(Hypertension. 2001;37:936.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Leptin Acts in the Central Nervous System to Produce Dose-Dependent Changes in Arterial Pressure
From the Specialized Center of Research in Hypertension Genetics, the Cardiovascular Center and Department of Internal Medicine, The University of Iowa, and Veterans Affairs Medical Center, Iowa City, Iowa.
Correspondence to William G. Haynes, MD, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242. E-mail william-g-haynes{at}uiowa.edu
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Abstract |
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Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt–fed rats also caused a sustained pressor response (+3±1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.
Key Words: hormones • sodium • obesity • hypertension, arterial • sympathetic nervous system
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Introduction |
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Leptin is a protein hormone produced mostly in adipose tissue that acts as a signaling mechanism to regulate body fat content.1 After crossing the blood-brain barrier through a saturable receptor-mediated mechanism, leptin binds to its long-form receptor situated in hypothalamic nuclei.2 In rodents, the hypothalamic actions of leptin consist of a reduction in appetite3 and sympathetic activation of thermogenic metabolism.4 Together, these actions decrease adipose mass and body weight.
Intravenous leptin increases sympathetic nerve activity to interscapular brown adipose tissue (BAT).5 In addition, injection of leptin into the third cerebral ventricle activates sympathetic nerves to BAT.6 Intravenous leptin also increases sympathetic nerve activity to the kidneys, hind limbs, and adrenal glands in anesthetized rats.5
Chronic high-dose intravenous or intracarotid administration of leptin increases arterial pressure and heart rate in conscious rats.7 It is not known whether these effects are peripherally or centrally mediated because no difference was found between the pressor effect of intravenous versus carotid administration of leptin. Dunbar et al8 and Casto et al9 have shown that acute administration of high doses of leptin into the lateral ventricle transiently increases arterial pressure in anesthetized and conscious rats, respectively.
We hypothesized that leptin-induced increases in arterial pressure after long-term administration are due to a central neural action. To test this hypothesis, we administered leptin or vehicle into the third cerebral ventricle or jugular vein and recorded hemodynamic variables through radiotelemetry in conscious, lean, normotensive rats. Weight loss is known to decrease arterial pressure in both normotensive and hypertensive animals.10 11 Similar findings have been reported in humans.12 To control for the effects of weight loss on arterial pressure, we pair-fed vehicle-treated animals so that their food intake matched that of leptin-treated rats. Finally, the interactions between leptin and salt intake were also studied by feeding rats a low-salt or high-salt diet.
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Methods |
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Animals and Drugs
Experiments were performed in male Sprague-Dawley rats (weight, 280 to 330 g) from Harlan Sprague-Dawley. Amgen Inc supplied recombinant murine leptin. All procedures were approved by the University of Iowa and Iowa City Veterans Affairs Animal Research Committees.
Procedures
Intracerebroventricular
Cannulation
Rats were anesthetized with sodium
pentobarbital (50 mg/kg, IP, Abbott Laboratories) and secured in a Kopf
900 stereotaxic instrument (David Kopf Instruments). A
23-gauge stainless steel guide catheter (20 mm in length) was
lowered 10 degrees from vertical into the third ventricle according to
standard stereotaxic procedures. The coordinates with
respect to bregma were -1.0 mm anteroposterior, +1.5 mm
lateral from the midline, and -9.0 mm dorsoventral from the
dura. At the end of the experiments, animals were euthanized and the
brains stained and fixed in 10% formalin. Methylene blue staining and
microtone slicing confirmed the correct placement of the
catheter.
Radiotelemetry
Immediately after cannulation of the third ventricle,
a midline laparotomy was performed. A radiotelemetry transducer (model
TA11PA-C40 or TL11 mol/L2-C50-PXT, Data Sciences Inc) was inserted and
glued into the exposed aorta. Rats were given postoperative antibiotics
(Penicillin G benzathine and G procaine in aqueous suspension, 30 000
UI IM; Phoenix Pharmaceuticals Inc) and placed in individual
Plexiglas cages. Measurements of systolic and
diastolic arterial pressure were recorded
continuously for 5 seconds every 8 minutes. These radiotelemetry
measurements were stored for later analyses with Dataquest
LabPro 3.01 software (Data Sciences Inc). Radiotelemetry data were
averaged over 24-hour intervals.
