Current Hypertension Reviews, 2011, 7, 273-283 273

Adrenomedullin in Heart Failure: Molecular Mechanism and Therapeutic

Implication

Toshio Nishikimi1,*, Kazuwa Nakao1 and Kenji Kangawa2

1
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara-
cho, Sakyo-ku, Kyoto 606-8507, Japan 2Department of Biochemistry, National Cerebral and Cardiovascular Center
Research Institute, Fujishirodai, Suita, Osaka 565-8565, Japan

Abstract: Many neurohumoral factors play an important role in regulation of the cardiovascular system and in the
pathophysiology of heart failure. Adrenomedullin (AM) is a potent long-lasting vasodilatory peptide that was discovered
in acid extracts of human pheochromocytoma tissues. Both AM and its gene expression are widely distributed in the
cardiovascular system, including the heart, vessels, and kidneys. AM co-localizes with its receptor components such as
calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the heart, vessels
and kidneys, suggesting that it plays an important role in the regulation of cardiovascular function through an autocrine
and/or paracrine mechanism. AM has inotropic action in vitro and in vivo and inhibits cardiac hypertrophy in myocytes as
well as proliferation and collagen production in cardiac fibroblasts. These results suggest that AM functions as an
antifibrotic, antihypertrophic and positive inotropic factor in the failing heart. In addition, AM has anti-apoptotic,
angiogenic, anti-inflammatory and anti-oxidant effects. Several mechanisms such as cAMP/PKA, NO/cGMP, PI-3K/Akt
and/or ERK are thought to mediate cellular AM signaling, suggesting that increased AM levels play a protective role in
heart failure. Indeed, acute AM administration exerts beneficial vasodilatory, diuretic, natriuretic and inotropic effects on
experimental and human heart failure. A recent pilot study has shown that AM has potential as a therapeutic drug in the
clinical setting of acute decompensated heart failure.

Keywords: Adrenomedullin, heart failure, antifibrotic effects, cardiovascular diseases.

INTRODUCTION actions related to regulation of the cardiovascular system

Heart failure has become an increasingly important
public health problem, because heart failure is the leading
cause of hospitalization and death for people aged 65 years
and over in the developed countries. Various neurohumoral
factors are involved in the pathophysiology of heart failure
[1]. Therefore, the pathophysiological roles of novel
neurohumoral factors in heart failure should be investigated,
since the findings can lead to the development of new drugs
[2]. In fact, angiotensin-converting enzyme inhibitors, beta-
blockers, aldosterone blockers, and angiotensin receptor
blockers, which were generated in this manner, are now
widely used worldwide for patients with heart failure
and they have significantly contributed to improvements
in prognoses and the quality of life for patients with this
syndrome.
Adrenomedullin (AM) is a powerful vasodilatory peptide
that was discovered in extracts of human pheochromocytoma
tissues in 1993 by monitoring cAMP activity in rat platelets
[3]. Subsequent studies revealed various biological actions in
addition to its vasodilatory activity [4]. Specifically, many
*Address correspondence to this author at the Department of Medicine and
Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin-
Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Tel: 81-75-751-4287;
Fax: 81-75-771-9452; E-mail nishikim@kuhp.kyoto-u.ac.jp
have been identified [5]. The cardiovascular system, including
the heart, kidneys and vessels, expresses considerable
amounts of AM mRNA [6] and immunoreactive AM is also
widely distributed in these organs. These findings suggest
that AM plays a role in cardiovascular function and/or the
pathophysiology of cardiovascular disease, and thus, this
protein has attracted considerable interest among cardio-
vascular investigators. We describe recent advances in the
biochemistry, receptor, signaling and cardiovascular action
of AM, its pathophysiological roles in the failing heart and
clinical applications in heart failure.
1. STRUCTURE AND TISSUE DISTRIBUTION OF AM
Human AM consists of 52 amino acids, of which the
carboxy-terminal tyrosine (Tyr) is amidated (Fig. 1), and one
intramolecular disulfide bond [3]. The sequence homology
of AM with human calcitonin gene-related peptide (CGRP)
and amylin is only about 30%, even though each of these
peptides has carboxy-terminal amides and a six-residue ring
structure formed by an intramolecular disulfide linkage. A
study of structure-activity relationships has shown that
amidation of the C-terminal residue of AM and its cyclic
structure are essential for receptor binding and the cAMP
response [7]. AM is therefore considered a member of the
CGRP superfamily. The sequence identity of recently
discovered AM 2 (AM2)/intermedin [8, 9] with AM is about

