Download Central Neuropeptide Y Signaling Ameliorates N

Central Neuropeptide Y Signaling Ameliorates
N(␻)-Nitro-L-Arginine Methyl Ester Hypertension in the Rat
Through a Y1 Receptor Mechanism
Mieczyslaw Michalkiewicz, Guiqing Zhao, Zhen Jia, Teresa Michalkiewicz, Mae J. Racadio
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Abstract—Neuropeptide Y is a potent inhibitory neurotransmitter expressed in the central neurons that control blood
pressure. NO also serves as an inhibitory neurotransmitter, and its deficit causes sympathetic overactivity, which then
contributes to hypertension. This study tested the hypothesis that neuropeptide Y functions as a central neurotransmitter
to lower blood pressure, therefore its increased signaling ameliorates hypertension induced by NO deficiency. Conscious
neuropeptide Y transgenic male rats, overexpressing the peptide under its natural promoter, and nontransgenic
littermates (controls) were used in this study. Neuropeptide Y, Y1 receptor antagonist BIBP3226, or vehicle (saline)
were administered continuously for 14 days into the cerebral lateral ventricle in unrestrained animals using osmotic
pumps. Blood pressure was measured by radiotelemetry. Compared with control animals, transgenic overexpression of
neuropeptide Y significantly ameliorated (by 9.7⫾1.5 mm Hg) NO deficiency hypertension (induced by administration
of N(␻)-nitro-L-arginine methyl ester in the drinking water). This hypotensive effect of neuropeptide Y upregulation was
associated with reduced proteinuria and cardiac hypertrophy and fibrosis. Central administration of neuropeptide Y in
nontransgenic rats also reduced (by 10.2⫾1.6 mm Hg) the NO deficiency hypertension, whereas a neuropeptide Y1
receptor antagonist centrally administered in the transgenic subjects during NO deficiency hypertension completely
attenuated the depressor effect of neuropeptide Y upregulation. Thus, acting at the level of the central nervous system
distinctively via a Y1 receptor–mediated mechanism, endogenous neuropeptide Y exerted a potent antihypertensive
function, and its enhanced signaling ameliorated NO deficiency hypertension. (Hypertension. 2005;45[part
2]:780-785.)
Key Words: hypotension 䡲 central nervous system 䡲 sympatholytics 䡲 catecholamines
䡲 rats, transgenic 䡲 nitric oxide
N
physiological role of a buffering neurotransmitter within the
central nervous system (CNS), and that its increased signaling
will ameliorate chronic hypertension induced by NO deficiency.
We chose the N(␻)-nitro-L-arginine methyl ester (L-NAME)–
induced NO deficiency hypertension because it is a commonly
used hypertension model because of (among others) overactivity
of the central sympathetic nervous system14 –17 and a close
anatomic coexistence of NPY with NO signaling system in the
sympathetic nuclei of the brain,1– 4,14 –17 indicating functional
cooperation between NPY and NO signaling systems in BP
regulation.18,19
The goal of this study was to elucidate the role of
endogenous NPY in the long-term regulation of BP. Specifically, we aimed to: (1) determine the effect of transgenic
upregulation of NPY on L-NAME hypertension in the rat; (2)
establish whether this effect takes place in the CNS; and (3)
identify the NPY receptor subtype involved in this effect.
europeptide Y (NPY) is extensively expressed in the
central neural circuits, which control blood pressure
(BP). Namely, NPY-containing neurons are present in the
paraventricular nucleus (PVN) of the hypothalamus, the
ventrolateral medulla (VLM), the nucleus of tractus solitari
(NTS), the presynaptic bulbospinal neurons of the brain stem,
and in the sympathetic fibers innervating blood vessels.1–5
This peptide elicits a wide variety of physiological effects,
including stimulation of feeding, sodium secretion, and reduction of sympathetic activity and behavioral stress.5–10 Four
subtypes of NPY receptors, Y1, Y2, Y4, and Y5, are
expressed in the rat brain, but the density of the Y1 seems to
predominate over the other subtypes.1–3
Considering the dense distribution of NPY within the cardiovascular neural centers, its colocalization with other excitatory
neurotransmitters, including norepinephrine or glutamate, and
inhibitory activity on the release of these neurotransmitters,11–13
we reasoned that this peptide is well positioned to play the
Materials and Methods
This study was reviewed and approved by the Medical College of
Wisconsin committee on animal care and use.
