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Neuropeptide Y: Neurotransmitter or Trophic
Factor in the Heart?
Lev Protas,1 Jihong Qu,1 and Richard B. Robinson1,2
1
Department of Pharmacology and 2Center for Molecular Therapeutics, Columbia University, New York, New York 10032
T
he influence of the sympathetic nervous system on both
normal physiology and pathophysiology of the heart
extends beyond the beat-to-beat regulation of rate and contractile force arising from acute exposure to neurally released
norepinephrine (NE). For example, postinfarction arrhythmias
have been ascribed to nerve sprouting and excess sympathetic
innervation (7). In addition, congenital arrhythmias in a German shepherd model of sudden death are associated with an
abnormal distribution and density of sympathetic innervation
as well as excess responsiveness to 1-adrenergic stimulation
(11). These results suggest a long-term influence of innervation
to modify the autonomic sensitivity of the heart and/or the
ionic channels that are the target of those autonomic agonists.
Here we define long-term, or trophic, actions as those appearing only after hours or days of exposure, as opposed to typical
neurotransmitter-like (short-term or acute) actions that occur
over a period of seconds or minutes.
Sympathetic innervation and neuropeptide Y
Abundant data support the general concept that innervation
influences phenotypic expression of target tissue. Examples
include denervation supersensitivity of blood vessels, correlation of cardiac autonomic sensitivity with the time course of
innervation, and induction by motor neuron innervation of a
Na+ channel isoform switch in skeletal muscle. Although there
are multiple trophic factor(s) and signaling cascades through
which innervation acts, in at least some cases neurally
released peptides such as neuropeptide Y (NPY) are involved.
Several studies have identified a trophic role for NPY in the
nervous (6) and vascular (20) systems and in cardiac hypertrophy (2, 9). In addition, we and others (16) have provided evidence that a number of developmental changes in cardiac ion
channel function and autonomic signaling are dependent on
the proper progression of sympathetic innervation. Our results
indicate that neurally released NPY serves as the trophic factor in some of these cases.
NPY is a 36-amino acid peptide that acts through a family
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of G protein-coupled receptors and has been associated with
numerous physiological processes, including feeding, memory, circadian rhythms, and regulation of blood pressure. NPY
is present in, and released from, peripheral sympathetic nerve
terminals. Five NPY receptors have been cloned (Y1, Y2, Y4, Y5,
Y6) and at least one other (Y3) has been suggested on the basis
of pharmacological evidence. Data indicate the presence of
multiple NPY receptors in the heart, including Y1, Y2, Y3, and
Y5. To some extent, these subtypes can be distinguished pharmacologically by the use of peptide fragments of NPY and
peptide analogs, which exhibit varying preferential activity at
the different receptor subtypes. More recently, both peptide
and nonpeptide subtype-selective antagonists have become
available (1).
Acute cardiac actions of NPY
To investigate the long-term effects of NPY, one must first
identify and eliminate from consideration the acute or rapidonset actions. NPY exhibits a variety of acute effects on cardiac
performance, and these involve both prejunctional and
postjunctional sites of action. Prejunctional effects, which
largely relate to reducing the release of both sympathetic and
vagal neurotransmitters, are not further considered here.
Postjunctional inotropic and chronotropic effects of NPY, on
whole heart or strips of tissues, vary with species and preparation. These effects can be contaminated by prejunctional effects
or by slow diffusion of NPY and related compounds toward the
site of action. For this reason, experiments on isolated cardiac
myocytes are more informative, and these have reported acute
actions of NPY on transient outward current (Ito), L-type Ca2+
current (ICa,L), and pacemaker current (If) (3, 4, 10).
NPY (100 nM) enhances the fast component of Ito by 65%
in adult rat ventricular myocytes and abolishes the positive
inotropic response of these cells to -adrenergic stimulation
by isoproterenol (10). Blocking Ito with 4-aminopyridine (0.5
mM) prevents the antiadrenergic inotropic effect of NPY (10).
In the same study, NPY increased peak slow inward current
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Neuropeptide Y (NPY) is released from sympathetic neurons and exerts short-term (acute) effects on
prejunctional nerve terminals and postjunctional cardiac ion channels. However, NPY also
exerts long-term (trophic) effects on angiogenesis, cardiac hypertrophy, autonomic signaling,
and cardiac ion channels, including effects on L-type Ca2+ and pacemaker channels.