1573-4021/11 $58.00+.00 © 2011 Bentham Science Publishers

274 Current Hypertension Reviews, 2011, Vol. 7, No. 4 Nishikimi et al.

Fig. (1). Biosynthesis of adrenomedullin (AM). Adrenomedullin, pro-AM N-terminal 20 peptide (PAMP) and mid-regional AM are
synthesized from the same precursor (prepro-AM: 185 amino acids). The signal peptide is removed and pro-AM is produced. Pro-AM is then
processed to glycine-extended AM (AM-glycine), glycine-extended PAMP and mid-regional AM. AM-glycine and glycine-extended PAMP
are inactive intermediate forms of AM and PAMP. Thereafter, AM-glycine and glycine-extended PAMP are converted to active mature AM
(AM-mature) and PAMP with a C-terminal amide structure by enzymatic amidation. Total AM (AM-T) = (AM-mature) + (AM-glycine).

30%, but the pharmacological activities (renal and cardio-
vascular) of these peptides are similar [10]. Thus, at least
two peptides comprise the AM family in mammals.
Immunoreactive AM is widely distributed in various
tissues. Levels of AM mRNA are notably high in
cardiovascular tissues such as ventricles, aorta, kidneys and
lungs, whereas levels of immunoreactive AM in the aorta,
ventricles and kidney are <5% of that in the adrenal gland
[11]. These low levels are attributed to the fact that AM
biosynthesized in these tissues is rapidly and constitutively
secreted into the blood or utilized as an autocrine or
paracrine regulator, or both [12]. Immunohistochemical
analyses have demonstrated AM immunoreactivity in cardiac
myocytes, vascular smooth muscle cells, endothelial cells
and renal distal and collecting tubules [13]. Immunoreactive
AM is also found in blood and urine [14].
2. RECEPTOR AND CELLULAR SIGNALS OF AM
McLatchie et al. [15] identified a cDNA encoding 148
amino-acid residues with a single transmembrane domain,
named receptor activity modified protein (RAMP). They
showed that co-transfection of calcitonin like receptor (CLR)
and RAMP1 into COS-7 cells resulted in functional CGRP
receptors, whereas transfection of either gene alone elicited
no effects (Fig. 2) [16]. In addition, a database search
identified two more members of the RAMP family,
designated as RAMP2 and RAMP3 [15]. Although sequence
similarity among these RAMP isoforms is <30% within the
same species, all three of them share conserved cysteine
residues at their extracellular domain and flanking the
transmembrane domain [16]. Co-transfection of CRLR with
RAMP2 or RAMP3 leads to functional AM receptors with
high affinity for AM, but not for CGRP (Fig. 2). In terms of
AM binding and cAMP responses, RAMP2 and RAMP3 are
apparently indistinguishable [16]. The co-expression of
CRLR with RAMP1 and RAMP2/3 in fact results in
pharmacologic activities of CGRP1 and AM receptors,
respectively (Fig. 2) [17].
Although AM was discovered based on elevated cAMP
activity in rat platelets, subsequent studies revealed many
cellular signaling mechanisms. AM receptors couple to Gq
protein and AM activates phospholipase C to form inositol
Adrenomedullin in Heart Failure
Fig. (2). Adrenomedullin receptor, signaling, downstream cascade and actions. Calcitonin receptor-like receptor pathway (CLR) and
receptor activity modifying protein (RAMP) isoforms determine ligand selectivity for AM and calcitonin-gene related peptides (CGRP).
Extracellular RAMP domains play important roles in ligand selectivity.
1,4,5-trisphosphate, and then activates nitric oxide synthase
in endothelial cells [18]. A later study showed that AM
induces Akt activation via the Ca/calmodulin-dependent
pathway, leading to NO production [19]. The AM-induced
phosphatidylinositol 3'-kinase/Akt pathway plays a protective
role against endothelial cell apoptosis [20]. Thus, the AM/
Akt/PI-3K pathway plays important roles in eNOS activation
and apoptosis. During angiogenesis, AM induces the
phosphorylation of Akt and of mitogen-activated protein
kinase (MAPK)/ERK in human umbilical vein endothelial
cells (HUVECs). AM also phosphorylates focal adhesion
kinase, and phosphatidylinositol 3'-kinase inhibitor inhibits
AM-induced focal adhesion kinase phosphorylation [21].
Thus, AM exerts angiogenic activity through the activation
of Akt, MAPK, and focal adhesion kinase in endothelial
cells.
AM induces cAMP in vascular smooth muscle cells,