Received October 12, 2004; first decision November 5, 2004; revision accepted December 9, 2004.
From the Department of Physiology, Human Molecular and Genetic Center, Medical College of Wisconsin, Milwaukee.
G.Z. and Z.J. contributed equally to this study.
Correspondence to Mieczyslaw Michalkiewicz, DVM, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, PO
Box 26509, Milwaukee, WI 53226-0509. E-mail [email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000153953.69799.f2
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Depressor Effect of Central Y1 Receptor
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Animals
NPY transgenic (NPY-tg) Sprague Dawley male rats carrying 5
copies of the genomic rat NPY transgene (line no. 400) and
nontransgenic littermates (wild-type control)20 –24 were used. Animals were individually housed in a temperature-controlled (21°C to
22°C) and light/dark cycle– controlled (lights on 6:00 AM to 6 PM)
room and were provided with 5001 LabDiet chow and water ad
libitum. All surgeries were done under anesthesia with intraperitoneal injections of ketamine (75 mg/kg⫺1) and xylazine (7.5 mg/kg⫺1).
Radiotelemetry
Mean arterial pressure (BP), heart rate (HR), and locomotor activity
of the animals were measured by 24-hour radiotelemetry (Data
Sciences, Inc.) as described previously.24 Telemetry transmitters
(TA11PA-C40) were implanted subcutaneously (under anesthesia),
and a catheter was inserted into the abdominal aorta via the femoral
artery. Animals were allowed to recover for 7 to 9 days.
Experiment 1: Pressor Response to L-NAME in
NPY-tg and Wild-Type Rats
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After completion of a 3-day baseline recording, rats received
L-NAME in drinking water ad libitum at a concentration of 100 mg/L
for 7 days. Then, for the next 9 days, the dose of the NO inhibitor
was increased to 200 mg/L. Subsequently, animals were transferred
to metabolic cages for 2 days, while continuously receiving the
higher dose of the NO inhibitor, to collect urine for protein assay.
Urine protein concentrations were determined by the Bradford
method (Bio-Rad Laboratories) using BSA as the standard. For
histological assessment, hearts fixed in a 5% formalin solution were
embedded in paraffin, sectioned, stained with Mason’s trichrome
stain, and examined by light microscopy. Each heart was sectioned
at its midpoint to ensure that sections were taken from an anatomically consistent site. The area of the left ventricular wall and the
degree of its interstitial fibrosis were then measured using a digital
imaging program.
Experiment 2: Effect of NPY and the Y1 Receptor
Antagonist BIBP3226 on Pressor Response to
L-NAME in the 2 Strains of Rats
A chronic cannula was implanted into the lateral cerebral ventricle (intracerebroventricularly) in an anesthetized rat using a Kopf
stereotaxic apparatus according to procedures described previously.25 Briefly, a stainless-steel 12-mm 23-gauge guide cannula was
implanted into the right intracerebroventricular on the bregma
line, 1.4 mm lateral from the midline and 3 mm below the surface
of the skull. At the same time, telemetry transmitters were
implanted. After recovery and 3 days of baseline BP recording, a
stainless 15.5-mm 30-gauge injection cannula was inserted into
the guide cannula, and synthetic rat NPY (7.0 nmol/kg per day in
saline), NPY receptor Y1 receptor antagonist BIBP3226 (63.3
nmol/kg per day in saline), or saline (vehicle) was continuously
delivered for 14 days using a subcutaneously implanted Alzet
osmotic pump (model 2002; infusion rate, 0.5 ␮L/hr). The doses
of NPY and BIBP3226 were chosen on the basis of their
effectiveness to increase or abolish food intake, respectively, in
rat.26,27 Animals were given L-NAME in drinking water (200
mg/L) at the same time. The correct placement of each cannula
was confirmed at the end of the experiment by methylene blue
staining and microtome section of the brain.
