Departments of Medicine and Physiology, Wayne State University School of Medicine and John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Endothelin (ET) acts within the
central nervous system to increase arterial pressure and arginine
vasopressin (AVP) secretion. This study assessed the role of the
paraventricular nuclei (PVN) in these actions. Intracerebroventricular
ET-1 (10 pmol) or the ETA antagonist BQ-123 (40 nmol) was
administered in conscious intact or sinoaortic-denervated (SAD)
Long-Evans rats with sham or bilateral electrolytic lesions of the
magnocellular region of the PVN. Baseline values did not differ among
groups, and artificial cerebrospinal fluid (CSF) induced no significant
changes. In sham-lesioned rats, ET-1 increased mean arterial pressure
(MAP) 15.9 ± 1.3 mmHg in intact and 22.3 ± 2.7 mmHg in SAD
(P < 0.001 ET-1 vs. CSF) rats. PVN lesions abolished
the rise in MAP: 0.1 ± 2.8 mmHg in intact and 0.0 ± 2.9 mmHg in SAD. AVP increased in only in the sham-lesioned SAD group
8.6 ± 3.5 pg/ml (P < 0.001 ET-1 vs. CSF). BQ-123
blocked the responses. Thus the integrity of the PVN is required for
intracerebroventricularly administered ET-1 to exert pressor and AVP
secretory effects.
antidiuretic hormone; endothelin-1; hemodynamics; intracerebroventricular injection; rats; subfornical organ
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
IN ADDITION TO potent direct vasoactive effects, considerable evidence exists to show that the endothelins (ET) act as neuromodulators or neurotransmitters within the central nervous system (32-35). All components of the ET system, including ET mRNA and peptides, its receptors, and ET-converting enzyme activity, have been demonstrated within nonvascular tissue in the brain (12, 31), particularly within loci implicated in the central regulation of cardiovascular function and arginine vasopressin (AVP) secretion (18, 31, 37).
Systemic arterial pressure increases in response to injection of ET-1 into the lateral ventricle in rats (19, 20, 24, 25, 36). This pressor response is mediated by increased sympathetic outflow (2, 9, 11, 24). In addition, several investigators have demonstrated that ET-1 stimulates AVP secretion both in vivo (13, 22, 24-26, 36) and in vitro (22, 23). Although early reports suggested that the pressor response is mediated by AVP secretion (16, 20, 36), the role of ET-1 may be more complex (24-26). For example, the Brattleboro mutant of the Long-Evans rat strain lacking central AVP exhibits an increase in arterial pressure identical to that of the wild-type rat with a normal AVP secretory response (25).
Among the circumventricular organs, the subfornical organ is generously endowed with ET receptors (5, 7). Miselis (15) demonstrated efferent projections from the subfornical organ to supraoptic and paraventricular nuclei (PVN). Notably, electrolytic lesions of the region anteroventral to the third ventricle (AV3V) that interrupt projections from the subfornical organ to the supraoptic nuclei block AVP secretion but not the increase in arterial pressure observed with central ET-1 administration (25). Furthermore, ET-1 acting at the subfornical organ elicits an excitatory effect on magnocellular neurons within the PVN (32, 33). Several investigators have shown that electrical or chemical stimulation of the PVN results in an increase in systemic arterial pressure (1, 4, 6, 13, 10), and lesions of the PVN prevent systemic hypertension (3, 32).
The present studies were designed to test the hypothesis that electrolytic ablation of the predominantly magnocellular regions of the PVN will selectively abolish the increase in systemic arterial pressure to centrally administered ET-1 while leaving the AVP secretory response intact.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Adult male Long-Evans rats weighing ~225-250 g were obtained from Harlan Sprague Dawley (Indianapolis, IN). They were housed under controlled conditions (21-23°C; lights on 0700-1900) and had free access to water and standard rat chow. The rats were cared for in accordance with the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals (Dept. of Health, Education, and Welfare no. 86-23). All protocols were reviewed and approved by our institutional Animal Investigation Committee.