which leads to vasodilation and the inhibition of proliferation
and migration [22]. In contrast, another study showed that
AM induces a rapid increase in extracellular signal-regulated
Current Hypertension Reviews, 2011, Vol. 7, No. 4 275
kinase (ERK) activity, followed by the expression of
the immediate early proto-oncogene c-fos and promotes
proliferation in quiescent vascular smooth muscle cells [23].
AM also induces ERK activation in adipocytes [24], but
decreases ERK activity in mesangial cells [25]. The
mechanism through which AM decreases ERK activity is
thought to be mediated at least in part by an increase in
protein phosphatase 2A activity in mesangial cells [25].
Cardiac AM induces cAMP activity in myocytes and
cardiac fibroblasts [26] and inhibits myocyte growth [27] as
well as collagen production [28] in fibroblasts. However, the
cAMP/PKA pathway does not mediate the inotropic action
of AM, which enhances cardiac contractility via cAMP-
independent mechanisms including Ca2+ release from intra-
cellular ryanodine- and thapsigargin-sensitive Ca2+ stores,
protein kinase C activation and Ca2+ influx through L-
type Ca2+ channels [29]. In addition, AM increases the
phosphorylation of Akt and glycogen synthase kinase
(GSK-3beta) and reduces caspase-3 activities in the heart.
AM protects against cardiomyocyte apoptosis induced by
276 Current Hypertension Reviews, 2011, Vol. 7, No. 4
ischemia/reperfusion injury through the Akt-GSK-caspase
signaling pathway [30]. Thus, AM signaling processes are
complex and different mechanisms seem to be involved
depending on the cellular situation.
3. PHYSIOLOGICAL EFFECTS OF AM
Table 1 shows representative pleiotropic effects of AM.
Table 1. Physiological Action of Adrenomedullin
1. Vessel
Vasodilatation
Nitric oxide production
Angiogenesis
2. Heart
Inotropic action
3. Kidney
Glomerulus
Dilatation of afferent arteriole and constriction of efferent arteriole
Renal Tubule
Diuresis
Natriuresis
4. Endocrine organ
Inhibition of aldosterone secretion
Inhibition of ACTH secretion
5. Cell Growth, Proliferation, Apoptosis
Inhibition of proliferation in vascular smooth muscle cells,
mesangial cells, and cardiac fibroblasts,
Growth-promoting effect in vascular smooth muscle cells
Inhibition of hypertrophy in cardiac myocytes
Antiapototic effect
Anti-inflammatory effects
6. Adipocyte
lipolysis
ACTH: adrenocorticotropic hormone.
3-1-1. Cardiac Actions of AM - Effect of AM on Cardiac
Contractility
Many physiological actions of AM in the heart have been
described [5]. The intravenous administration of AM in
animals significantly increases cardiac output [31], but
whether this is a direct effect of AM or a secondary effect
resulting from reduced afterload remains unclear. An early
study initially indicated direct negative inotropic actions of
AM in the perfused rat heart [32]. Others also reported that
AM dose-dependently reduces both contractility and Ca2+
concentrations in isolated rabbit cardiac myocytes through
the NO/cGMP pathway [33]. Another group showed that
AM augments NO synthesis in the heart through a cAMP
pathway in response to cytokine stimulation [34]. These
findings suggest that increased AM in the heart leads to
reduced cardiac contractility through a nitric oxide/cGMP
Nishikimi et al.
pathway that decreases cytoplasmic Ca2+ concentrations. In
contrast, AM is reported to have direct inotropic activity in
vitro [29] and increases myocardial contractility in vivo [35].
Szokodi et al. [29] demonstrated that AM has positive
inotropic action via cAMP-independent mechanisms and
showed that AM is an endogenous inotropic peptide in the
heart. The same group examined whether AM can modulate
the increase in blood pressure and changes in systolic and
diastolic function produced by long-term therapy with
angiotensin II or norepinephrine in rats. They found that AM
selectively suppresses the increase in blood pressure and
improves the systolic function induced by angiotensin II,
suggesting that circulating AM mainly acts as a regulator of
vascular tone and cardiac function [36]. In agreement with
these findings, intravenous AM enhances left ventricular
myocardial contraction and improves left ventricular
