Clin. Cardiol. Vol.
21 (Suppl I), 1-20-1-24 (1998)
The Effects of Norepinephrine on Myocardial Biology: Implications for the
Therapy of Heart Failure
WIISONS. Co~uccr,M.D.
The Myocardial Biology Unit and Cardiomyopathy Program, Boston University School of Medicine and the Cardiovabculx Division.
Boston University Medical Center, Boston. Massachusetts, USA
Summary: Increased sympathetic nervous system (SNS)
activity in patients with heart failure may help to support
cardiovascular function. However, increased SNS activity,
particularly if prolonged, may exert deleterious effects on
cardiovascular structure and function by stimulating path-
ologic myocardial remodeling. In vitro, norepinephrine
mimics many features of myocardial remodeling, including
hypertrophy of individual myocytes and reinduction of fetal
genes. Furthermore, stimulation of the beta-adrenergic path-
way has been shown to stimulate apoptosis of cardiac my-
ocytes in vitro, in rats infused with isoproterenol, and in mice
that overexpress the stimulatory G-protein, G,. Thus, in-
creased SNS activity, acting via beta-adrenergic receptors,
may play an important role in the progression of myocardial
failure by acting directly on myocytes and other cell types in
the heart to regulate fundamental biologic properties such as
growth, apoptosis, and the composition of the extracellular
matrix. This thesis provides a mechanism by which beta-
adrenergic antagonists may inhibit or reverse pathologic re-
modeling, improve myocardial structure and function, and
prolong patient survival.
Key words: norepinephrine, apoptosis, remodeling
Increased SympatheticActivity in Heart Failure
The activity ofthe sympathetic nervous system (SNS) is in-
creased in patients with heart failure.'" Most information
about the activity of the SNS comes from measurement of
Address for reprints:
Wilson S. Colucci. M.D.
Cardiovascular Divisioll
Boston Medical Center
XX East Newton Street
Bostori. M A 021 I X , USA
plasma norepinephrine, which generally reflects sy inpathetic
outflow activity, but also is influenced by changes in norc-
pinephrine uptake and degradation. Further evidence of in-
creased SNS activity is based on the demonstration that the
electrical activity in the perineal nerve is increased, reflecting
increased sympathetic trafiic to skeletal muscle." The evi-
dence for increased SNS activity in the heart in patients with
heart failure is based on the demonstration of an increased :lor-
tdcoronary sinus gradient of norepinephrine5and radiotracer
studies of norepinephrinetumover.6 The latter demonstratethat
the increased norepinephrine gradient across the heart is due to
both a several-fold increase in spillover of norepinephrine and
a reduction in e~traction.~ Thus, it appears that the availability
of norepinephrine to cardiac cells is increased both due to
increased sympathetic nerve activity and a reduction in the
clearance of norepinephnne.
In contrast to the renin-angiotensin system, thc activation
of which shows little or no relationship to the severity of hemo-
dynamic dysfunction, SNS activity generally relates 10 the
severity of hernodynamic dysfunction. The SNS tends to be
activated earlier than the renin-angiotensin system, even in
asymptomatic patients with left ventricular (LV) dysfunction,
whereas the renin-angiotensinsystem tends to be activn!ed lat-
er, after patients have become symptomatic.8Using norepinc-
phrine radiotracer methods, Runquist rt d.') showed that t h ~
cardiac spillover of norepinephrine was increased in p;Iticnts
With only mild symptoms of heart failure at il r i m when lhcrc
was no increase in total body or renal spillover,suggesting [I,:,,
the heart is the fist target of increased sympathetic acti"Ily'ln
patients with heart failure,
Opposing Actions of the Sympathetic Nervous Systcnl
in Heart Failure

W. S. Colucci: Effects of norepinephrine on myocardial biology
supplement, with time there is downregulation and desensiti-
zation of the beta-adrenergic effector pathway such that the
myocardial response to norepinephrine is attenuated.
However, increased SNS activity, particularly if prolong-
ed, may exeit deleterious effects on cardiovascular structure
and function. Arterial and venous constriction and increased
salt and water retention by the kidneys increase preload and
afterload and thereby increase diastolic and systolic wall
stresses. respectively. Increased SNS activity may activate
other neurohumoral systems such as the renin-angiotensin
system. In addition, as discussed below, it now appears likely
that norepinephrine, the major transmitter of the SNS, can
directly affect the biology of cardiac cells leading to changes
in the structure and function of the heart by the process of
remodeling.
