(Hypertension. 2001;37:1382.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Central Orexin-A Augments Sympathoadrenal Outflow in Conscious Rabbits
From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Correspondence to Kiyoshi Matsumura, MD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail matsumk{at}intmed2.med.kyushu-u.ac.jp
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Abstract |
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Abstract—We determined the cardiovascular and neurohormonal responses to intracerebroventricular administration of orexin-A in conscious rabbits. Intracerebroventricular injection of orexin-A elicited dose-related increases in mean arterial pressure and renal sympathetic nerve activity. Peak values of mean arterial pressure and renal sympathetic nerve activity induced by intracerebroventricular injection of 100 pmol of orexin-A (14.0±0.7 mm Hg and 55.4±14.9%, respectively) were obtained at 40 and 25 minutes after injection, respectively. Plasma epinephrine and glucose concentrations were significantly increased at 60 and 90 minutes after intracerebroventricular injection of orexin-A (control versus 90 minutes; for epinephrine, 38.0±12.8 versus 167.5±42.5 pg/mL, P<0.01; for glucose, 6.66±0.18 versus 7.75±0.14 mmol/L, P<0.01). Plasma norepinephrine and insulin concentrations increased at 60 and 90 minutes but did not attain significant values. Intracerebroventricular injection of orexin-A also caused significant increases in plasma vasopressin concentrations. However, pretreatment with an intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, abolished these cardiovascular and neurohormonal responses. On the other hand, intravenous injection of the same dose of orexin-A (100 pmol) used in the intracerebroventricular experiment failed to cause any cardiovascular and renal sympathetic nerve responses. These results suggest that intracerebroventricular orexin-A acts in the central nervous system and activates sympathoadrenal outflow, resulting in increases in arterial pressure and plasma glucose levels in conscious rabbits.
Key Words: catecholamines • central nervous system • glucose • peptides • renal nerves
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Introduction |
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Appetite and feeding behavior are regulated by many neurotransmitters, such as neuropeptide Y, corticotrophin-releasing factor,
-melanocyte–stimulating hormone, and melanin-concentrating
hormone.1 2 The
orexins are a recently identified class of neuropeptides that stimulate
food intake.3 4
Orexin-A and orexin-B are 33– and 28–amino acid peptides,
respectively, sharing a 46%
identity.3 4
Immunohistochemical studies have shown that orexin-immunoreactive nerve
fibers are present not only in the hypothalamus but also in the
medulla.5 6 7
Intracerebroventricular injections of
orexins have been seen to induce
c-fos expression in the
paraventricular thalamic nucleus, locus ceruleus,
arcuate nucleus, central gray substance, raphe nuclei, nucleus
of the solitary tract, dorsal motor nucleus of the vagus,
suprachiasmatic nucleus, and supraoptic
nucleus,5 suggesting the
contribution of the peptides to autonomic and neuroendocrine control in
the central nervous system. Recently, Shirasaka et al8 showed that intracerebroventricular injections of orexin-A and orexin-B cause increases in arterial pressure, renal sympathetic nerve activity (RSNA), and plasma catecholamine concentrations in conscious rats. Their results and immunohistochemical studies suggest that central orexins participate not only in the regulation of food intake but also in cardiovascular and sympathetic regulations. We anticipated that activation of sympathoadrenal outflow induced by intracerebroventricular injection of orexins might elicit an increase in plasma glucose levels. Moreover, we considered that central orexins might stimulate the secretion of vasopressin, because one of the putative brain regions in which orexins act to stimulate food intake is the hypothalamus.1 We hypothesized that intracerebroventricular injection of orexins stimulates the secretion of vasopressin and activates sympathoadrenal outflow, resulting in increases in arterial pressure and plasma glucose levels in conscious animals. Because compared with orexin-B, orexin-A is more potent in increasing arterial pressure and RSNA,8 9 we focused on the central effects of orexin-A in the present study. In addition, baroreceptor reflex and the sympathetic nervous system are greatly influenced by the anesthesia used in the experiments10 11 ; therefore, the present study was designed particularly to investigate the central effect of orexin-A on blood pressure, the sympathetic nervous system, and blood variables, including plasma catecholamines, vasopressin, insulin, and glucose levels, in conscious rabbits by directly recording the RSNA.