Surgical Procedures
Sinoaortic denervation. On day 1, the rats were anesthetized with pentobarbital sodium (40 mg/kg body wt ip). Sinoaortic denervation (SAD) or sham operation was performed as described previously (8). A ventral midline incision was made in the neck. The sternocleidomastoid muscle was retracted, and the aortic depressor nerve and its accompanying fibers were identified under a stereoscopic microscope. Denervation was accomplished by surgically sectioning the cervical sympathetic trunks, the aortic depressor nerve, and the superior laryngeal nerve. The carotid baroreceptors were denervated by cutting the carotid sinus nerve and stripping the area of the carotid sinus. Identical dissection was performed in sham-denervated rats, but the nerves were left intact.
Catheter placement. Immediately after sham or SAD, arterial and jugular catheters were inserted in the carotid artery and jugular vein, respectively. The catheters were secured, tunneled subcutaneously, and exteriorized at the back of the neck (24). Catheter patency was maintained by filling the lumen with 1,000 U/ml of 50 µl sodium heparin. The rats were returned to individual cages and allowed to recover.
Stereotaxic surgery.
On day 3, rats that met testing criteria for baroreflex
status (see Verification of SAD) were anesthetized with
pentobarbital sodium (40 mg/kg body wt iv). Each rat was positioned
within a cranial stereotaxic instrument (Kopf, Tujunga, CA), and the
PVN were lesioned bilaterally (coordinates on the midline: 1.5
anteroposterior,
0.6 and +0.6 mediolateral, and +8.6 dorsoventral) by
passing a 3-mA direct current for 25 s via a concentric bipolar
stainless steel electrode insulated to within 0.5 mm of the tip. For
sham lesions, the electrode was lowered 4.0 mm bilaterally, and no current was passed. During the same surgical session, a 22-gauge stainless steel guide cannula (Plastics One, Roanoke, VA) was inserted
in the right lateral cerebral ventricle (coordinates to bregma:
0.3
anteroposterior, 1.3 mediolateral, and +2.5 dorsoventral) and affixed
with cranioplastic cement. A dummy cannula was placed in the guide
cannula to maintain patency. The rat was then allowed to recover.
Verification of lesion placement was performed histologically for each rat.
Verification of SAD
To assess baroreflex status, testing was performed on day 3 in conscious rats. The change in heart rate was ascertained in response to a 40-mmHg pressor stimulus evoked by 2.5-5 µg/kg phenylephrine or a 40-mmHg depressor stimulus elicited by 2-5 µg/kg nitroprusside in 200 µl saline intravenously. Mean arterial pressure (MAP) and heart rate were monitored continuously for at least 10 min before injection, during the stimulus, and for 10 min afterward. Only rats displaying >95% blunting of baroreceptor reflex changes in heart rate were considered SAD. Partially denervated animals were not used in subsequent experimental protocols (29). One day after baroreflex testing, SAD and sham-operated rats underwent PVN lesioning and placement of the intracerebroventricular cannula as described above.Protocol
This set of experiments was designed to compare the effect of bilateral electrolytic lesions of the PVN on the pressor and AVP secretory responses to exogenous ET-1 and selective ETA antagonism of endogenous ET-1 in intact and SAD rats.On days 7-9, each animal was conditioned to remain for 120 min in a Plexiglas study chamber (Braintree Scientific, Braintree, MA). All experimental protocols were performed on conscious conditioned rats on day 10. After positioning the rat in the chamber, the arterial catheter was connected to a pressure transducer (Grass Instruments), and the dummy cannula was replaced with a 28-gauge infusion cannula whose internal tip projected 1 mm below the guide cannula. Systemic arterial pressure and heart rate were monitored continuously and recorded to disc using the Hemodynamic Monitoring Package (Biotech Products, Greenwood, IN).