relaxation without increasing myocardial oxygen consump-
tion in patients with old myocardial infarctions and left
ventricular dysfunction [37].
AM knockout mice were first generated in 2001 [38].
The phenotype is severe edema and cardiac abnormalities
that lead to embryonic lethality [39]. Aortic constriction
reduces ejection fraction more in AM+/- than in wild type
mice [39]. These results suggest that the AM/CLR/RAMP2
system preserves cardiac function as an endogenous factor.
The reasons for the discrepancies among studies
are unknown, but may involve differences in species,
experimental conditions, or the ages of the animals. The
results of animal studies in vivo seem to consistently indicate
that AM has inotropic action. Since it has inotropic activity
in humans [37, 40], AM might be clinically applicable to
patients with acute heart failure.
3-1-2. Cardiac Actions of AM - Effects on Cardiac
Hypertrophy
AM significantly reduces 14C-phenylalanine incorporation
into cardiac myocytes stimulated by 10% fetal bovine serum
and angiotensin II [28]. This effect is dose-dependently
abolished by the AM receptor antagonist, CGRP[8-37].
AM also significantly and dose-dependently reduces the
angiotensin II- or ET-1-stimulated incorporation of 3H-
thymidine and 3H-phenylalanine into cardiac fibroblasts [29,
41], and CGRP[8-37] attenuates these effects. AM dose-
dependently stimulates cAMP accumulation in these cells
[26], an effect that is significantly attenuated by CGRP
[8-37]. Both 8-bromo cAMP and forskolin suppress the
synthesis of DNA and collagen by cardiac fibroblasts.
Furthermore, a cAMP-specific phosphodiesterase inhibitor
decreases the synthesis of both DNA and collagen in
fibroblasts and augments the inhibitory effects of AM on
such synthesis [27]. AM antisense oligodeoxynucleotides
significantly decrease AM levels in culture medium and
collagen synthesis in cytokine-stimulated cardiac fibroblasts
[42], suggesting that endogenous AM indeed functions as an
anti-fibrotic factor. These results suggest that AM has an
important role in modulating the growth of cardiac
fibroblasts in an autocrine or a paracrine fashion, at least in
Adrenomedullin in Heart Failure
part via a cAMP signaling mechanism. The effect of AM on
cardiac hypertrophy was assessed in an in vivo rat model of
hypertrophy induced by aortic banding [43]. Both AM and
hydralazine similarly decreased blood pressure compared
with an untreated group with aortic banding, but the left
ventricular weight/body weight ratio was reduced only in the
group infused with AM. Left ventricular AM levels were
22% greater and plasma AM levels were about 5-fold higher
in the group infused with AM than in the untreated group
with aortic banding. These findings have been supported by
studies of engineered mice. AM heterozygous KO mice
develop more pronounced fibrosis and left ventricular
hypertrophy than wild type mice after aortic constriction
[39]. The activation of ERK was more enhanced in the heart
after aortic constriction in AM heterozygous KO mice
than in wild type mice. These findings suggest that AM
plays a pathophysiological role in the development of
left ventricular hypertrophy. In addition, AM inhibits
cardiomyocyte apoptosis induced by doxorubicin [44] and
ischemia/reperfusion injury [45]. Thus, AM may act as an
antifibrotic, antihypertrophic, antiapoptotic and positive
inotropic factor in the failing or hypertrophied heart.
3-2. Vascular Action of AM
The systemic intravenous injection of AM elicits a potent
and long-lasting hypotensive effect in anesthetized rats [3]
that is closely associated with a decrease in total peripheral
resistance and concomitant with increases in cardiac output
and stroke volume [31]. In addition, acute or chronic AM
administration induces a significant decrease in systemic
blood pressure in rabbits, sheep and humans. Vasodilatory
actions of AM have been studied in not only the systemic
vasculature, but also in regional vascular beds, including the
renal, pulmonary, cerebral and coronary circulation [23].
These vasodilatory effects of AM are mediated by at least a
direct action on vascular smooth muscle cells and an indirect
effect through primary actions on endothelial cells via nitric
oxide production.
