrine applied before or after
testing for a response to ANG II. Of 23 cells that responded to
angiotensin, an application of norepinephrine (50 µM for 20 s)
produced membrane depolarization in 5 cells and membrane
hyperpolarization in 11 cells, responses that have been recently
ascribed to postsynaptic 
1- and
2-receptors, respectively (1).
Thus, although the same MnPO neurons may contain postsynaptic receptors
for norepinephrine and angiotensin, a comparison of their response
patterns did not reveal any indication of a pattern (Fig.
7). The possibility of presynaptic
interactions remains for investigation.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study represents an initial effort to use the patch-clamp technique in vitro to identify some of the intrinsic properties unique to rat MnPO neurons and to evaluate the neuronal distribution and functional features of the angiotensin AT1-type receptors in an area where hybridization studies indicate a high expression (8). Our observations with intracellular labeling suggest that MnPO neurons have a simple and rather similar morphology. By contrast, these cells demonstrate heterogeneity in terms of their intrinsic properties, as expressed by different types and various degrees of inward rectification. Although these features may or may not be related to their ability to respond to ANG II, it is certain that only ~50% of cells demonstrate evidence for functional postsynaptic ANG II receptors, the activation of which induces membrane depolarization and an inward current, associated with a reduction in membrane conductance. The observation that the net ANG II-induced current is reduced, but not reversed, at hyperpolarized membrane potentials and that the postburst afterhyperpolarization and spike frequency adaptation were attenuated during an ANG II-induced response suggests reduction in one or more potassium conductances. However, we have not extended this analysis to an evaluation of the ionic mechanisms underlying the ANG II-induced response, in part because of the uniquely prolonged nature and probable desensitization of the response, even at the lowest effective concentrations.
An extended profile of the response to ANG II is not unique to this preparation, inasmuch as prolonged responses have also been observed in extracellular studies from hypothalamic supraoptic and paraventricular magnocellular neurons recorded in vivo (20) and in vitro (10, 22). Features similar to those reported here were noted with intracellular recordings from supraoptic neurons in a hypothalamic explant preparation (32). Interestingly, the time course of angiotensin-induced depolarization (i.e., >15 min) bears similarity with the extended duration of the dipsogenic response that follows administration of angiotensin in the SFO (26). It is tempting to speculate that the behavioral and cellular events associated with this peptide relate to a long-lasting ligand-receptor interaction and/or intracellular signal transduction cascade, events that cannot easily be addressed with the techniques used here.
Although the response to ANG II is quite dramatic when recorded in the
current-clamp mode, recordings in the voltage-clamp mode revealed only
a relatively modest inward current in the 10-pA range. This is not
surprising when one considers that MnPO cells have a rather high input
resistance (~1.1 G), so that a current of this magnitude would be
sufficient to depolarize these cells by ~10 mV, enough to reach the
threshold for generation of sodium-dependent action potentials.
As mentioned above, the net ANG II-induced current reflects a reduction
in membrane conductance at hyperpolarized levels (Fig. 5C). This may indicate that a
closure of ion channels, possibly for potassium, represents a
component of the response. Angiotensin has been noted to reduce a
resting potassium conductance in medullary neurons (9) and to
suppress a transient outward potassium conductance, termed
IA, in
magnocellular neurosecretory neurons (11, 19). Possible
explanations as to why the net angiotensin current failed to reverse
near the calculated potassium reversal potential (97 mV) in MnPO
neurons may reflect an ineffective space clamp over an extensive
dendritic arborization, although a reversal was possible with
norepinephrine-induced
2-mediated currents in these
same neurons (1). Another possibility is that angiotensin may activate a "competing" conductance that also carries inward current at hyperpolarized membrane potentials. Because the actions of ANG II in
supraoptic nucleus neurons appear to involve an increase in a
nonselective cationic conductance (32), there may indeed be another
conductance involved, which could alter the shape of the net
I-V relationship. The situation may
prove to be similar to that observed in spinal neonatal lateral horn
cells, where another peptide, thyrotropin-releasing hormone, initiates
membrane depolarization and inward current through reduction
in a potassium conductance and increase in a putative nonselective
cationic conductance in the same neurons (6).