Myocardial Remodeling
Myocardial dysfunction is a progressive process. The initial
insult to the heart (e.g., myocardial infarction) may be relative-
ly mild, such that there is little or no immediate reduction in
global cardiac function and no evidence of clinical heart fail-
ure. However, over time there is often progressive deteriora-
tion in both the structure and function of the ventricle leading
to the clinical syndrome of heart failure. The fundamental
mechanism that underlies the progressive nature of myocar-
dial dysfunction has been termed "remodeling."'o
Myocardial remodeling is a normal feature of maturation
and may be a useful adaptation to increased demands (e.g.,
with athletic training) in the adult. However, when this pro-
cess occurs in response to pathologic stimuli (e.g., abnormal
wall stresses), the remodeling that ensues, although perhaps
adaptive in the short term, is maladaptive in the long term and
often eventuates in furlher myocardial dysfunction. This pro-
cess consists of a complex of molecular and cellular events
that lead to important changes in the structure, function, and
phenotype of the myocardium. At the molecular and cellu-
lar level, myocardial remodeling includes hypertrophy and
apoptosis of myocytes, regression to a molecular phenotype
characterized by the expression of' fetal genes and proteins,
and alterations in the quantity and composition of the extra-
cellular matrix.
Role ot'theSympathetic Nervous System in
Myocardial Remodeling
In vitro studies in cultured cells have identified numerous
factorc that can mimic the features of myocardial remodeling
and thus must be considered as possible mediators of the pro-
cess. Among these factors. the most information is available
regarding mechanical stress, angiotensin, and norepinephrine.
The clinical relevance of these factors, in particular, has been
supported by the demonstration that agents which reduce my-
ocardial wall stress (e.g., vasodilators) or which directly block
the actions of angiotensinor norepinephrine [e.g., angiotensin-
19328737, 1998, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960211305, Wiley Online Library on [20/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1-21
converting enzyme (ACE) inhibitors and beta-adrenergic an-
tagonists] can slow the progression of myocardial dysfunction
in patients with heart failure.
As reviewed elsewhere," it appears likely that additional
factors produced primarily within the myocardium may be
involved in the progression of myocardial remodeling. The
levels of endothelin, inflamnatory cytokines, peptide growth
factors, nitric oxide, and reactive oxygen species may be in-
creased in the myocardium in response to mechanical strain,
norepinephrine, and angiotensin and may play an important
role in mediating the progression of remodeling via autocrine
or paracrine actions on cardiac myocytes and fibroblasts. In
the following sections, we will summarize the evidence that
norepinephrine plays a central role in myocardial remodeling
by focusing on several key aspects of the process.
Effects of Norepinephrineon Myocyte Growth and
Phenotype
A central feature in myocardial remodeling is an increase
in myocardial mass which is associated with a change in the
shape of the ventricle(s). The major mechanism for the in-
crease in myocardial mass is hypertrophy of individual my-
ocytes. Many of the initial observations regarding myocyte
hypertrophy were obtained in vitro using cardiac myocytes
cultured from neonatal rat hearts. In this system, norepine-
phrine causes an increase in myocyte size due to increased
protein synthesis in the absence of cell division.I2 In my-
ocytes derived from neonatal rats, the hypertrophic response
to norepinephnne is mediated primarily by the cy I -adrenergic
pathway." However, in myocytes isolated from adult rats,
both the cy1- and beta-adrenergic receptor pathways couple to
hypertrophy.'-'
Another hallmark of ventricular remodeling is the rein-
duction of fetal genes that are normally not expressed in adult
myocardium. For example, ribonucleic acid (nlRNA) levels
for atrial natriuretic peptide (ANP) and brain natriuretic pep-
tide (BNP), which are expressed in fetal cardiac tissue but not
in normal adult ventricular tissue, are reexpressed in LV myo-
cardium from patients with heart f a i l ~ r e .This
' ~ reinduction is
often, but not invariably, associated with a reciprocal decrease
in the expression of certain adult, muscle-specificgenes. Thus,
the amount of mRNAs for proteins which are important for
excitationxontraction coupling and are normally expressed
in abundance in normal adult myocardium, is reduced in ven-
tricular myocardium from patients with heart failure. For ex-
ample, the mRNA levels for sarcoplasmic reticulum calcium
adenosine triphosphatase (ATPase) (SERCA2), voltage-
dependent calcium channels, and phospholamban are depress-
ed in myocardium obtained from patients with idiopathic and
ischemic dilated cardiomyopathy'"18 and may contribute to
the abnormal calcium handling observed in such tissue.19
In vitro, norepinephrine is a potent stimulus for the re-
expression of several fetal genes such as ANP, alpha-skeletal
actin, and beta-myosin heavy chain. Although less well char-
acterized, norepinephrine also causes the downregulation of
 19328737, 1998, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960211305, Wiley Online Library on [20/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1-22 Clin. Cardiol. Vol. 21 (Suppl I) December 1998

\everal “adult” genes that are involved in excitation-contrac-
tion coupling. For example, incubation of adult rat cardiac my-
ocytes with norepinephrine for 24 h causes a marked decrease
in the expression of SERCA2 mRNA, which is mediated by
both alpha- and beta-adrenergicreceptors.20
Myocyte Death and Apoptosis
There is evidence that pathologic remodeling involves the
death of myocytes by apoptosis, or programmed cell death.