3-3. Effect of AM on Renal Function
AM has renal, as well as hypotensive actions. AM and its
gene are expressed in the glomerulus, distal tubules and
medullary collecting duct cells of the kidney [46, 47]. The
genes encoding CRLR, RAMP2, and RAMP3, which are
components of AM receptors, are also expressed in the rat
renal cortex and medulla [48]. Immunohistochemical analysis
of the human kidney has revealed CRLR-like immuno-
reactivity in the juxtaglomerular arteries, the glomerular
capillaries and chief cells of the collecting duct [49]. These
results suggest that AM and its receptor system in the kidney
are involved in the regulation of renal hemodynamics,
glomerular filtration and tubular sodium homeostasis in vivo.
An intravenous infusion of AM attenuates a reduction in
blood pressure and an increase in renal blood flow [50]. An
early study found that the intrarenal arterial administration of
AM in the anesthetized dog elicits a dose-dependent increase
in renal blood flow with a slight increase in the glomerular
filtration rate at high doses [51], suggesting that AM
Current Hypertension Reviews, 2011, Vol. 7, No. 4 277
similarly dilates both afferent and efferent arterioles. They
also showed that the intrarenal arterial administration of AM
induces an increase in urinary flow rates and urinary sodium
excretion even at a low dose without affecting glomerular
filtration rates. These findings suggest that AM inhibits
tubular sodium and water reabsorption. AM increases the
diameters of both afferent and efferent arterioles in the rat
hydronephrotic kidney [52]. AM-induced renal vasodilator,
diuretic and natriuretic responses might be partially mediated
by the release of endogenous nitric oxide [53, 54] and renal
prostaglandins [55]. The inhibition of neutral endopeptidase
(NEP) potentiates an increase in sodium excretion in the
absence of an increase in the glomerular filtration rate
or further increases in renal blood flow in response to
exogenous AM [56], indicating that NEP induces natriuresis
by inhibiting tubular sodium reabsorption through attenuation
of AM metabolism. Collectively, these results suggest that
endogenous AM compensates for pathological conditions
such as atrial natriuretic peptide under specific pathological
conditions such as heart failure.
3-4. Endocrine Action of AM
AM inhibits aldosterone secretion induced by angiotensin
II [57], potassium [58], and Ca2+ ionophores [59] in dispersed
ZG cells and prevents increases in the plasma aldosterone
level in vivo induced by an infusion of angiotensin II [60], a
sodium-deficient diet or bilateral nephrectomy [61]. These
results suggest that AM plays an inhibitory role in the
secretion of aldosterone from zona glomerulosa cells and
that this inhibitory effect plays a role in pressure and volume
homeostasis.
AM immunoreactivity has been detected in the
hypothalamo-pituitary-adrenal axis of humans, rats and
pigs [62], suggesting that AM functions in modulating the
secretion of pituitary and adrenal hormones. Indeed, AM
dose-dependently inhibits adrenocorticotropic hormone
(ACTH) release and attenuates CRH-stimulated ACTH
production from primary cultures of rat anterior pituitary
cells [63]. This effect is also evident in vivo [64]. These
findings suggest that AM functions in inhibiting ACTH
release. Thus, AM in the hypothalamo-pituitary complex
might play a role in the regulation of fluid and electrolyte
homeostasis and modify the pathophysiology of heart failure.
4. PLASMA AM LEVELS
AM is found in plasma. Although high levels of AM
peptide and mRNA are expressed in the adrenal gland, heart,
kidneys and lungs, this is not true of the coronary sinus,
renal vein, adrenal veins and aorta [65]. Therefore, the
source of the plasma AM is now considered to be the
vasculature, because AM mRNA is more prominently
expressed in endothelial and vascular smooth muscle cells.
Plasma AM levels are increased in proportion to the severity
of heart failure [66-69].
AM is produced from a precursor via two enzymatic
steps. Firstly, the signal peptide [1-21] is removed from
prepro-AM [1-185] to produce pro-AM [22-185], which is
converted into glycine-extended AM (AM-Gly), glycine-
278 Current Hypertension Reviews, 2011, Vol. 7, No. 4 Nishikimi et al.