(ICa,L) by 51% and (in the presence of 4-aminopyridine but
absence of isoproterenol) increased the contraction of the cell.
The latter effect is eliminated by the Ca2+-channel blocker verapamil. Thus stimulation of Ito mediates the negative inotropic
antiadrenergic effects of NPY, whereas increased ICa,L is probably responsible for the positive inotropic effects. This can
explain why in guinea pig ventricular myocytes, which do not
have significant Ito, NPY evokes a verapamil-sensitive increase
“NPY is also associated with
cardiac hypertrophy.”
NPY and cell growth
NPY exerts an angiogenic effect (20). This has been demonstrated both in vitro and in vivo, and evidence suggests that
the mechanism is largely Y2 mediated, although Y1 receptors
also have been implicated. NPY promotes vessel sprouting
and capillary tube formation by endothelial cells.
NPY also is associated with cardiac hypertrophy. Evidence
for hypertrophic effects of NPY comes from studies of adult rat
cardiac myocytes in culture (2, 9). Twenty-four-hour incubation of 7-day cultures with 10 nM NPY increases total cell protein by 45%, and both decreased protein degradation and
increased synthesis contribute to the hypertrophy. In 1-day
cultures only protein degradation is influenced, and the total
protein increases just 10%. However, in 1-day cultures of cells
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NPY and cardiac autonomic signaling
Prolonged NPY incubation has been reported to increase adrenergic receptor density via a PTX-sensitive pathway in
neonatal rat ventricle cultures (see Ref. 14). However, this is
not associated with increased sensitivity to -adrenergic agonists.
Other evidence demonstrates that neurally released NPY
exerts a trophic effect on cardiac -adrenergic signaling and
in particular on its developmental regulation (16). Neonatal
canine cardiac Purkinje fibers preferentially exhibit a
monophasic positive chronotropic response to -adrenergic
agonists. In comparison, fibers from adult animals exhibit a
biphasic chronotropic response, negative at low doses and
positive at higher doses. Other evidence suggests a temporal
association between onset of the negative chronotropic
response and the ontogeny of cardiac sympathetic innervation
(16). A similar phenomenon is observed in a rat ventricular
septal preparation, which provides additional in vivo evidence
of the link between sympathetic innervation and a negative
chronotropic -adrenergic response. Ventricular septal preparations were studied on postnatal day 10 following daily injection of NGF or NGF antibody to accelerate or delay the onset
of sympathetic innervation, respectively. Relative to a vehicle
group, the percentage of preparations exhibiting a negative
chronotropic -adrenergic response is smaller in the NGF
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in contractility but does not reduce the positive inotropic
response evoked by isoproterenol. It should be noted, however, that in other studies (3) on guinea pig ventricular
myocytes, ICa,L was reduced by 100 nM NPY; this effect is sensitive to pertussis toxin (PTX) and nonhydrolyzable GTP
analogs. The two opposing inotropic effects of NPY in adult rat
cardiac myocytes are mediated by different NPY receptor subtypes: positive effects by Y1 and negative effects by Y2 receptors. Moreover, different intracellular signaling pathways
appear to be involved because only the negative effect is PTX
sensitive.
The effect of NPY on If was studied in isolated canine Purkinje fibers. NPY (200 nM) reduces the current, and this effect
is inhibited by the NPY antagonist NPY-(1836). NPY acts by
shifting If activation to more negative potentials. These results
indicate that NPY may affect heart rate by decreasing If. They
also are interesting because, as with prejunctional actions of
NPY, the effect would be to mitigate the action of coreleased
NE. However, there are no published data on the effect of NPY
on the primary pacemaker (sinus node) of the heart.