Apoptosis is a central feature of normal tissue development in
the fetus and of cell replacement in certain adult tissues ( e g ,
thymus). In contrast to cell necrosis, apoptosis is a tightly reg-
ulated series of energy-dependent molecular and biochemical
events orchestrated by a genetic program. Since apoptosis is
pinephrine could cause apoptosis. Cardiac myocytes cultured
from adult rat hearts were exposed to norepinephrine for 24 h
and apoptosis was assessed by several methods. It was found
that norepinephrine increased the laddering of DNA on an
agarose gel, which is indicative of internucleosonial DNA
breakage and increased the number of cell nuclei that were
stained in situ by terminal deoxynucleotidyl transfcrasc-
mediated nick end-labeling (TUNEL-staining), which is in-
dicative of double-stranded DNA breakage (Fig. I ). Third,
flow cytometric analysis of cellular DNA content showed that
20

I
most often associated with cells that are progressing through c
the cell cycle, it has generally been believed that apoptosis d0 15
c
does not occur in terminally differentiated adult cells such as +-
0
cardiac myocytes and neurons. However, several investiga- g
. ~ ~Olivetti et ~ 1 . :have
tors, including Narula et ~ 2 1 and ~ pro- -
ul

vided evidence that apoptosis occurs in the myocardium of

3 10
E
patients with end-stage dilated cardiomyopathy.Although the -Q
0
relevance of apoptosis to the pathophysiology of myocardial a0
failure remains to be determined, these observations have led 9 5
to the intriguing thesis that progressive myocardial failure re- I
Hects the continuing loss of viable myocytes (reviewed in
Ref. No. 23).
0
In several in vitro systems and animal models it appears that
CTL NE NE NE
apoptosis can be stimulated by a variety of insults, including +
i~chemia-reperfusion,~~ myocardial infar~tion:~rapid ventric- (4 Pi0 PZ
ularpaicing,26mechanical ~ t r e t c h ?and
~ pressure overloaddue
to aortic constriction.28Furthermore, several molecular medi-
ators known or suspected to be present in failing myocardium, * *
including catecholamines, angiotensin, inflammatory cy- T T
tokines, reactive oxygen species, mechanical stress, nitric ox-
ide, and natriuretic peptides, have been shown to cause apop-
tosis of cardiac myocytes in vitro.
For many years it has been appreciated that exposure to
high levels of catecholamines is toxic to cardiac myocytes
(reviewed in Ref. No. 29), and several mechanisms have been
theorized, such as hypoxia, increased sarcolemmal permea-
bility, calcium overload, elevation of cyclic adenoside mono-
phosphate (CAMP),activation of alpha- or beta-adrenergic re-
ceptors, and the formation of oxidative catecholamine
i-rietabolites.2”-”Mann et a1.’* advanced this thesis by show-
ing that exposure to norepinephrine exerts a direct toxic effect
on cardiac myocytes in cell culture. Of importance, they
(6) CTL IS0 FSK
showed that the toxic effect of norepinephrine was mediated Fig. 1 Norepinephrine (NE)stimulates apoptosis in cardiac my-
by beta-adrenergic receptor stimulation, since it could be ocytes.Cultured myocytes obtained from adult rats were exposed to
completely blocked by a beta-adrenergic antagonist, thus in- NE for 24 h and apoptosis was assessed by fluorescence-activat~~i
dicating that ischemia and oxidation of catecholamines were flow cytometric analysis of DNA content in myocytes stained with
not necessary for this phenomenon to occur. They further propidium iodide. (A) NE-stimulated apoptosis was inhibited by the
beta-adrenergicantagonist propranolol (PRO), but not the a I-udren-
showed that increases in both CAMPand calcium influx were ergic antagonist prazosin (PZ). (B) Exposure to the beta-adrenergic
involved. agonist isoproterenol (ISO) or the adenylyl cyclase activator
Since the mechanism by which norepinephrine caused forskolin (FSK)mimicked the etfort of NE to stimulate apoptosis.
myocyte death was not known, we33examined whether nore- = p < 0.01 versus control. t = p c 0.05 versus NE.