Data Analysis
Data are presented as means⫾SE. The statistical methods used are
indicated in each figure legend. A P-value ⬍0.05 was considered
statistically significant.
Results
Transgenic Upregulation of NPY Ameliorated
L-NAME Hypertension, Protecting the Heart and
Kidney (Experiment 1)
In the control animals, BP increased in a dose-dependent
manner in response to the increasing doses of L-NAME
Figure 1. Effects of L-NAME on BP (A) and HR (B) in conscious
NPY-tg rats and nontransgenic (wild-type) littermates. The
radiotelemetry signals were recorded for 10 seconds, every 2
minutes, continuously from several animals simultaneously. Data
were averaged over 24-hour intervals. Two-way repeatedmeasures ANOVA (1-factor repetition) with Tukey’s post hoc
test were used to determine the effect of genotype on the variables for each period (n⫽10 to 11). There was a statistically significant (P⬍0.05) interaction between the genotype and the
treatment. On days 18 and 19, animals were transferred to metabolic cages, and telemetry was not performed. *Statistically,
these were significantly lower compared with wild-type rats at
the same time point.
(Figure 1A). BP was significantly (P⬍0.05) raised
(131.0⫾2.3 mm Hg) from the baseline measurement during
administration of 100 mg/L of the inhibitor, and it gradually
rose higher in response to doubling the dose of L-NAME,
reaching a level of 155.3⫾3.3 mm Hg.
Compared with the control subjects, the pressor response
of the NPY-tg rats to 100 mg/L L-NAME was significantly
(P⬍0.05) lower (122.7⫾2.2 mm Hg). Moreover, unlike the
nontransgenic controls, the higher dose of L-NAME had no
additional pressor effect on these subjects. In both groups,
after cessation of drug administration, BP decreased gradually, reaching the basal level 4 to 5 days after stopping the
treatment, confirming that the pressor response was specifically related to the treatment with NO synthase inhibitor.
HR was reduced during L-NAME treatment in both strains
of rats (Figure 1B), but there was a statistically significant
(P⬍0.05) difference between the genotypes. Although the
bradycardia of the NPY-tg subjects remained steady during
the treatment, the HR of the wild-type rats gradually in-
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TABLE 1. Effects of Treatment With L-NAME on Selected Indices of Metabolism
in NPY-tg Rats and Nontransgenic (Wild-Type) Littermates
Basal
Wild-Type
Basal
NPY-tg
L-NAME
Wild-Type
L-NAME
424.7⫾30.9
395.9⫾33.8
434.7⫾18.9
429.3⫾18.7
Food intake, g/day
22.4⫾0.8
21.9⫾0.4
22.7⫾1.2
23.3⫾0.6
Water intake, g/day
29.8⫾2.1
33.6⫾2.2
53.7*⫾2.1
51.6*⫾1.9
Urine output, mL/day
12.8⫾1.1
12.9⫾1.1
19.7*⫾1.4
18.1*⫾0.6
Proteinuria, mg/24 hours
49.9⫾5.77
51.8⫾6.6
129.0*⫾21.2
65.0†⫾6.5
Heart weight, % of body weight
0.23⫾0.01
0.22⫾0.01
0.28*⫾0.01
0.24†⫾0.01
Variable
Body weight, g
2
NPY-tg
Left ventricle wall, mm
56.8⫾1.3
55.9⫾1.3
61.9*⫾2.03
55.2†⫾1.3
Cardiac fibrosis, % of wall area
0.18⫾0.05
0.14⫾0.01
1.13*⫾0.41
0.56†⫾0.07
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Two-way repeated measures ANOVA (1-factor repetition) with Tukey’s post hoc test was used to
determine the effect of genotype on the variables in baseline and during treatment with L-NAME.
The cardiac-related variables were compared by 2-way ANOVA with Tukey’s post hoc test.