The best-characterized signaling pathway for the acute
effects of NPY in cardiac myocytes is inhibition of adenylyl
cyclase by stimulation of PTX-sensitive G protein(s) and
reduction of cAMP level (basal or -adrenergic stimulated). An
alternative pathway has been proposed (18) that includes
interaction with Y1 or Y2 receptors, inhibition of PTX-insensitive Gq protein, and reduction of inositol 1,4,5-trisphosphate
formation.
obtained from adult spontaneously hypertensive rats, 24-h
incubation with NPY produces hypertrophy by increasing protein synthesis. The effect is age dependent, with a maximum
(20% increase of de novo protein synthesis) observed in cells
from 16-wk-old animals. This dependence of the hypertrophic
effect of NPY on the “history” of the pathological condition
and the finding of an increased level of NPY in patients with
cardiac hypertrophy and heart failure indicate that NPY may
contribute to development of hypertrophy in the course of
some heart diseases. In addition, NPY can potentiate the effect
of NE to produce hypertrophy in adult and neonatal cardiac
myocytes in culture.
The hypertrophic effect of NPY is accompanied by
increased activity of cytosolic creatine kinase (CK) and completely or partially abolished by PTX (5, 9, 19). Short-term
exposure (15 min) to NPY induces activation of PKC and PKCdependent activation of MAPK in adult and neonatal myocyte
cultures and activation of phosphoinositol 3-kinase (PI3K) in
adult cultures. In adult cultures, inhibition of PI3K or inhibition of p70s6k (a downstream target of PI3K) prevents NPYinduced hypertrophy. At the same time, NPY-induced MAPK
activation in these cells is not affected by PTX. These findings
suggest that the PI3K/p70s6k pathway, rather than the
PKC/MAPK/CK pathway, participates in the hypertrophic
effect of NPY. On the other hand, PMA abolishes the effect of
NPY in neonatal cardiac cultures, indicating that in this model
PKC and MAPK may be involved
Experiments using selective NPY agonists and antagonists
suggest that the hypertrophic effect of NPY in cardiac
myocytes isolated from spontaneously hypertensive rats is
mediated by Y5 receptors (2).
myocytes in the presence of nerve-conditioned medium, suggesting that any neurally released trophic factor is not present
in the bulk medium in significant quantity. However, the effect
of innervation is reproduced by maintaining the neonatal
myocytes in culture for several days in the sustained presence
of NPY (Fig. 1). NPY-treated cultures exhibit a predominantly
negative chronotropic response to the -adrenergic agonist
phenylephrine, whereas control cultures exhibit a positive
chronotropic response. There is no effect of short-term NPY
exposure on the percentage of cultures exhibiting a positive or
negative chronotropic response to a fixed concentration (108
M) of phenylephrine, but 96-h NPY exposure fully mimics the
effect of innervation. In addition, long-term but not short-term
exposure of innervated cultures to an NPY antagonist prevents
the effect of innervation on -adrenergic chronotropy (17).
The 1B-adrenergic receptor is the subtype responsible for the
negative chronotropic response in NPY-treated rat ventricle
cultures, the same subtype previously associated with negative chronotropy in the intact rat ventricle (16). Data generated
by using a series of NPY peptide analogs suggest that the NPY
Y2 receptor is the subtype likely mediating the trophic effect of
NPY on -adrenergic signaling in the neonatal rat ventricle
This same study, by using a series of NPY peptide analogs, provided data suggesting that the NPY Y2 receptor is the subtype
likely mediating the trophic effect of NPY on -adrenergic signaling in the neonatal rat ventricle.
The evidence indicates that, during postnatal development,
sustained release of NPY from sympathetic nerve terminals
acts on NPY Y2 receptors to modify -adrenergic signaling.
This results in the functional availability of a PTX-sensitive 1Badrenergic signaling cascade. Both the 1B-adrenergic receptor and PTX-sensitive G proteins are present in the neonatal rat
heart but are not well coupled before innervation.
NPY and ICa,L
FIGURE 1. Innervation or neuropeptide Y (NPY) alters -adrenergic
chronotropic response in neonatal rat ventricle cultures. Top: incubation of
myocytes for several days results in appearance of a negative chronotropic
response to the -adrenergic agonist phenylephrine. Bottom left: with
increasing incubation time in NPY, a progressively greater percentage of noninnervated muscle (M) cultures exhibit a negative chronotropic response to
phenylephrine. Bottom right: innervated (NM) cultures also exhibit a negative
chronotropic response to phenylephrine, which is prevented if the cultures
are incubated with an NPY antagonist {Ac-[3(2-6-dichlorobenzyl)-Tyr27,36,DThr32]NPY-(2736); PYX} for 96 h but not when the incubation is only 0.5 h.