extended PAMP and mid-regional AM by a processing
enzyme. The inactive 53-amino-acid intermediate form of
AM, AM-Gly, is then converted by enzymatic amidation into
active mature AM (AM-m), a 52-amino-acid peptide with a
C-terminal amide structure (Fig. 1). Both AM-Gly and AM-
m are increased in heart failure [70]. A mid-regional stable
AM fragment of 45-92 amino acids that is secreted in an
equimolar fashion [71, 72] is an important prognostic marker
of heart failure and myocardial infarction as well as BNP and
NT-proBNP [73, 74].
5. ROLE OF THE CARDIAC AM SYSTEM IN CAR-
DIAC HYPERTROPHY AND THE FAILING HEART
AM immunoreactivity is increased in the failing heart
[67] and both mRNA and AM immunoreactivity are
increased in a model of heart failure [75]. In addition, the
increased AM immunoreactivity in pressure-overloaded
cardiac hypertrophy closely correlates with left ventricular
mass [43]. Thus, cardiac AM levels are upregulated in
cardiac hypertrophy and the failing heart in association with
an increase in ventricular weight or fetal cardiac gene
expression [76]. Plasma AM levels in human heart failure
are higher in coronary sinus than in the aorta, suggesting that
cardiac AM production is increased in the failing heart.
Two molecular forms of AM, AM-mature and AM-
glycine (see Fig. 1), its mRNA, and receptors (CLR and
RAMPs) have been investigated in cardiac hypertrophy and
heart failure. The gene expression levels of AM, CLR,
RAMP2, and RAMP3 in the left ventricle are significantly
higher in cardiac hypertrophy and in the failing heart than in
controls [77, 78]. Cardiac tissue levels of AM-mature and
AM-glycine were also significantly higher in cardiac
hypertrophy and in the failing heart than in controls, and the
AM-mature/AM-glycine ratio is also significantly higher in
left ventricular tissue than in plasma, suggesting the
increased amidating enzymatic activity. Furthermore, this
AM-mature/AM-glycine ratio in left ventricular tissue
significantly correlates with the ratio of left ventricular
weight/body weight [78, 79]. These results suggest that the
amidating enzymatic activity of AM, its ligand, and receptor