Experiments were performed using a protocol identical to that reported previously by our laboratory (24-26). After a 30-min baseline period, a blood sample (800 µl) was collected over 30 s in prechilled heparinized tubes to avoid stimulation of AVP secretion or degradation of AVP during collection. The rat was transfused immediately thereafter via the venous catheter with an equal volume of donor blood that had been allowed to remain at room temperature for 30 min to allow intrinsic AVP to be catabolized (random AVP levels of donor blood <0.1 pg/ml). Subsequently, the rat received a 10-µl intracerebroventricular injection over 10 s with one of the following dissolved in artificial cerebrospinal fluid (CSF): 1) artificial CSF, 2) 10 pmol ET-1, 3) 10 pmol ET-1 with 40 nmol BQ-123, or 4) 40 nmol BQ-123. Agonists and antagonists were used at doses determined in previous experiments (24-26). Ten minutes after the intracerebroventricular injection, blood was collected again, and the rat was transfused as before. Hemodynamic parameters were monitored for an additional 20 min. Particular care was exerted to assure that all rats had free access to water during the course of the experiment to avoid changes in plasma volume and osmolality.
At the end of the protocol, each rat was killed with pentobarbital sodium (120 mg/kg body wt iv). The brain was perfusion flushed with ice-cold saline until clear, followed by 10% neutral buffered Formalin in saline. The brains were removed and postfixed in 10% neutral buffered Formalin overnight and then were transferred to a 30% sucrose-Formalin solution, where they remained until they sank. Frozen 10-µm serial sections were cut on a microtome and processed for staining of Nissl substance with cresyl violet. Sections were evaluated for PVN lesions by an investigator blinded to the lesioning status (Rossi).
Analytical Methods
The Hemodynamic Monitoring Package (Biotech Products) calculated and displayed blood pressure and heart rate beat-by-beat for each experiment. Values were also recorded on computer disc for off-line analysis. Data were sampled continuously at 6 Hz using a DAP 3216a/415 data acquisition processor as the hardware platform.Baroreflex gain for sham and SAD rats was calculated as the maximal change in heart rate divided by the change in MAP. For each experiment, MAP and heart rate were the running average of the last 3 min of the period before the first blood sample (baseline) and 7-10 min after intracerebroventricular injection just before the second blood sample (test).
Plasma osmolality was measured by freezing point depression (Precision
Systems 5004, Sudbury, MA). The remaining plasma was stored at 70°C
until RIA. Plasma AVP concentration was assessed using previously
reported methods (26). Briefly, the plasma samples were
extracted before assay. All standards and samples were assayed in
duplicate with purified AVP (Ferring, Malmo, Sweden) as the standard,
[125I]-iodotyrosyl AVP as the tracer (Amersham, Arlington
Heights, IL), and anti-AVP antibody no. 2849 (gift of Drs. J. Durr and M. Lindheimer) at a dilution of 1:3.6 × 105.
Statistics
Comparisons of MAP, heart rate, plasma osmolality, and plasma AVP concentration among the groups between baseline and test periods were made using one-way ANOVA and the Tukey-Kramer analysis for multiple comparisons. Differences during the test period among groups were analyzed by two-way ANOVA. All data are reported as means ± SE. A significant difference among means was assigned at P < 0.05. ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Resting baseline heart rate and MAP was higher in the SAD groups
on day 3 and displayed significantly diminished baroreflex gain compared with their respective sham-denervated groups (Table 1). In the aggregate, heart rate changed
117 ± 36 beats/min in response to a 44 ± 7 mmHg change in
MAP in the sham-denervated rats (n = 49), whereas heart
rate changed only 4 ± 14 beats/min in the SAD groups in response
to a 44 ± 9 mmHg change in MAP (n = 45). Thus the
change in heart rate in the SAD rats was <1% of the resting heart
rate, consistent with adequate denervation.
|
Figure 1 depicts the PVN regions of
typical sham and bilaterally lesioned animals. On the day the protocols
were performed, baseline heart rate, MAP, plasma osmolality, and plasma
AVP values did not differ significantly among the groups (Table
2).
|
|
Artificial CSF did not change MAP or plasma AVP concentrations from
baseline values in any of the groups (Fig.