Adapted from Ref. 17.
Another developmental change that can be reproduced by
sympathetic innervation of neonatal ventricle myocytes in culture involves ICa,L. Current density and channel protein level
increase postnatally, and current density is greater in sympathetically innervated neonatal ventricle cells in culture than in
noninnervated myocytes (12, 14). -Adrenergic receptor activation increases dihydropyridine binding (an index of channel
density) and transcription of the 1C-subunit of the L-type Ca2+
channel (8), consistent with the effect of in vitro innervation
being mediated by NE acting at -adrenergic receptors. However, sustained incubation of neonatal myocytes with NPY in
culture fully mimics the effect of sympathetic innervation on
ICa,L density. Furthermore, sustained incubation of innervated
cultures with an NPY antagonist fully prevents the effect of
innervation (Fig. 2) (14). These data argue that NPY, rather than
NE, is the relevant trophic factor released from sympathetic
neurons in vitro.
As in the case of -adrenergic signaling, the effects of innervation and NPY in cell culture are intriguing but require in vivo
confirmation of physiological significance. Such evidence has
recently been obtained by taking advantage of a transgenic
mouse in which the gene for NPY has been disrupted (13). AniNews Physiol Sci • Vol. 18 • October 2003 • www.nips.org
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antibody group and greater in the NGF group (16).
Neonatal rat ventricular cells maintained in primary culture
are a convenient preparation for studying the role of sympathetic innervation because the rat ventricle is not sympathetically innervated before birth and neonatal myocytes are readily maintained in short-term cell culture, beat spontaneously
in culture, and can be innervated in vitro by neurons dissociated from the paravertebral sympathetic chain (16). Noninnervated neonatal rat ventricular myocytes in culture exhibit an
exclusively positive chronotropic response to -adrenergic
agonists, whereas approximately two-thirds of innervated cultures exhibit a negative chronotropic response. The negative
chronotropic response observed after in vitro innervation is
lost when the cultures are treated with PTX, suggesting that the
inhibitory -adrenergic signaling cascade is mediated by a
PTX-sensitive G protein. Other studies (16) demonstrate that
the positive and negative chronotropic responses in rat ventricle are associated with distinct -adrenergic receptor subtypes.
This cell culture system was used to identify NPY as the
trophic signal released by the sympathetic nerves. The effect of
sympathetic innervation is not reproduced by growing
mals that are homozygous for the disruption lack endogenous
NPY. When ventricular myocytes are isolated and studied from
these animals and strain-matched control animals, there is no
postnatal increase in ICa,L density in NPY-deficient animals.
Adult myocytes from these mice exhibit ICa,L density that is not
only less than that of the control cells but identical to current
density in neonatal cells of both the control and NPY-deficient
mice. This indicates that the influence of NPY on ICa,L in vivo is
entirely postnatal (since newborn control and NPY-deficient
ICa,L current-voltage curves are identical) and that NPY is the
only contributor to the postnatal increase in ICa,L density (since
newborn and adult current density in the NPY-deficient
myocytes are identical). Furthermore, the 68% increase in ICa,L
density of control vs. NPY-deficient cells in this in vivo mouse
model is remarkably similar to the effect observed in vitro in rat
myocytes, either as a result of sympathetic innervation or sustained exposure to NPY (see Fig. 2).
nervated cells in the combined presence of both NPY and NE
(15). Experiments with various pharmacological agents suggest that the NE action is -adrenergically mediated and that
both the NPY receptor subtype and -adrenergic receptor
subtype are the same as those implicated in developmental
maturation of the negative chronotropic -adrenergic
response.