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Methods |
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Preparation of Animals
The experiments were conducted on 26 male Japanese White rabbits weighing 2.5 to 2.7 kg. All experiments were carried out according to the institutional guidelines for animal experimentation at Kyushu University. Rabbits were anesthetized with pentobarbital sodium (30 mg/kg IV). Three days before experimentation, bipolar electrodes were implanted on the left renal sympathetic nerve, and a stainless-steel cannula was placed in the right lateral cerebral ventricle. RSNA was recorded as described previously.12 13 Briefly, under aseptic conditions, the left kidney was exposed retroperitoneally, and a branch of the renal nerve was separated from the renal plexus and the surrounding connective tissues with the use of a dissecting microscope. RSNA was recorded by a pair of electrodes made from polytetrafluoroethylene (Teflon)-insulated 7-stranded steel wire (Medwire). The area of the nerve and wire interface was embedded in silicone cement (Elastosil RT 604A and B cement, Wacker Chemicals).
A 23-gauge stainless-steel cannula was implanted into the right lateral cerebral ventricle, 4 mm lateral to the bregma and 6 mm below the cerebral surface. The position of the cannula in the lateral cerebral ventricle was confirmed by the staining of all 4 ventricles after injection of 0.1 mL dye at the end of the experiments. The cannula was fixed to the skull with 3 jeweler’s screws and dental cement. A 27-gauge obturator was used to seal the cannula. After surgery, disodium sulbenicillin (200 mg IV) was given to the rabbits to prevent postoperative infections.
At least 3 days after the surgical procedures, the following experiments were carried out on conscious rabbits placed in a box. On the day of the experiment, polyethylene catheters (PE-50) were inserted into the central ear artery and marginal ear vein under 1% lidocaine local anesthesia. The arterial catheter was connected to a pressure transducer (model P50, Gould Inc) to measure arterial pressure. Heart rate (HR) was monitored by use of a cardiotachometer (model 1332, NEC San-ei).
RSNA was amplified (model DPA-100E, Dia Medical System) and filtered (100 to 3000 Hz), and the waveforms were integrated after a full-wave rectification by using an integrator amplifier (model 1322, NEC San-ei) with the sample-hold function reset to baseline by an internal timer set at 5 seconds. The residual integrated RSNA that existed after intravenous administration of hexamethonium bromide (30 mg/kg IV) was taken as the noise level associated with nerve recording. This value was subtracted from absolute values of integrated RSNA before further data analysis was performed.
To minimize the influence of circadian changes in blood pressure and endocrine factors, the experiments were started at 9:00 AM and finished before 2:00 PM. All drugs for intracerebroventricular injection were dissolved in artificial cerebrospinal fluid (aCSF; in mmol/L: NaCl 133.3, KCl 3.4, CaCl2 1.3, MgCl2 1.2, NaH2PO4 0.6, NaHCO3 32.0, and glucose 3.4).
Relationship Between Dose of
Intracerebroventricular Orexin-A and
Cardiovascular Responses
To determine the dose of orexin-A (Peptide Institute)
needed to increase arterial pressure, aCSF (80 µL) and 10
and 100 pmol of orexin-A were injected
intracerebroventricularly in the order
of ascending concentrations (n=5 for each). These doses of orexin-A
were dissolved in 80 µL of aCSF. The administration of each dose of
orexin-A was separated by 90 minutes. Arterial pressure,
HR, and RSNA were monitored continuously.
Effect of
Intracerebroventricular Orexin-A on
Cardiovascular and Neurohormonal Responses
Two different groups of rabbits were used to
determine the effect of
intracerebroventricular orexin-A on
cardiovascular and neurohormonal responses. After a
control period, a blood sample (3.0 mL) was drawn from the
arterial catheter to measure plasma
catecholamines (epinephrine and
norepinephrine), plasma vasopressin, plasma glucose, plasma
insulin, plasma osmolality, and hematocrit in both groups. One group of
rabbits (n=6) was injected with orexin-A (100 pmol) in a volume of 80
µL, and another group (n=5) was injected with aCSF (80 µL) via the
intracerebroventricular cannula.
Additional blood samples were drawn at 60 and 90 minutes after
intracerebroventricular injection of
orexin-A or aCSF. The blood samples were replaced by the same volume of
0.9% saline. Arterial pressure, HR, and RSNA were
monitored continuously.