W. S . Colucci: Effects of norepinephrine on myocardial biology
norepinephrine increased the number of hypodiploid cells.
Norepinephrine-stimulated apoptosis was inhibited by the
beta-adrenergic antagonist propranolol but not the alpha-
adrenergic antagonist prazosin. These effects were mimicked
by isoproterenol and forskolin and abolished by the protein
kinase A inhibitor H-89 or the voltage-dependent calcium-
channel blockers diltiazem and nifedipine, further implicat-
ing the beta-adrenergic pathway.
Several recent observations in rats and mice suggest that
beta-adrenergic receptor-stimulated apoptosis may be rele-
vant in vivo. It has been shown that the infusion of isopro-
terenol into rats for 24 h causes myocardial a p o p t o ~ i s . ~ ~
Transgenic mice that overexpressthe Gsol subunit in the myo-
cardium develop dilated ~ardiomyopathy~~ which appears to
be associated with increased apoptosis.36It is interesting that
cardiac myocytes cultured from these mice also develop
apoptosis in vim when exposed to isopr~terenol.~~ It should
be noted, however, that transgenic mice that overexpress the
Pz-adrenergic receptor in the heart do not appear to develop
dilated cardiomyopathy.38
ExtracellularMatrix
The extracellular matrix, consisting of collagens, proteo-
glycans, glycoproteins (e.g., fibronectin),peptide growth fac-
tors, and proteases plays an important role in determiningthe
structural characteristics of the myocardium by providing the
connections between myocytes and between myocytes and
nonmyocytes (e.g., fibroblasts). The extracellular matrix is
also an important source of cell-to-cell signals mediated by
growth factors and integrins which may be involved in the reg-
ulation of fundamental biologic processes such as growth,
apoptosis, and phenotype. Changes in the nature and quantity
of the extracellular matrix may therefore play a central role in
determining the response of the myocardium to pathologic
Pathologic myocardial hypertrophy often involves
interstitial fibrosis which may impair myocardial relaxation@
and disrupt normal cell-to-cell communication. Conversely,
reduced levels of certain structural proteins could compro-
mise the integrityof the extracellular matrix and lead to cham-
ber dilatation.
Norepinephrinehas potent effects on many components of
the extracellular matrix. In fibroblasts cultured from neonatal
rat hearts, norepinephrine stimulatesboth proliferation, as in-
dicated by increased DNA synthesis, and increased protein
~ynthesis.~' In rats, the chronic infusion of isoproterenol
results in interstitialfibrosis associated with ventricularhyper-
trophy and increased expression of mRNAs for fibronectin
and transforminggrowth Thus, norepinephnne has
potentially important effects on the extracellular matrix that
could contribute to pathologic remodeling.
Conclusionand Implications
Myocardial remodeling is a central feature in the progres-
sion of myocardial failure. This process involves changes in
19328737, 1998, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960211305, Wiley Online Library on [20/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1-23
the structure and function of the myocardium including my-
ocyte hypertrophy and apptosis, changes in the molecular
phenotypewith reinduction of a fetal gene program, and alter-
ations in the quantity and composition of the extracellularma-
trix. In vitro studies suggest that norepinephrinehas the ability
to cause many of the centralfeaturesof pathologic myocardial
remodeling including hypertrophy, fetal gene expression and
apoptosis in myocytes, and activationgrowth and protein syn-
thesis in fibroblast.
Thus, increased SNS activity, acting largely via beta-adren-
ergic receptors, may play an important role in the progression
of myocardial failure by acting directly on myocytes, fibrob-
lasts, and other cell types in the heart to regulate fundamental
biologic properties such as growth, apoptosis, and the compo-
sition of the extracellularmatrix. This thesis provides a mech-
anism by which beta-adrenergic antagonists may inhibit or
reverse pathologicremodeling, improve myocardial structure
and function, and prolong patient survival.
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