Osmotic Minipump Implantation
After a 2-week recovery period, rats were briefly
anesthetized with methohexital sodium (Brevital, 50 mg/kg IP).
Primed miniosmotic pumps (Alza) were connected through PE-050 tubes to
the intracerebroventricular catheters
or implanted into the right external jugular vein. The osmotic
minipumps were placed subcutaneously.
Air-Jet Stress
Rats were placed in Plexiglas holders, which
permitted only forward and backward movements, for 10 minutes before an
equal period of baseline measurements. Acute environmental stress
consisted of a jet of air directed to the neck through a tube located 4
to 6 cm from the rat and lasted 10 minutes. Arterial
pressure and heart rate were recorded for 5 seconds every minute.
With this protocol, pressor responses to 2 episodes of air-jet stress,
separated by 1 week, were closely correlated
(r=0.68;
P=0.001).
Study Design
After implantation of the radiotelemetry devices and
intracerebroventricular catheters,
there was a 1-week recovery period during which animals were left
undisturbed and had free access to regular rat chow and water. Daily
food intake and body weight were then recorded for a 1-week control
period and during treatment period in all groups. At the end of the
control period, osmotic minipumps were implanted and the regular rat
chow was switched to salt-restricted (0.13%, ICN Nutritional
Biochemicals) or salt-rich (4%, ICN) diets. Telemetry was recorded
continuously. Control animals were treated with vehicle and pair-fed to
the leptin-treated groups or allowed free access to food in each
protocol. At the end of each treatment period, cerebrospinal fluid
(CSF) and blood were drawn before a lethal injection of methohexital
sodium for measurement of leptin levels.
Intracerebroventricular
Administration
Two doses of leptin were given by
intracerebroventricular administration
to rats fed 0.13% salt diet: 200 ng/h and 1000 ng/h. In the low-dose
study, 200 ng/h of leptin (n=15) or vehicle (n=10) was administered by
osmotic minipumps (model 2002; infusion rate, 0.5 µL/h; total
capacity, 200 µL) for 2 weeks. In the high-dose study, osmotic
minipumps (model 2004; infusion rate, 0.25 µL/h; total capacity, 200
µL) were used to infuse 1000 ng/h of leptin (n=10) or vehicle (n=10)
for 28 days. In a subgroup of rats (n=5), high-dose leptin was
identically infused, but animals were euthanized after 14 days to
measure CSF levels of leptin. Free-fed rats (n=6) served as controls
for both low-dose and high-dose studies. Air-jet stress was applied
every 7 days.
An additional group of animals was treated with intracerebroventricular leptin at 1000 ng/h for 2 weeks and fed a 4% salt diet (n=10). Vehicle pair-fed (n=10) and free-fed animals (n=10) served as control animals.
Intravenous Administration
Leptin at 1000 ng/h (n=6), 18 000 ng/h (n=10) or
vehicle (n=6) was delivered by osmotic minipumps for 28 days.
Vehicle-treated animals pair-fed to rats treated with
intravenous leptin at 1000 and 18 000 ng/h groups were
also obtained (n=6 and 10, respectively). The higher dose was delivered
by model 2 ML4 minipump (infusion rate, 2.5 µL/h; total capacity, 2
mL). We reasoned that if 1000 ng/h given intravenously did
not alter arterial pressure, then the effects of the
intracerebroventricular administration
of 1000 ng/h of leptin could not be attributed to the possibility of
spillover into the systemic circulation. A free-fed group (n=10)
was also obtained. The 18 000 ng/h group was included as a positive
control; this dose has been previously shown to have
hemodynamic
effects.7
Analytical
Plasma and CSF murine leptin concentrations were
measured by radioimmunoassay (Linco Inc). Interassay coefficient of
variance in our laboratory is 2.7% at 1.18 ng/mL, and the sensitivity
is 0.2 ng/mL.
Data Analyses
All parameters were expressed as
mean±SEM of absolute change relative to the respective control
average. Differences between leptin and vehicle-treated rats were
assessed by repeated-measures ANOVA or by Student’s
t test. Statistical
analysis was performed with StatView 521+ software for
Macintosh (BrainPower Inc). A value of
P<0.05 was considered
statistically significant.