Effect of Pentolinium on
Cardiovascular Responses Induced by
Intracerebroventricular Injection of
Orexin-A
To evaluate the contribution of the sympathetic
nervous system to cardiovascular responses induced by
intracerebroventricular orexin-A,
pentolinium (5 mg/kg in 0.3 mL IV, Sigma Chemical Co), a
ganglion-blocking agent, was injected in a different group of rabbits
(n=5). Five minutes later, a blood sample (3.0 mL) was drawn from the
arterial catheter to measure plasma
catecholamines (epinephrine and
norepinephrine), plasma vasopressin, plasma glucose, plasma
insulin, plasma osmolality, and hematocrit. Ten minutes after the
intravenous injection of pentolinium, orexin-A (100 pmol)
was injected intracerebroventricularly.
An additional blood sample was drawn 60 minutes after
intracerebroventricular injection of
orexin-A. Additional pentolinium (2.5 mg/kg in 0.15 mL) was then
injected intravenously to suppress sympathetic nerve
activity at least 90 minutes after the
intracerebroventricular injection of
orexin-A. The last blood sample was drawn 90 minutes after the
intracerebroventricular injection of
orexin-A. The blood samples were replaced by the same volume of 0.9%
saline. Arterial pressure, HR, and RSNA were monitored
continuously.
Effect of Intravenous Injection of
Orexin-A on Cardiovascular and Sympathetic
Responses
To evaluate the leakage of
intracerebroventricular injected
orexin-A into the systemic circulation, the same dose of orexin-A (100
pmol) used in the
intracerebroventricular injection
experiment was injected intravenously (n=5).
Arterial pressure, HR, and RSNA were monitored
continuously.
Blood Collection and Analysis
Blood samples for measurement of plasma
catecholamines, vasopressin, and insulin were
centrifuged at 4°C. Plasma for catecholamines was
stored at -80°C, and other plasma was stored at -20°C until
assay. The plasma catecholamine concentrations were
measured by high-performance liquid
chromatography,14
and plasma vasopressin and insulin levels were measured by
radioimmunoassay.12 13 15
The assay sensitivities for vasopressin, catecholamines
(epinephrine and norepinephrine), and insulin were
0.45 pg/mL, 10 pg/mL, and 1 µU/mL, respectively. Plasma glucose
levels were measured by use of a Glucose Analyzer 2 (Beckman
Instruments).12 13
Plasma osmolality was measured with a freezing-point osmometer
(Osmotron-20, Orion
Riken).12 13
Statistical Analysis
All values are expressed as mean±SE. To determine
the effects of intracerebroventricular
and intravenous injections of orexin-A on
cardiovascular and RSNA responses or blood
variables, 1-way ANOVA with repeated measurements was performed,
followed by the Duncan’s multiple range test to determine which means
differed from the control means. In addition, 2-way ANOVA with repeated
measurements was applied to compare the cardiovascular
and neurohormonal responses to
intracerebroventricular orexin-A with
the responses to the
intracerebroventricular administration
of aCSF. A value of P<0.05 was
considered significant.
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Results |
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Relationship Between Dose of Intracerebroventricular Orexin-A and Cardiovascular Responses
Baseline values for mean arterial pressure (MAP) and HR before the intracerebroventricular injection of orexin-A were 94.0±2.5 mm Hg and 212.0±14.5 bpm, respectively. Intracerebroventricular injection of orexin-A elicited dose-related increases in MAP and RSNA (Figure 1). The results shown in Figure 1 illustrate the peak responses for MAP, HR, and RSNA obtained during a 90-minute recording period. Because 100 pmol of orexin-A caused significant increases in MAP and RSNA, we used this dose of orexin-A in the following experiments.
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Effect of
Intracerebroventricular Orexin-A on
Cardiovascular and Neurohormonal Responses
Figure 2 shows the typical responses of MAP, HR, and RSNA
that were elicited by
intracerebroventricular injection of
orexin-A (100 pmol).
Intracerebroventricular injection of
100 pmol of orexin-A provoked significant increases in MAP and RSNA,
and the peak values of these variables were obtained after 40 and
25 minutes, respectively
(Figure 3). After the peak values were obtained, MAP and RSNA
decreased and returned to their baseline levels within 90 to 120
minutes. The interactions between the effect of the treatments
(orexin-A or aCSF administration) and time course of MAP and RSNA in
2-way ANOVA with repeated measurements were
P=0.0001 and
P=0.0001, respectively. HR did
not show any significant changes; however, the interactions between the
effect of the treatments (orexin-A or aCSF administration) and time
course of HR in 2-way ANOVA with repeated measurements was
P=0.0001.