2). In both groups with sham PVN lesions,
intracerebroventricular injection of ET-1 elicited a significant
increase in MAP. Plasma AVP levels increased only in the group of rats
with SAD and sham PVN lesions. Figure 3
shows a typical hemodynamic response in sham PVN-lesioned animals.
These real time tracings also show that the heart rate variability in
the SAD rat is higher and that ET administration did not significantly
alter pulse pressure.
|
|
Heart rate consistently increased in the ET-1-treated, sham
PVN-lesioned groups [50 ± 29 beats/min (sham denervated) and
43 ± 26 beats/min (SAD)] but changed very little from baseline
in the corresponding artificial CSF-treated groups: 16 ± 22 and 4 ± 17 beats/min. Nevertheless, the heart rate responses were highly variable so that comparisons between ET-1-treated and baseline or corresponding artificial CSF groups were not statistically significant by ANOVA.
In contrast to the sham PVN-lesioned groups, MAP did not increase with
intracerebroventricular ET-1 injection in the rats with bilateral PVN
lesions. The PVN lesions also abolished the rise in plasma AVP levels
observed in the SAD group (Fig. 2). Typical hemodynamic tracings in
PVN-lesioned rats given ET-1 are shown in Fig.
4. Heart rate did not increase in the
PVN-lesioned groups after ET-1 [12 ± 10 beats/min (sham
denervated) and
2 ± 25 beats/min (SAD)]. In animals in which
the electrolytic lesions were histologically verified to be adjacent
but outside the PVN and which also received ET-1, MAP increased 16 ± 2 mmHg and plasma AVP rose 13 ± 4 pg/ml. Of these, two were
SAD.
|
ETA receptor antagonism significantly inhibited the rise in MAP and plasma AVP concentrations elicited by ET-1 in the sham PVN-lesioned groups. When given alone, BQ-123 induced no changes from baseline in any of the groups.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The major finding of the present study is that bilateral lesions of the magnocellular region of the PVN prevent the increase in both systemic arterial pressure and AVP secretion observed with intracerebroventricular ET-1.
These data confirm the observations by a number of laboratories including our own that injection of ET-1 in the lateral cerebral ventricles increases arterial pressure and AVP secretion (19, 20, 24-26, 36). It has been postulated that the ET-1-induced rise in arterial pressure is mediated by a vasopressinergic mechanism (16, 20, 36); however, it has become increasingly evident that AVP contributes to the pressor response only under selected physiological settings. Such conditions include those when afferent input from the arterial baroreceptors is prevented by SAD (26), when cardiopulmonary baroreceptors are stimulated by volume depletion (20), or when anesthesia and acute surgery result in circulating pressor levels of AVP before administration of ET-1 (16, 17). On the contrary, in the awake euvolemic baroreflex-intact rat, central ET-1 induces a comparable rise in pressure before and after antagonism of V1 vasopressinergic vascular receptors (24). Moreover, Long-Evans rats and homozygous Brattleboro rats devoid of circulating AVP exhibit equivalent increases in MAP (24). These findings are in agreement with the recent observation that lesions of the AV3V region that disrupt neuronal pathways from the subfornical organ to the anterior hypothalamus significantly attenuate the rise in AVP but not the increase in arterial pressure (25). The dissociation of the pressor action from the AVP secretory effect of ET-1 suggests that an alternative neural pathway mediates the pressor response.
Several laboratories have shown that the ET-1-induced pressor response is mediated by increased sympathetic outflow (2, 9, 19, 24). Systemic and intracerebroventricular ET-1 can gain access to the circumventricular organs. Of these, the subfornical organ in particular possesses abundant ET receptors (5, 7). The subfornical organ sends out two major efferent projections: 1) precommissural bundles to the AV3V, including the median preoptic nucleus, the organum vasculosum of the lamina terminalis, and supraoptic nuclei, and 2) postcommissural fibers, some of which pass through the PVN to terminate in the supraoptic nuclei and others that terminate in the PVN itself (11, 15). Consistent with these known pathways, intracerebroventricular ET-1 induces c-fos expression in the PVN (38). Whether this is a direct effect of ET-1 or a postsynaptic effect as may occur with ET-1 action on the subfornical organ with subsequent stimulation of PVN neurons has not been identified. In turn, chemical or electrical stimulation of PVN neurons elicits an increase in efferent sympathetic activity and a concurrent rise in heart rate and arterial pressure (4, 10, 13). Ablation of the subfornical organ reduces the proportion of PVN neurons excited by intracerebroventricular ET-1 (33), but concurrent effects on arterial pressure and AVP levels are not known. Thus the PVN occupies a pivotal position for integrating the hormonal and autonomic responses to ET-1.