Fig. (3). Our working hypothesis regarding the myocardial and circulating AM system in transition from hypertension ~ LVH to
heart failure. In hypertension ~ LVH, plasma AM-mature and AM-glycine are increased. In myocardium, AM-glycine (inactive form) is
increased and AM-mature (active form) is further increased, because amidating enzyme activity (see Fig. 1) is increased in LVH. Receptor
mRNA levels are also increased. In heart failure, plasma, AM-mature and AM-glycine are further increased, whereas AM-mature/AM-
glycine ratio is not changed. In myocardium, AM-mature (active form) is markedly increased with a increased receptor mRNA levels. These
changes show the upregulation of AM system in plasma and myocardium in heart failure, compensating heart failure and inhibiting cardiac
remodeling. AM-m: AM-mature, AM-gly: AM-glycine, AM-m/gly ratio = AM-mature/AM-glycine ratio
Adrenomedullin in Heart Failure
system are all upregulated in severe cardiac hypertrophy and
the failing heart. Thus, the entire cardiac AM system is
upregulated under these conditions (Fig. 3).
Adenovirus-mediated AM gene delivery and the chronic
administration of AM have been attempted to determine
whether increased plasma and tissue AM levels in cardiac
hypertrophy or the failing heart have cardioprotective effects.
Somatic gene delivery using an adenovirus containing human
AM cDNA under the control of the cytomegalovirus promoter/
enhancer significantly decreased left ventricular weight
and cardiomyocyte diameter, accompanied by reductions in
interstitial fibrosis, extracellular matrix formation and blood
pressure in severely hypertensive rats [80]. These findings
suggest that increased AM levels protect against cardiac
remodeling and renal damage in hypertension.
The effects of long-term AM infusions have been
investigated in a rat model to determine the role of
endogenous AM in the transition from LVH to heart failure
[81]. Long-term infusions of human AM decreased left
ventricular end-diastolic pressure, right ventricular systolic
pressure, right atrial pressure and the left ventricular
weight/body weight ratio without significantly altering mean
arterial pressure and significantly decreased endogenous
plasma AM levels in these model rats. In addition, long-
term AM infusion significantly decreased plasma renin,
aldosterone, and atrial natriuretic peptide levels and
prolonged survival. These results suggest that endogenous
AM plays a compensatory role in heart failure. In addition
to these salutary effects in heart failure, long-term AM
administration attenuates left ventricular remodeling after
acute myocardial infarction, partly via the inhibition of
oxidative stress and expression of the angiotensin converting
enzyme gene [82]. A protective effect of endogenous
AM against stress-induced cardiac hypertrophy has been
investigated using the AM-null mutation AM+/- mice
described above [39].
Thus, up-regulated cardiac expression of AM and its
receptor might be an adaptive and protective response under
conditions of stress such as cardiac hypertrophy and heart
failure. This hypothesis is supported by the results of recent
studies using AM gene delivery, long-term AM infusion
and knockout mice. The beneficial effects of increased AM
might be associated with the inhibition of oxidative stress,
the renin-angiotensin-aldosterone system and other factors
[22, 45, 81-84].
6. ADMINISTRATION OF AM IN OTHER ANIMALS
WITH HEART FAILURE
The above findings indicate that increased endogenous
plasma and tissue levels of AM in cardiac hypertrophy and
heart failure have cardioprotective effects. Together with
evidence of vasodilatory, diuretic, and natriuretic effects and
inhibited aldosterone secretion, AM might be a useful
treatment strategy for patients with heart failure.
The intravenous infusion of AM decreases calculated
peripheral resistance, mean arterial pressure and left atrial
pressure, and increased cardiac output in sheep with pacing-
Current Hypertension Reviews, 2011, Vol. 7, No. 4 279
induced heart failure [85]. AM also increases urinary
sodium, creatinine and cAMP excretion, and creatinine
clearance along with a reduction in plasma aldosterone
levels [85]. We also examined the cardiovascular and renal
effects of two intravenous doses of infused AM in rats
with heart failure [86]. A low dose of AM increased urine
flow and urinary sodium excretion without changing any
hemodynamic variables, whereas a high dose decreased
mean arterial pressure, right ventricular systolic pressure and
right atrial pressure, and significantly increased cardiac
output in rats with heart failure and in normal rats. A high
dose of AM significantly increased glomerular filtration rate
and renal plasma flow, as well as urine flow and urinary
sodium excretion [86]. In addition, AM administration
for four days has pronounced and sustained cardiovascular
and renal effects in experimental heart failure, including
reductions in cardiac preload and afterload as well as the
augmentation of cardiac output, sodium excretion and
glomerular filtration [87]. These results imply that AM plays
an important pathophysiological role in the regulation of
pressure and volume in heart failure and raises the prospect
of developing new therapeutic approaches to this syndrome.
AM, when combined with other drugs such as angiotensin
converting enzyme inhibitor, neutral endopeptidase inhibition
or natriuretic peptides, has beneficial and complementary
effects [88-90].
7. EFFECTS OF AM IN PATIENTS WITH HEART
FAILURE
The benefits determined in experimental heart failure
suggested that AM would be effective against human heart
failure.
We found that an intravenous infusion of AM (0.05
μg/kg/min) for 30 minutes significantly increased the cardiac
index and decreased pulmonary capillary wedge pressure in
patients with heart failure and in normal individuals [91].
AM significantly decreased mean pulmonary arterial
pressure only in those with heart failure and increased urine
volume and urinary sodium excretion in both groups. Plasma
aldosterone fell significantly during and after AM infusion
only in the patients. These findings indicated that the acute
intravenous infusion of AM has beneficial hemodynamic,
renal and endocrine effects in patients with heart failure [91].
The Christchurch group also studied the effects of AM
infusion on human heart failure [92] and found a significant
decrease in mean arterial pressure (MAP) and LV end-
systolic volume, and increased cardiac output. Despite a
large drop in MAP, urine volume, urinary sodium excretion
and creatinine clearance were not altered. These results
suggest that a short-term AM infusion improves heart failure
and that AM can be therapeutically administered to patients
with heart failure.
We then examined whether long-term AM (0.02
μg/kg/min) + human atrial natriuretic peptide (hANP; 0.05
μg/kg/min) can be administered as a therapeutic strategy to
patients with acute decompensated heart failure (ADHF)
in the clinical setting [93]. Seven patients with acute
280 Current Hypertension Reviews, 2011, Vol. 7, No. 4 Nishikimi et al.