This led to the hypothesis that the requirement for NPY and
NE is actually sequential rather than simultaneous. The reasoning is that chronic exposure to NPY, most likely acting via
the Y2 receptor, results in the functional availability of the 1Badrenergic cascade, which is then chronically activated by
NE. Therefore, sequential exposure to NPY followed by NE
should mimic the effect of innervation, but sequential exposure to NE followed by NPY should be ineffective. As pre-
NPY and If
If is present throughout the heart and exhibits marked variation in voltage dependence with cardiac region, age, and disease. Activation threshold varies by >80 mV between sinoatrial node, where activation is relatively positive, and ventricle. Adult ventricle activation threshold occurs negative to the
cell’s resting potential, so that the channel is physiologically
silent. However, with cardiac disease ventricular activation is
observed within the physiological range, where it may contribute to arrhythmogenesis. It thus becomes important to
understand the regulatory processes controlling voltage
dependence of If, and since the channel also activates at lessnegative potentials in neonatal ventricle, clues may be found
in studies of development.
Using the cell culture model of innervation described earlier, it was found that sympathetic innervation shifts If activation negative by ~20 mV. This effect of innervation cannot be
reproduced by incubating noninnervated cells in either NPY
or NE. However, it can be reproduced by incubating nonin184
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FIGURE 3. Innervation or NPY+NE shifts pacemaker voltage dependence in
neonatal rat ventricle cultures. Average If activation curves from noninnervated control muscle cultures (M), innervated muscle cultures (NM), and cultures exposed first to NPY and then norepinephrine (M+NPYNE). The solid
lines are the Boltzmann fit to the experimental data. Midpoint of activation
(V1/2) values are 77, 88, and 91 mV, respectively. NE and NPY concentrations were 107 M. The V1/2 of M differs significantly from that of M+N or
M+NPYNE. Adapted from Ref. 15.
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FIGURE 2. Innervation or NPY increases ICa,L density, and an NPY antagonist prevents the effect of innervation in neonatal rat ventricle cultures. Current-voltage
relation was constructed from nifedipine-sensitive currents. Curves are normalized to the maximal peak value obtained from the smaller curve in each panel.
Left: noninnervated control (M) cells vs. innervated (NM) cells. Middle: noninnervated control cells vs. cells incubated with NPY (100 nM) for 7296 h. Right:
innervated cells incubated in the presence or absence of an NPY antagonist (T4-[NPY-(3336)]4; 350 nM) for 7296 h. Maximal current density increased significantly by 63, 51, and 71% at left, middle, and right, respectively. Adapted from Ref. 14.
the trophic actions of NPY also remain to be determined, but
in most cases studied to date the Y2 or Y5 NPY receptor
appears to be involved.
References
dicted, when neonatal myocytes are incubated in culture with
NPY for 23 days, followed by removal of the NPY and subsequent 2- to 3-day incubation with NE, the If activation curve
shifts negative and is comparable with that observed after in
vitro innervation (Fig. 3). When the order of incubation with
NPY and NE is reversed, there is no effect. The signaling pathways involved in this developmental regulation of If, as well as
that for the earlier-described regulation of ICa,L, are schematically illustrated in Fig. 4.
Conclusion
The role of innervation to regulate heart rate and force on a
beat-to-beat basis is well established. More recently, attention
has focused on the long-term influence of innervation and its
disruption in the setting of cardiac disease. In this context, it
becomes important to understand both the short- and longterm effects of not only the traditional neurotransmitters but
also the other substances present in and released from nerve
terminals within the heart. NPY is the major neuropeptide in
sympathetic nerve terminals, and it clearly possesses trophic
actions on cell growth (angiogenesis and cardiac hypertrophy), autonomic signaling cascades, and cardiac ion channel
function. At least some of these effects contribute to the normal phenotypic development of the heart, but their contribution to pathological cardiac remodeling remains to be determined. The details of the signaling cascade(s) contributing to
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FIGURE 4. Schematic representation of trophic actions of neurally released
NPY on -adrenergic signaling, L-type Ca2+ channels, and pacemaker f channels. Chronic release of NPY from sympathetic nerve terminals results in two
distinct trophic actions: 1) an increase in L-type Ca2+ current density and 2)
functional expression of an -adrenergic signaling cascade whose acute activation is linked to negative chronotropy. Once this -adrenergic signaling
cascade has been rendered functionally available by long-term exposure to
NPY, chronic activation of the cascade by norepinephrine leads to a third
trophic effect, modification of the voltage dependence of pacemaker f channels.
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