The present findings clearly show that both the rise in arterial pressure and AVP release in response to intracerebroventricular ET-1 are totally averted by electrolytic lesions of the PVN. Nonspecific damage from the electrolytic lesions is not likely to have resulted in these observations, since lesions of areas immediately adjacent or encompassing only one PVN fail to block either AVP release or the rise in arterial pressure. Given the known neural pathways connecting the subfornical organ, PVN, supraoptic nuclei, and existing electrophysiological data (4, 10, 13, 33, 34, 38), the present observations do not unequivocally exclude the possibility that the electrolytic lesions disrupted fibers of passage, particularly those from the subfornical organ through the PVN to the supraoptic nuclei (11, 15). Nonetheless, the lesions ablated a significant portion of neuronal cell bodies within the area of the PVN where a substantial component of subfornical projections terminate (11, 15) and that is associated with the pressor response (4, 13, 38).
Indeed, Wall and Ferguson (33) have reported that 60% of
subfornical organ neurons antidromically identified as projecting to
the PVN exhibit excitatory responses to intravenously administered ET-1. After electrolytic destruction of at least 50% of the
subfornical organ, the proportion of vasopressinergic cells in the PVN
responsive to systemic ET-1 decreases dramatically to 7%
(33). However, direct microinjection of ET-1 into the PVN
did not increase arterial pressure or plasma AVP levels
(17). Accordingly, the pressor response does not appear to
result from direct action of ET-1 on PVN neurons. Rather, these
observations support a model with the PVN acting as a relay for
ET-1-stimulated pathways projecting from the subfornical organ. Inputs
to neurons within the magnocellular region of the PVN then lead to
activation of projections emerging from the PVN to caudal
cardiovascular control centers that result in increased arterial
pressure (Fig. 5).
|
That AVP release is also completely blocked by bilateral PVN lesions was unexpected, given that AV3V lesions significantly attenuate AVP release (25). Our initial hypothesis rather simplistically predicted the following two independent pathways: one rostroventrally from the subfornical organ to the supraoptic nuclei (interrupted by the AV3V lesion) that mediates only AVP release and a second pathway projecting more caudally from the subfornical organ to the PVN that only leads to increased arterial pressure. The data support a more complex scheme. ET-1, via the subfornical organ, elicits excitatory responses in 21% of the AV3V neurons (35) and 60% of PVN neurons (33, 34). In addition to supraoptic neurons receiving afferent projections from the ipsilateral PVN, up to 77% of magnocellular neurons within the PVN receive inputs from the supraoptic nucleus. Moreover, the majority of these inputs are excitatory (27, 28, 30). It has been suggested that these internuclear connections serve to synchronize the firing patterns of the neurons and, consequently, neurohypophysial hormone release. Such a model would provide some explanation for our present observations. On the one hand, interruption of the pathways from the subfornical organ passing through the AV3V region interrupts signaling to the supraoptic nuclei. AVP release by vasopressinergic cells within the supraoptic nuclei would fail to occur. Stimulatory inputs from the supraoptic nuclei to the PVN would also be affected, thereby preventing AVP secretion from PVN projections to the posterior pituitary. On the other hand, bilateral lesions of the PVN disrupt pathways directly from the subfornical organ to magnocellular neurons within the PVN that project to the neurohypophysis. Fibers coursing through the PVN to supraoptic nuclei and excitatory inputs from the supraoptic nuclei to magnocellular neurons within the PVN are also interrupted. The data suggest that synchronization of supraoptic nuclei and PVN activity is required for a measurable increase in circulating AVP to occur. Thus either bilateral PVN lesions or an AV3V lesion can abolish AVP secretion.