*, †Statistically significantly difference between the treatments within the strain or between the
strains within the treatment, respectively. n⫽10 to 11, except for the left ventricle wall and cardiac
fibrosis areas, where 5 to 6 animals were used.
creased, starting on day 4 of the higher dose. Like BP, the HR
response completely reversed in both strains after stopping
the treatment.
The heart weight and the left ventricular wall size of the
NPY-tg rats treated with L-NAME were smaller (P⬍0.05)
than those of the nontransgenic littermates (Table 1). In
addition, NPY overexpression reduced the development of
cardiac fibrosis and proteinuria because of L-NAME hypertension. In the basal state, these cardiac and renal indices
were not different between the strains (Table 1). Body
weight, food intake (Table 1), and locomotor activity (data
not shown) did not differ between the 2 strains and were not
affected by the L-NAME treatment.
Central NPY Ameliorated the L-NAME
Hypertension Involving a Y1 Receptor Mechanism
(Experiment 2)
Treatment with L-NAME resulted in a significant increase
in BP in all groups (Figure 2A). Consistent with the results
of experiment 1, L-NAME hypertension was significantly
reduced (P⬍0.05) in the NPY-tg subjects when compared
with wild-type rats (122.7⫾1.5 versus 132.4⫾1.6 mm Hg,
respectively). Likewise, centrally given NPY in wild-type
rats reduced L-NAME hypertension compared with treatment with vehicle (122.2⫾1.7 versus 132.4⫾1.6 mm Hg,
respectively; P⬍0.05). Interestingly, the magnitude of the
reduction of L-NAME hypertension in response to intracerebroventricular administration of NPY was similar to the
reduction of hypertension observed in the NPY-tg rats.
In contrast, for the NPY-tg rats treated intracerebroventricularly with the NPY receptor Y1 antagonist BIBP3226, the
L-NAME hypertension was significantly higher than in the
NPY-tg animals treated intracerebroventricularly with vehicle (132.7⫾1.7 versus 122.7⫾1.5, respectively; P⬍0.05). In
fact, the L-NAME hypertension in this group was as high as
that observed in the wild-type animals treated intracerebroventricularly with vehicle. Thus, intracerebroventricular administration of a specific Y1 receptor antagonist completely
attenuated the depressor effect of transgenic NPY upregulation in L-NAME hypertension.
Treatment with L-NAME produced substantial bradycardia
(P⬍0.05) in all groups, which tended to decrease in the
second week of treatment. Chronic intracerebroventricular
administration of NPY temporarily reduced the HR in the
wild-type rats (Figure 2B). This treatment also resulted in
increased body weight gain and water intake and reduced
locomotor activity (Table 2). The increase in water intake in
this group, which also increased L-NAME intake, was most
likely secondary to the increased food intake because of
central NPY administration. However, this higher L-NAME
intake did not prevent the depressor effect of intracerebroventricular NPY infusion because the BP was lowest in this
group.
Discussion
The novel observation from this study was that transgenic
overexpression of NPY under its natural promoter in the rat
significantly ameliorated L-NAME hypertension. A similar
effect was demonstrated during long-term intracerebroventricular infusion of synthetic NPY in the wild-type rats.
Furthermore, the present work demonstrated that the hypotensive effect of enhanced NPY signaling was mediated by
the central Y1 receptor subtype because the ameliorating
effect of transgenic overexpression was completely blocked
by intracerebroventricular administration of the specific Y1
receptor antagonist BIBP3226. Thus, we can report that the
Y1 receptor is a potent antihypertensive receptor of the CNS.
In the present study, we used transgenic rats overexpressing NPY under its natural promoter, telemetry for continuously monitoring BP in a conscious state, and chronic NPY
receptor ligand delivery using osmotic pumps. This approach
allowed us to assess the role of endogenous NPY in long-term
control of BP under experimental conditions that excluded
complications associated with anesthesia, restraint, and shortterm drug administration.