Fig. (4). Effects of long-term administration of AM on hemodynamics in patients with decompensated heart failure. Effects of
AM + hANP and hANP monotherapy on mean arterial pressure (MAP), systemic vascular resistance (SVR), mean pulmonary arterial
pressure (mPAP), pulmonary arterial resistance (PAR), pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) in patients with
decompensated heart failure. * P < 0.05 vs. time 0.

decompensated heart failure accompanied by dyspnea and CONCLUSIONS

pulmonary congestion were infused with AM and
Current evidence suggests that increased endogenous
recombinant ANP for 12 h followed by hANP for 12 h and
levels of AM play a protective role in cardiac hypertrophy
then hemodynamic, renal, hormonal and oxidative stress
and the failing heart. Thus, AM might be a novel and
responses were evaluated. AM + hANP significantly reduced
promising approach to the treatment of patients with heart
mean arterial pressure, pulmonary arterial pressure, and
failure. A small pilot study recently indicated that AM exerts
systemic and pulmonary vascular resistance without
beneficial therapeutic effects against ADHF. A larger
changing heart rate, and increased cardiac output at most
clinical trial is required to confirm this finding.
time points compared with baseline values (Fig. 4). This
combination also reduced aldosterone, BNP and free radical DISCLOSURE
metabolites, and increased urine volume and urinary sodium
Part of information included in this chapter/article has
excretion compared with baseline data. After switching to
been previously published in " http://www.ingentaconnect.
hANP monotherapy, MAP and systemic vascular resistance
com/content/ben/chyr Current Hypertension Reviews, Volume
increased and cardiac index decreased, but urinary volume
and urinary sodium excretion did not significantly change 1, Number 2, June 2005, pp. 169-181(13).
[93]. Although this was a small pilot trial, the combination of CONFLICT OF INTEREST
AM with hANP exerted beneficial hemodynamic and
hormonal effects in patients with ADHF. The ability of AM Declared none.
to reduce systemic and pulmonary vascular resistance and ACKNOWLEDGMENTS
increase the cardiac index was particularly prominent. Thus,
intravenous infusions of AM with hANP should be This study was supported in part by a Scientific Research
therapeutically applicable to patients with ADHF. However, Grant-in-Aid (14570692,18590787, 20590837) from the
these data are preliminary and require confirmation in a Ministry of Education, Culture, Sports, Science and
larger clinical study. Technology, by a Science Research Promotion Fund from
Adrenomedullin in Heart Failure Current Hypertension Reviews, 2011, Vol. 7, No. 4 281

the Promotion and Mutual Aid Corporation for Private [19] Nishimatsu H, Suzuki E, Nagata D, et al. Adrenomedullin induces
Schools of Japan, and by Suzuken memorial foundation. endothelium-dependent vasorelaxation via the phosphatidylinositol
3-kinase/Akt-dependent pathway in rat aorta. Circ Res 2001; 89:
We thank Dr. Naoto Minamino, Dr. Toshihiko Ishimitsu, 63-70.
[20] Kim W, Moon SO, Sung MJ, et al. Protective effect of
Dr. Takeshi Horio, Dr. Fumiki Yoshihara, Dr. Noritoshi adrenomedullin in mannitol-induced apoptosis. Apoptosis 2002; 7:
Nagaya, Dr. Koichiro Kuwahara, Dr. Yasuaki Nakagawa, 527-36.
and Dr. Hideyuki Kinoshita for helpful advice. We also [21] Kim W, Moon SO, Sung MJ, et al. Angiogenic role of adrenomedullin
thank Mr. Kazumim Akimoto, Mr. Hisato Hirata, Mr. through activation of Akt, mitogen-activated protein kinase, and
focal adhesion kinase in endothelial cells. FASEB J 2003; 17:
Yoshifumi Machida, Ms. Yasuko Mamada, Ms. Keiko 1937-9.
Fukuda, Ms. Kyoko Tabei, Ms. Masako Minato, and Ms. [22] Nishikimi T, Matsuoka H. Adrenomedullin in hypertension.
Machiko Sakata for excellent technical assistance. Current Hypertension Review 2005; 1: 169-181
[23] Iwasaki H, Eguchi S, Shichiri M, Marumo F, Hirata Y.
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Accepted: September 10, 2011