In summary, previous observations together with the current findings support the concept shown in Fig. 5. Basically, fibers disrupted by the AV3V lesions carry predominantly stimulatory signals from the subfornical organ via the anterior hypothalamus to the supraoptic nuclei for AVP release. The more lateral and caudal pathways, including those to the PVN, remain uninterrupted, and the pressor response remains intact. Bilateral lesions of the PVN disrupt pathways from anterior brain structures to nuclei in the medulla and spinal cord that mediate sympathetic outflow and cardiovascular responses, consequently blocking the pressor effect of ET-1. Because bilateral PVN lesions completely prevent the rise in plasma AVP levels, inputs from the anterior hypothalamus that terminate on magnocellular neurons within the PVN and/or fibers of passage through the PVN to the supraoptic nuclei are necessary for AVP release. Because either an AV3V lesion or bilateral PVN lesions can abolish AVP secretion, the data suggest that synchronization of inputs between supraoptic nuclei and PVN is required for ET-1 to elicit a measurable rise in plasma AVP. Further studies are required to confirm this putative mechanism. Finally, ET-1 injected in the lateral ventricles stimulates AVP release and increased systemic arterial pressure via pathway(s) that require the integrity of the PVN.
![]() |
ACKNOWLEDGEMENTS |
---|
We appreciate the gracious help of Robert Pawlowicz for invaluable computer expertise.
![]() |
FOOTNOTES |
---|
This work was supported by a Merit Award from the Department of Veterans Affairs to N. F. Rossi.
Address for reprint requests and other correspondence: N. F. Rossi, Depts. of Medicine and Physiology, Wayne State Univ. School of Medicine, 4160 John R no. 908, Detroit, MI 48201 (E-mail: nrossi{at}intmed.wayne.edu).
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.
Received 22 June 2000; accepted in final form 20 September 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Duan, Y-F,
Winters RW,
McCabe PM,
Green EJ,
and
Schneiderman N.
Cardiorespiratory components of the defense reaction elicited from the paraventricular nucleus.
Physiol Behav
61:
325-330,
1997[ISI][Medline].
2.
Gulati, A,
Rebello S,
and
Kumar A.
Role of sympathetic nervous system in cardiovascular effects of centrally administered endothelin-1 in rats.
Am J Physiol Heart Circ Physiol
273:
H1177-H1186,
1997
3.
Gutman, MB,
Ciriello J,
and
Mogenson GJ.
Effect of paraventricular nucleus lesions on cardiovascular responses elicited by stimulation of the subfornical organ in the rat.
Can J Physiol Pharmacol
63:
816-824,
1985[ISI][Medline].
4.
Haselton, JR,
and
Vari RC.
Neuronal cell bodies in paraventricular nucleus affect renal hemodynamics and excretion via the renal nerves.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R1334-R1342,
1998
5.
Jones CR, Hiley CR, Pelton JR, and Mohr M. Autoradiographic
visualization of the binding sites for [125I]endothelin
in rat and human brain. Neurosci Lett 97: 276-279.
6.
Kannan, J,
Hayashida Y,
and
Yamashita H.
Increase in sympathetic outflow by paraventricular nucleus stimulation in awake rats.
Am J Physiol Regulatory Integrative Comp Physiol
256:
R1325-R1330,
1989
7.
Koseki, C,
Imai M,
Hirata Y,
Yanagisawa M,
and
Masaki T.
Autoradiographic distribution in rat tissues of binding sites for endothelin: a neuropeptide?
Am J Physiol Regulatory Integrative Comp Physiol
256:
R858-R866,
1989
8.
Krieger, EM.
Neurogenic hypertension in the rat.
Circ Res
15:
511-520,
1964[ISI][Medline].
9.
Kuwaki, T,
Cao W-H,
and
Kumada M.