In some MnPO neurons the angiotensin-induced net current (Fig. 5C) appeared to be voltage dependent. The mirror image (against the voltage axis) of this net current (i.e., the current blocked by angiotensin) clearly shows inward rectification. This might reflect an error caused by the noncompensated series resistance. However, we cannot rule out a blocking effect of ANG II on the inward rectifying potassium channels. Indirectly supporting the latter possibility is the observation that many, but clearly not all, angiotensin-responsive cells express a strong IR (Fig. 6B). Although angiotensin has been shown to block IR in renal glomerular cells (7), this has not been reported in neuronal tissues for this peptide. Nonetheless, other neurotransmitters can block IR in different mammalian neurons (27, 30, 31).
Although the reduction by angiotensin of spike frequency adaptation and postburst afterhyperpolarization may simply reflect increased cellular responsiveness due to membrane conductance reduction, an additional suppressant action on calcium-activated potassium conductances is suspected for the following reasons. During comparisons of the burst activity induced by a 2-s current injection, we noted that the averaged firing frequency for the first five spikes in a burst elicited during an angiotensin response was not significantly increased; in fact, it was slightly decreased from that of control (Fig. 3), contrary to what would be expected with reduction in membrane conductance. Additionally, even with an increased total number of action potentials in a current-induced burst, presumably allowing for more calcium entry, the postburst afterhyperpolarizations during an angiotensin response were smaller than the controls (Fig. 3, A and B). This bears a striking resemblance to the modulation of spike frequency adaption and slow afterhyperpolarization by receptors for catecholamines (14, 15, 17, 24) and neurotensin (5).
Perspectives
A body of experimental data supports the proposal that circulating angiotensin can be "sensed" by SFO neurons that use the same molecule as a possible neurotransmitter released from central angiotensinergic projections to induce drinking behavior and pressor responses (4). The confirmation of angiotensin AT1 receptors localized to a subset of MnPO cells offers the potential to evaluate whether angiotensin does indeed have a neurotransmitter role in SFO efferents. Interestingly, extracellular recordings from the hypothalamic supraoptic nucleus, a target for SFO efferents, reveal that a single shock delivered in the SFO organ can produce a prolonged increase in neuronal excitability, a response that can be partially blocked by saralasin, a nonselective angiotensin receptor antagonist (3). In future studies it should be possible to detect the cellular characteristics of an angiotensinergic input to the MnPO nucleus and, aided by the availability of newer and more selective nonpeptide receptor antagonists, assist in the understanding of the possible neurotransmitter functions of this peptide in the central nervous system.| |
ACKNOWLEDGEMENTS |
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This work was supported by the Medical Research Council and the Heart and Stroke Foundation of Canada. D. Bai held a Fellowship of the Heart and Stroke Foundation of Canada, and L. P. Renaud is a Senior Scientist of the Medical Research Council.
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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. §1734 solely to indicate this fact.
Address for reprint requests: L. P. Renaud, Neurology/Neuroscience, Ottawa Civic Hospital, 1053 Carling Ave., Ottawa, ON, Canada K1Y 4E9.
Received 13 February 1998; accepted in final form 17 April 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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; B) and a prominent
postburst afterhyperpolarization (open arrowhead). In response to ANG
II (horizontal bar), cell features a prolonged membrane depolarization
with superimposed action potentials (
,
n = 27) or lack of response (
,
n = 25) to ANG II suggests no obvious
regional localization. B: histogram of
distribution of ANG II-responsive and -unresponsive neurons according
to cell type indicates that although responsive neurons were observed
in all categories, a preponderance was present among type 2b cells
(96%) compared with type 1 (40%) and type 2a neurons (12%).