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Table 1 shows the effects of intracerebroventricular injection of orexin-A or aCSF on plasma catecholamine and vasopressin concentrations and other variables. Intracerebroventricular injection of orexin-A caused significant increases in plasma epinephrine and glucose concentrations at 60 and 90 minutes. Plasma vasopressin concentration also significantly increased at 90 minutes after intracerebroventricular injection of orexin-A. Plasma norepinephrine and insulin concentrations increased at 60 and 90 minutes but did not attain the significant values. Plasma osmolality and hematocrit did not show any changes. In contrast, intracerebroventricular injection of aCSF failed to cause any significant changes in blood variables. The interactions between the effect of the treatments (orexin-A or aCSF administration) and the time course of epinephrine, norepinephrine, vasopressin, or glucose concentrations were statistically significant by 2-way ANOVA with repeated measurements (P<0.05 for each). Rabbits sat quietly in the box, and behavioral effects of intracerebroventricular orexin-A were not observed throughout the experimental period.
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Effect of Pentolinium on
Cardiovascular Responses Induced by
Intracerebroventricular Injection of
Orexin-A
After pentolinium administration, MAP fell from
90.8±2.5 to 52.8±3.3 mm Hg, and HR increased from 225.0±11.5
to 276.0±34.0 bpm. However,
intracerebroventricular injection of
orexin-A failed to cause any further responses in MAP or HR, and RSNA
was almost completely suppressed until 90 minutes after injection of
orexin-A.
Table 2 shows the effects of pentolinium on blood
variables induced by
intracerebroventricular injection of
orexin-A. Plasma epinephrine, norepinephrine,
insulin, and glucose levels did not show any significant changes.
Intravenous injection of pentolinium increased plasma
vasopressin concentrations; however,
intracerebroventricular injection of
orexin-A failed to cause further changes in plasma vasopressin
concentrations.
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Effect of Intravenous Injection of
Orexin-A on Cardiovascular and Sympathetic
Responses
The same dose of orexin-A (100 pmol) used in the
intracerebroventricular experiment was
injected intravenously. After intravenous
injection of orexin-A, arterial pressure, HR, and RSNA
remained within 5% of their control
values.
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Discussion |
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The present study demonstrated that intracerebroventricular injection of orexin-A caused significant increases in arterial pressure, RSNA, and plasma epinephrine concentrations. Intravenous injection of pentolinium, a ganglion-blocking agent, abolished the responses of arterial pressure and of plasma epinephrine concentrations. These results suggest that the pressor response induced by the intracerebroventricular injection of orexin-A can be attributed primarily to enhanced sympathetic outflow, although plasma norepinephrine concentrations did not change significantly. Furthermore, intravenous injection of the same dose of orexin-A used in the intracerebroventricular injection experiment failed to cause any cardiovascular and sympathetic responses, suggesting that the responses induced by the intracerebroventricular injection of orexin-A were not caused by a leakage of orexin-A into the systemic circulation. To the best of our knowledge, this is the first study to demonstrate simultaneously the responses of RSNA, plasma catecholamines, vasopressin, insulin, and glucose levels to the central administration of orexin-A in conscious animals.
Intracerebroventricular injection of orexin-A (100 pmol) elicited only a small increase in HR in the present study. In contrast, Shirasaka et al8 demonstrated that intracerebroventricular injection of orexin-A (3 nmol) caused a significant increase in HR in conscious rats. This different response of HR might be attributed to both the difference in species used in the experiments and applied doses of orexin-A.
Central orexins stimulate food intake3 ; however, the effects of orexin-A on blood glucose and insulin levels remain to be investigated. Haynes et al16 reported that intracerebroventricular infusion of orexin-A (18 nmol/d) for 8 days did not change blood glucose and plasma insulin levels in rats. In contrast, Nowak et al17 showed that a subcutaneous bolus injection of orexin-A (1 or 2 nmol) increased both blood glucose and insulin levels and that orexin-A stimulated insulin secretion in an in vitro perfusion system of a rat pancreatic preparation. In the present study, intracerebroventricular injection of orexin-A caused significant and long-lasting increases in plasma epinephrine and glucose concentrations. In contrast, plasma insulin levels increased but did not reach significant levels. The effects of orexin-A on blood glucose levels may vary depending on whether its administration is acute or chronic. The present study has an advantage in that the experiments were conducted on conscious animals and that serial changes of plasma catecholamine concentrations were determined. Parallel changes of plasma glucose levels and plasma epinephrine concentrations suggest a close relationship between these 2 variables. Hyperglycemia has been shown to be evoked by an increase in plasma epinephrine concentration18 ; thus, this response of the plasma glucose level was likely attributable to the increased plasma epinephrine concentration. Subsequently, this increase in the plasma glucose level might induce a slight increase in the plasma insulin level in the present study.