Endothelin in the brain and its effect on central control of the circulation and other functions.
Jap J Physiol
44:
1-18,
1994[ISI][Medline].
10.
Langraf, R,
Malkinson T,
Horn T,
Veale WL,
Lederis K,
and
Pittman QJ.
Release of vasopressin and oxytocin by periventricular nucleus stimulation in rats.
Am J Physiol Regulatory Integrative Comp Physiol
258:
R155-R159,
1990
11.
Lind, RW,
Van Hoesen GW,
and
Johnson AK.
An HRP study of the connections of the subfornical organ of the rat.
J Comp Neurol
210:
265-277,
1982[ISI][Medline].
12.
MacCumber, MW,
Ross CA,
Glaser BM,
and
Masaki T.
Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action.
Proc Natl Acad Sci USA
86:
7285-7289,
1989[Abstract].
13.
Martin, DS,
and
Haywood JR.
Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus.
Brain Res
577:
261-267,
1992[ISI][Medline].
14.
Minimisawa, K,
Hashimoto R,
Ishii M,
and
Kimura F.
Complicated central effects of endothelin on blood pressure in rats.
Japn J Physiol
39:
825-832,
1989[ISI][Medline].
15.
Miselis, RR.
The efferent projections of the subfornical organ of the rat: a circumventricular organ within the neural network subserving water balance.
Brain Res
230:
1-23,
1981[ISI][Medline].
16.
Mosqueda-Garcia, R,
Fernandez-Violante R,
Hamakubo T,
and
Stainback R.
Vasopressin mediates the pressor effects of endothelin in the subfornical organ of the rat.
J Pharmacol Exp Ther
277:
1034-1042,
1996[Abstract].
17.
Mosqueda-Garcia, R,
Stainback R,
Fernandez-Violante R,
and
Hamakubo T.
Cardiovascular effects of endothelin injection into brain nuclei regulating vasopressin release.
J Cardiovasc Pharmacol
26, Suppl 3:
S159-S162,
1995[ISI][Medline].
18.
Nakamura, S,
Naruse M,
Naruse K,
Shioda S,
Nakai Y,
and
Uemura H.
Colocalization of immunoreactive endothelin-1 and neurohypophysial hormones in the axons of the neural lobe of the rat pituitary.
Endocrinology
132:
530-533,
1993[Abstract].
19.
Nishimura, M,
Takahashi J,
Masusawa M,
Ikegaki I,
Nakanishi T,
Hirabayashi M,
and
Yoshimura M.
Intracerebroventricular injections of endothelin increase arterial pressure in conscious rats.
Japn Circ J
54:
662-670,
1990[ISI][Medline].
20.
Nishimura, M,
Takahashi J.,
Masususawa M,
Ikegaki I,
Nakanishi T,
Hirabarashi M,
and
Yoshimura M.
Chronic intracerebroventricular infusions of endothelin elevate arterial pressure in rats.
J Hypertens
9:
71-76,
1991[ISI][Medline].
21.
Ouchi, Y,
Kim S,
Souza AC,
Iijima S,
Hattori A,
Orimo H,
Yoshizumi M,
Kurihara H,
and
Yasaki Y.
Central effects of endothelin on blood pressure in conscious rats.
Am J Physiol Heart Circ Physiol
256:
H1747-H1751,
1989
22.
Rossi, NF.
Effect of endothelin 3 on vasopressin release in vitro and water excretion in vivo in Long Evans rats.
J Physiol (Lond)
461:
501-511,
1993[Abstract].
23.
Rossi, NF.
Cation channel mechanisms in endothelin 3-induced vasopressin secretion by rat hypothalamo-neurohypophysial explants.
Am J Physiol Endocrinol Metab
268:
E467-E475,
1995
24.
Rossi, NF,
O'Leary DS,
and
Chen H.
Mechanisms of centrally administered ET-1-induced increases in systemic arterial pressure and AVP secretion.
Am J Physiol Endocrinol Metab
272:
E126-E132,
1997
25.