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Results |
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Intracerebroventricular Leptin at 200 ng/h in Rats Fed Low-Salt Diet
Food intake decreased after surgery in all groups (Table 1), possibly because of the change to a low-salt diet. However, leptin and vehicle pair-fed groups lost weight, whereas free-fed animals gained weight. Heart rate (HR) increased in leptin-treated rats (+45±2 bpm) but decreased or did not change in the vehicle-treated animals. As compared with baseline, mean arterial pressure (MAP) decreased in all 3 groups (Table 1). Surprisingly, MAP decreased more in the leptin-treated group (-8±1 mm Hg) compared with vehicle pair-fed (-2±1 mm Hg, P<0.001 versus leptin) and free-fed rats (-4±1 mm Hg, P<0.001 versus leptin) (Table 1).
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Intracerebroventricular
Leptin at 1000 ng/h in Rats Fed Low-Salt Diet
Food intake decreased approximately equally in the
group given 1000 ng/h leptin and in the vehicle pair-fed groups and, to
a lesser degree, in the free-fed group
(Table 2 and
Figure 1). Body weight decreased substantially in
leptin-treated and vehicle pair-fed groups, whereas vehicle free-fed
rats gained weight
(Figure 1). Food intake and body weight started to return
toward baseline after 2 weeks of treatment. At 4 weeks, food intake in
leptin-treated and vehicle-treated animals was similar; however,
vehicle-treated free-fed animals were substantially heavier than
leptin-treated and vehicle-treated, pair-fed rats
(Table 2).
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HR during the second week of treatment increased substantially in leptin-treated rats (+54±5 bpm), whereas it decreased in the pair-fed (-68±2 bpm, P<0.001 versus leptin) and free-fed (-12±1 bpm, P<0.001 versus leptin) groups (Table 2 and Figure 2). MAP increased in rats receiving leptin (+4±1 mm Hg) during the first week of treatment, in contrast to a reduction in MAP in pair-fed (-4±1 mm Hg, P<0.001 versus leptin) and in free-fed rats (-2±1 mm Hg, P<0.01 versus leptin) (Table 2 and Figure 2). However, MAP gradually decreased during the second week of leptin treatment, so that there was no difference between groups at 4 weeks (Table 2).
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Intracerebroventricular
Leptin at 1000 ng/h in Rats Fed High-Salt Diet
Food intake and body weight decreased substantially in
the leptin-treated (1000 ng/h) and vehicle-treated, pair-fed groups,
whereas vehicle-treated, free-fed rats gained weight
(Table 3 and
Figure 3). The HR during the second week of treatment
increased substantially in leptin-treated rats (+53±2 bpm) and
slightly in the free-fed control rats (+8±3 bpm,
P<0.05 versus leptin).
Meanwhile, HR decreased in the pair-fed rats (-58±1 bpm,
P<0.001 versus leptin)
(Figure 4). MAP increased steadily in leptin-treated rats
(+3±1 mm Hg), whereas MAP decreased in pair-fed rats
(-6±1 mm Hg, P<0.01
versus leptin)
(Figure 4). MAP did not change in free-fed rats (-1±1
mm Hg, P=NS versus leptin)
(Figure 4).
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Air-Jet Stress in Rats Treated With
Intracerebrovascular Leptin (1000 ng/h)
The MAP response to air-jet stress was greater in
leptin-treated animals on the low-salt diet compared with the pair-fed
control rats after 1 week of treatment, but there was no difference at
2 weeks
(Figure 5). The HR response to air-jet stress decreased in
the leptin group
(Figure 5).
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Intravenous Leptin at 1000 and
18 000 ng/h in Rats Fed Low-Salt Diet
In a control study, intravenous
administration of 1000 ng/h of leptin did not decrease food intake or
body weight and did not alter MAP or HR
(Table 4).
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Intravenous administration of 18 000 ng/h of leptin caused a sustained reduction in food intake and a transient decrease in body weight (Table 4). Similar effects were seen in the pair-fed control rats (Table 4). HR increased after leptin treatment, whereas pair-fed control rats showed bradycardia (Table 4). As with the highest intracerebroventricular dose, intravenous leptin at 18 000 ng/h prevented the depressor effect of weight loss (Table 4).