Intracerebroventricular injection of orexin-A also elicited an increase in plasma vasopressin concentration. In the present study, because neither plasma osmolality nor hematocrit changed after intracerebroventricular injection of orexin-A and because increased plasma levels of epinephrine would be expected to cause an increase in venous return,19 the changes in the central venous pressure were not considered to stimulate the release of vasopressin. Orexin-containing fibers are present both in the paraventricular thalamic nucleus and in the supraoptic nucleus.5 6 7 In addition, intracerebroventricular injections of orexins have been shown to induce c-fos expression in both nuclei.5 Therefore, these anatomic and functional studies suggest that intracerebroventricular injected orexin-A in the present study might directly stimulate the paraventricular nucleus or supraoptic nucleus of the hypothalamus, resulting in the release of vasopressin into the systemic circulation.
The present study did not clarify the exact site at which orexin-A acts in the central nervous system or the mechanisms of pressor response and activation of sympathetic nervous system induced by intracerebroventricular orexin-A. Recently, Chen et al9 demonstrated that intracisternal injection of orexin-A caused an increase in arterial pressure and that microinjection of orexin-A into the rostral ventrolateral medulla elicited a long-lasting increase in arterial pressure in anesthetized rats. Their findings suggest that intracerebroventricular orexin-A may directly stimulate the rostral ventrolateral medulla to activate the sympathetic nervous system and to increase arterial pressure. On the other hand, high orexin contents are reportedly present in the lateral hypothalamus, ventromedial hypothalamic nucleus, and paraventricular thalamic nuclus,20 and primary sites of the brain at which orexins act to stimulate food intake have been considered to be in the hypothalamus.21 Immunohistochemical study showed that orexin-A immunoreactive neurons in the tuberal hypothalamus project to the medulla.22 Therefore, intracerebroventricular orexin-A might primarily act at the hypothalamic nuclei and, subsequently, stimulate the cardiovascular center of the medulla, such as the ventrolateral medulla or the nucleus of the solitary tract. The fact that intracerebroventricular orexin-A stimulated vasopressin secretion in the present study may support this hypothesis. A study focusing on the microinjection of orexin-A into the hypothalamus will be necessary to clarify the role of orexin-A in the hypothalamus in cardiovascular and sympathetic regulations.
Neurotransmitters, such as neuropeptide Y, agouti-related
protein, cocaine- and amphetamine-regulated transcript,
-melanocyte–stimulating hormone, and orexins, have been shown to be
involved in feeding in the central nervous system and to interact with
leptin.1 2 These
neurotransmitters seem to function together in
cardiovascular and sympathetic regulations as well as
in the regulations of food intake and energy expenditure. Central
leptin activates the sympathetic nervous system and increases
arterial
pressure23 24 ;
conversely, central neuropeptide Y has been shown to suppress the
sympathetic nervous system25
and decrease arterial
pressure.26 Our recent
findings also demonstrated that leptin inhibited the central
cardiovascular action of neuropeptide Y in conscious
rabbits.27 Orexin-A may also
interact with these peptides to participate in
cardiovascular and sympathetic regulation, although
direct evidence remains to be demonstrated.
In conclusion, orexin-A exerted a central pressor action mediated primarily by enhanced sympathoadrenal outflow, and these effects were accompanied by increases in plasma vasopressin and glucose levels. Orexin-A may participate in central cardiovascular and sympathetic regulation as well as in the regulation of appetite and food intake, although physiological implications have not yet been determined. Further studies are necessary to determine the exact site of the brain at which orexin-A acts to augment the sympathoadrenal outflow.
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Acknowledgments |
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This work was supported in part by a grant from the Ministry of Education, Japan (No. 11670705). A part of this study was performed in the Kyushu University Station for Collaborative Research. We thank Akemi Takushima and Rie Imaizumi for expert technical assistance.
Received October 4, 2000; first decision November 16, 2000; accepted November 28, 2000.
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T. Shirasaka, M. Takasaki, and H. Kannan Cardiovascular effects of leptin and orexins Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R639 - R651. [Abstract] [Full Text] [PDF]
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K. Matsumura, T. Tsuchihashi, and I. Abe Central Human Cocaine- and Amphetamine-Regulated Transcript Peptide 55-102 Increases Arterial Pressure in Conscious Rabbits Hypertension, November 1, 2001; 38(5): 1096 - 1100. [Abstract] [Full Text] [PDF]
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