Rossi, NF,
O'Leary DS,
Scislo TJ,
Caspers ML,
and
Chen H.
Central endothelin 1 regulation of arterial pressure and arginine vasopressin secretion via the AV3V region.
Kidney Int
52, Suppl 61:
S22-S26,
1997.
26.
Rossi, NF,
O'Leary DS DS, D,
Woodbury H,
and
Chen
Endothelin 1 in hypertension in the baroreflex-intact SHR: a role independent from vasopressin.
Am J Physiol Endocrinol Metab
279:
E18-E24,
2000
27.
Sapier, D,
and
Feldman S.
Electrophysiologic evidence for neural connections between the paraventricular nucleus and neurons of the supraoptic nucleus in the rat.
Exp Neurol
88:
289-294,
1985.
28.
Sapier, D.,
and
Feldman S.
Electrophysiology of supraoptico-paraventricular nucleus connections in the rat.
Exp Brain Res
69:
60-66,
1987[ISI][Medline].
29.
Schreihofer, AM,
and
Sved AF.
Use of sinoaortic denervation to study the role of baroreceptors in cardiovascular regulation.
Am J Physiol Regulatory Integrative Comp Physiol
266:
R1705-R1710,
1994
30.
Sofroniew, MV.,
Weindl A,
Schinko I,
and
Wetzstein R.
The distribution of vasopressin-, oxytocin-, and neurophysin-producing neurons in the guinea pig brain. I. The classical hypothalamo-neurohypophyseal system.
Cell Tissue Res
196:
367-384,
1979[ISI][Medline].
31.
Takahashi, K,
Ghatei MA,
Jones PM,
Murphy JK,
Lam H-C,
O'Halloran DJ,
and
Bloom SR.
Endothelin in human brain and pituitary gland: presence of immunoreactive endothelin, endothelin messenger ribonucleic acid, and endothelin receptors.
J Clin Endocrinol Metab
72:
693-699,
1991[Abstract].
32.
Takeda, K,
Nakata T,
Takesako T,
Itoh H,
Hirata M,
Kawasaki S,
Hayashi J,
Ogura M,
Sasaki S,
and
Nakagawa M.
Sympathetic inhibition and attenuation of spontaneous hypertension by PVN lesions in rats.
Brain Res
543:
286-300,
1991.
33.
Wall, KM,
and
Ferguson AV.
Endothelin acts at the subfornical organ to influence the activity of putative vasopressin and oxytocin-secreting neurons.
Brain Res
586:
111-116,
1992[ISI][Medline].
34.
Wall, KM,
Nasr M,
and
Ferguson AV.
Actions of endothelin at the subfornical organ.
Brain Res
570:
180-187,
1992[ISI][Medline].
35.
Yamamoto, S,
Inenaga K,
Kannan H,
Eto S,
and
Yamashita H.
The actions of endothelin on sigle cells in the anterventral third ventricular region and supaoptic nucleus in rat hypothalamic slices.
J Neuroendocrinol
5:
427-434,
1993[ISI][Medline].
36.
Yamamoto, T,
Kimura T,
Ota K,
Shoji M,
Inoue M,
Sato K,
Ohta M,
and
Yoshinaga K.
Central effects of endothelin 1 on vasopressin and atrial natriuretic peptide release and cardiovascular and renal function in conscious rats.
J Cardiovasc Pharmacol
17:
S316-S318,
1991[ISI][Medline].
37.
Yoshizawa, T,
Shinmi O,
Giaid A,
Yanagisawa M,
Gibson SJ,
Kimura S,
Uchiyama Y,
Polak JM,
Masaki T,
and
Kanazawa I.
Endothelin: a novel peptide in the posterior pituitary system.
Science
247:
462-464,
1990[ISI][Medline].
38.
Zhu, B,
and
Herbert J.
Behavioral, autonomic and endocrine responses associated with c-fos expression in the forebrain and brainstem after intracerebroventricular infusions of endothelins.
Neuroscience
71:
1049-1062,
1996[ISI][Medline].