Michalkiewicz et al
Depressor Effect of Central Y1 Receptor
783
TABLE 2. Effects of Chronic Intracerebroventricular
Administration of Synthetic NPY in Conscious Wild-Type Rats
or NPY Receptor Y1 Antagonist BIBP3226 in NPY-tg Rats on
Body Weight Change, Water Intake, and Locomotor Activity
During Treatment With L-NAME
Treatment
Wild⫹Vehicle (7)
Wild⫹NPY (8)
Body
Weight
Change, g
Water
Intake,
g/day
Locomotor
Activity,
Arbitrary Units
6.0⫾9.1
51.4⫾3.1
2.27⫾0.09
23.9*⫾10.2
66.1†⫾5.8
1.73‡⫾0.09
NPY-tg⫹Vehicle (10)
⫺13.5⫾7.2
54.5⫾3.0
2.14⫾0.08
NPY-tg⫹BIBP3226 (9)
⫺13.7⫾9.2
51.0⫾2.2
1.97⫾0.08
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Values are mean⫾SE.
Body weight change is the difference between the last and the first day of
treatment.
One-way ANOVA was used to determine the effect of treatment on body
weight, water intake, and activity.
*Statistically significant difference between NPY-tg⫹Vehicle and NPYtg⫹BIBP3226 groups; †different from NPY-tg⫹BIBP3226 and wild-type
(Wild)⫹Vehicle groups; ‡different from Wild⫹Vehicle and NPY-tg⫹Vehicle
groups.
Numbers of animals are indicated in parentheses.
Figure 2. Effects of chronic intracerebroventricular administration of synthetic NPY in conscious wild-type rats or NPY receptor Y1 antagonist BIBP3226 in NPY-tg on BP (A) and HR (B)
during treatment with L-NAME. BP was measured and data statistically analyzed as described in the Figure 1 legend. *Statistically, these were significantly lower compared with wild-type
plus vehicle (Wild⫹Veh; 7) and NPY-tg⫹BIBP3226 groups (9).
#Statistically, these were significantly higher compared with
NPY-tg⫹Veh (10) and Wild⫹NPY (8) groups. Numbers of animals are indicated in parentheses.
The present finding is coherent with anatomic and
functional reports that indicate potent sympatholytic and
hypotensive functions of central NPY signaling. The
peptide and its Y1 receptor subtype are expressed in the
central neurons participating in the processing of cardiovascular signals, including the PVN, NTS, VLM, and in
the presynaptic bulbospinal neurons.1–5 On the basis of its
ability to inhibit the neuronal excitability and the release of
excitatory neurotransmitters, NPY is considered a potent
inhibitory neurotransmitter of the CNS.7–13,28 Microinjections of NPY into the PVN or intracerebroventricularly
reduced the release of norepinephrine, peripheral sympathetic nerve activity, HR, and BP.7–10 Compared with
wild-type rats, the concentrations of NPY in the CNS,
including the hypothalamic nuclei, were significantly in-
creased in the NPY-tg subjects used for the present
study.21,22,24 The phenotypes of these NPY-tg rats reported
previously, including reduced BP and sympathetic drive to
the blood vessels, lower catecholamines, diminished behavioral and pressor responsiveness to acute stress, and
enhanced vascular response to exogenous norepinephrine,
point to a potent sympathoinhibitory effect of transgenic
NPY upregulation.21–24 NO is also a potent sympatholytic
and depressor neurotransmitter of the CNS.14 –17,19
L-NAME, when administered systemically, crosses the
blood– brain barrier and inhibits NO production in the
brain.16 The resulting increased sympathetic outflow is an
important component of L-NAME hypertension.14 –17
Thus, it is very likely that in the present experiment, Y1
receptor–induced reduction of sympathetic outflow underlies
the mechanism of ameliorated L-NAME hypertension by
central NPY.