Leptin Concentration in CSF and Plasma
Neither CSF nor plasma concentrations of leptin were
different between rats treated with 200 ng/h ICV leptin or vehicle
(Table 5). In the group treated with 1000 ng/h of leptin for
2 weeks, the CSF leptin concentration increased markedly. At 4 weeks,
the CSF leptin concentration had fallen, almost back to control levels.
There was no significant difference in plasma leptin between animals
receiving intracerebroventricular
leptin or vehicle
(Table 5). In rats given
intracerebroventricular leptin and on a
high-salt diet, leptin CSF concentration at 2 weeks was also
substantially elevated
(Table 5). Leptin concentrations in the CSF did not differ
between rats treated with 1000 ng/h IV leptin or vehicle
(Table 5).
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Discussion |
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We have demonstrated that leptin dose-dependently decreases food intake and body weight in rats through a CNS mechanism, confirming previous reports.3 13 14 Our main new finding was that long-term intracerebroventricular administration of 1000 ng/h of leptin modestly increases arterial pressure despite a substantial reduction in body weight. The absence of spillover to plasma and lack of hemodynamic effect of intravenous leptin at the same dose (1000 ng/h) suggest that leptin acted in the CNS to increase arterial pressure. We were surprised to find that arterial pressure decreased in rats treated with 200 ng/h ICV leptin. This may reflect a depressor effect of weight loss in the face of a dose of leptin that failed to increase arterial pressure. However, the arterial pressure did not change in vehicle-treated, pair-fed animals despite weight loss. Therefore, we speculate that intracerebroventricular administration of leptin at 200 ng/h may directly decrease arterial pressure.
In a control study, intracerebroventricular administration of leptin at 18 000 ng/h also caused weight loss and tachycardia and prevented the depressor effect of weight loss in low-salt–fed animals. This observation corroborates the results of Shek et al7 and supports the biological activity of leptin as administered by osmotic minipump.
Leptin has been shown to cause sympathoactivation after intravenous or intracerebroventricular administration.5 8 Several peripheral actions of leptin have also been described that may alter arterial pressure. Human leptin but not murine or rat leptin has been shown to induce natriuresis and diuresis by acting locally in the rat kidney.15 16 In addition, leptin stimulates endothelial nitric oxide–mediated vasorelaxation in vitro17 and in vivo.18 Leptin acutely increases insulin sensitivity.19 These peripheral effects of leptin may potentially decrease arterial pressure.
The mechanism by which leptin increased arterial pressure in our study probably reflects central activation of the sympathetic nervous system.5 8 Unequivocal evidence for sympathetic activation mediated by leptin could not be obtained from our experiments. Nevertheless, indirect evidence suggests the participation of sympathetic mechanisms to increase arterial pressure. First, a substantial dose-dependent increase in heart rate was observed in leptin-treated animals as opposed to bradycardia exhibited by the vehicle-treated, pair-fed control rats. Second, leptin-treated animals exhibited an enhanced pressor response during environmental stress. Finally, our group and others have reported that leptin administered into the cerebral ventricles of anesthetized rats increases sympathetic activity to the kidneys, adrenals, hind limbs, and BAT.5 8 In addition, Aizawa-Abe et al20 have shown that adrenergic antagonists prevent the pressor effect caused by human leptin overexpressed in the liver of transgenic mice.
Leptin CSF concentration was highest at 2 weeks and fell toward baseline at 4 weeks (Table 5). The pressor effect of leptin was proportional to the CSF concentration of leptin. Failure of the administration system or peptide inactivation might explain the decrease in CSF concentrations at 4 weeks. Whatever the mechanism, the decrease in arterial pressure as CSF leptin concentrations decreased strengthens rather than weakens the hypothesis that leptin acts in the CNS to increase arterial pressure.
Salt-sensitive hypertension develops in obese rats.21 Obesity is usually accompanied by hyperleptinemia. Therefore, we have studied the effects of a high-salt diet on the pressor responses of intracerebroventricular administration of leptin. Weight loss did not decrease arterial pressure to as great an extent in high-salt–fed as compared with low-salt–fed animals. We have shown that increases in arterial pressure were similar in leptin-treated rats fed a low-salt or a high-salt diet, indicating that leptin-dependent mechanisms in the central nervous system do not alter arterial pressure sensitivity to salt. This result suggests that leptin may not contribute to arterial pressure sensitivity to salt in hyperleptinemic obese rats.
Study Limitations
One limitation of our study is that the CSF
concentration of leptin that increased arterial pressure
was much higher than the usual concentration observed
physiologically. The CSF leptin concentration
in vehicle-treated, free-fed animals probably reflects the
physiological level in Sprague-Dawley rats.
However, obesity is associated with elevated leptin concentrations in
the CSF and
plasma,22 23 so
these results may be relevant to the pathophysiology of obesity-related
hypertension. Also, the use of leptin as a pharmacological agent for
therapy of obesity may result in similarly high CSF concentrations.
Another potential limitation is that recombinant murine leptin was used
rather than rat leptin. However, we demonstrated that murine leptin was
biologically active in rats, inhibiting appetite and decreasing body
weight.24
Conclusions
We have shown that local central nervous system
administration of leptin causes pressor and positive chronotropic
actions that probably are mediated through central sympathetic
mechanisms. The pressor effect of leptin appears to oppose the
hypotensive effect of food restriction. Finally, leptin does not appear
to increase salt sensitivity of arterial
pressure.
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Acknowledgments |
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This study was supported by grants HL-14388, HL-44546, and HL-43514 from the National Heart, Lung, and Blood Institute and by funds from the Department of Veterans Affairs and the Juvenile Diabetes Foundation. Dr Correia was supported in part by the State University of Rio de Janeiro (Brazil). Dr Haynes was the recipient of the Pharmaceutical Research Manufacturers of America Faculty Development Award. The authors thank Richard Schaffer and Judy Herlein for technical assistance and Amgen Inc for supplying leptin.
Received July 31, 2000; first decision August 31, 2000; accepted September 15, 2000.
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B. E. Levin, A. A. Dunn-Meynell, and W. A. Banks Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R143 - R150. [Abstract] [Full Text]
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 A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity Am J Physiol Renal Physiol, October 1, 2003; 285(4): F619 - F628. [Abstract] [Full Text] [PDF]
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A. J. Marsh, M. A.P. Fontes, S. Killinger, D. B. Pawlak, J. W. Polson, and R. A.L. Dampney Cardiovascular Responses Evoked by Leptin Acting on Neurons in the Ventromedial and Dorsomedial Hypothalamus Hypertension, October 1, 2003; 42(4): 488 - 493. [Abstract] [Full Text] [PDF]
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 C. J. Lyon, R. E. Law, and W. A. Hsueh Minireview: Adiposity, Inflammation, and Atherogenesis Endocrinology, June 1, 2003; 144(6): 2195 - 2200. [Abstract] [Full Text] [PDF]
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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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A. Fortuno, A. Rodriguez, J. Gomez-Ambrosi, P. Muniz, J. Salvador, J. Diez, and G. Fruhbeck Leptin Inhibits Angiotensin II-Induced Intracellular Calcium Increase and Vasoconstriction in the Rat Aorta Endocrinology, September 1, 2002; 143(9): 3555 - 3560. [Abstract] [Full Text] [PDF]
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M. Carlyle, O. B. Jones, J. J. Kuo, and J. E. Hall Chronic Cardiovascular and Renal Actions of Leptin: Role of Adrenergic Activity Hypertension, February 1, 2002; 39(2): 496 - 501. [Abstract] [Full Text] [PDF]
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S. J. Swoap Altered leptin signaling is sufficient, but not required, for hypotension associated with caloric restriction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2473 - H2479. [Abstract] [Full Text] [PDF]
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J. L. Mitchell, D. A. Morgan, M. L.G. Correia, A. L. Mark, W. I. Sivitz, and W. G. Haynes Does Leptin Stimulate Nitric Oxide to Oppose the Effects of Sympathetic Activation? Hypertension, November 1, 2001; 38(5): 1081 - 1086. [Abstract] [Full Text] [PDF]
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M. L.G. Correia, D. A. Morgan, J. L. Mitchell, W. I. Sivitz, A. L. Mark, and W. G. Haynes Role of Corticotrophin-Releasing Factor in Effects of Leptin on Sympathetic Nerve Activity and Arterial Pressure Hypertension, September 1, 2001; 38(3): 384 - 388. [Abstract] [Full Text] [PDF]
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