It has been demonstrated that NPY-producing neurons
of the rat hypothalamus make synaptic contact with NO
neurons that express the Y1 receptor,3 and that stimulation
of this receptor enhances NO production in the rat hypothalamus and cerebral cortex.3,29,30 Thus, it seems reasonable to suggest that the depressor effect of NPY in the
present experiment was a result of its direct interaction
with the NO-producing neurons. NPY-induced NO production might be possible despite treatment with L-NAME
because although this drug easily crosses the blood– brain
barrier,16 it may not completely block the neuronal NO
synthase in the brain. In addition, in the present experiment, increased NPY could compensate for NO deficiency
in another way by inhibiting the activity of NO-receptive
neurons in the circuits controlling sympathetic outflow.
Such compensation seems possible because NO and NPY
are inhibitory neurotransmitters and are synthesized together within the same neural circuits, perhaps affecting
the same neurons.1,4,14,15,17
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The disappearance of L-NAME–induced bradycardia in the
wild-type but not in the NPY-tg rats (experiment 1) indicates
that an increased sensitivity of the baroreceptor reflex in the
transgenic animals might partially contribute to the attenuated
L-NAME hypertension in this group. Indeed, treatment with
NPY increased sensitivity of the baroreceptor reflex in the
rat,5 and this could also explain the enhanced bradycardia in
the wild-type animals treated intracerebroventricularly with
synthetic NPY (experiment 2).
We also report that NPY overexpression reduced L-NAME–
induced hypertrophy of the heart and diminished the extent of
cardiac fibrosis. In addition to its cardioprotective effect, NPY
also reduced urinary excretion of protein in the NPY-tg rats
treated with the NO synthase inhibitor. These observations are
very consistent with the increased longevity of these transgenic
rats.24 It is likely that the lower BP contributed to the reduction
of cardiac damage and proteinuria in the NPY-tg subjects treated
with L-NAME.
Food intake and body weight were not affected by
transgenic overexpression of NPY. This observation was in
contrast to the known orexigenic effect of exogenous
NPY6 and the increased body weight gain and water intake
induced by infusion of synthetic NPY in the present study.
The increased water intake in this group was most likely
secondary to the increased food intake. The lack of body
weight phenotype in this transgenic rat22,24 is consistent
with the reported NPY and Y1 receptor knockout experiments in mice, in which body weight and appetite were
also unaffected.31,32
In conclusion, this study demonstrates that increased NPY
expression in the NPY-tg rat significantly ameliorated
L-NAME hypertension and protected the heart and kidney
from hypertension-induced left ventricular hypertrophy and
proteinuria, respectively. Furthermore, we have established
that the CNS is the major site of the antihypertensive function
of endogenous NPY, and that this effect is specifically
mediated by the Y1 receptor subtype. Thus, central Y1
receptor signaling emerges as an endogenous buffering mechanism responsible for reducing BP and conferring protection
of the cardiovascular system and end organs during NO
deficiency.
Perspectives
The results presented here suggest that endogenous NPY
functions within the CNS to protect the cardiovascular
system in situations of chronic hyperexcitation and hypertension. This buffering function could be particularly
important in states of chronic hyperactivity and neural
hypertension, including chronic psychosocial anxieties,
NO deficiency, or heart failure. The mechanism underlying
the antihypertensive and organ-protective activities of
NPY may stem from the peptide neuroinhibitory properties
and may involve interaction with other signaling pathways,
including adrenergic or NO, leading to sympathoinhibition
and lowering BP. In addition, there is a significant
possibility that NPY may also directly stimulate NO
production in the central neurons involved in cardiovascular regulation.
Acknowledgments
This study was supported by National Institutes of Health grant
HL-57921. We thank Drs Leon F. Tseng and Thom R. Feroah for
help with chronic intracerebroventricular infusion, Glenn R. Slocum
for assistance with digital microscopy, and Beverly Ventura for
editing this manuscript.
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Central Neuropeptide Y Signaling Ameliorates N(ω)-Nitro-l-Arginine Methyl Ester
Hypertension in the Rat Through a Y1 Receptor Mechanism
Mieczyslaw Michalkiewicz, Guiqing Zhao, Zhen Jia, Teresa Michalkiewicz and Mae J. Racadio
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Hypertension. 2005;45:780-785; originally published online February 7, 2005;
doi: 10.1161/01.HYP.0000153953.69799.f2
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