Despite recent therapeutic advances, the
prognosis for patients with heart failure remains dismal. Unchecked
neurohumoral excitation is a critical element in the progressive
clinical deterioration associated with the heart failure syndrome, and
its peripheral manifestations have become the principal targets for
intervention. The link between peripheral systems activated in heart
failure and the central nervous system as a source of neurohumoral
drive has therefore come under close scrutiny. In this context, the forebrain and particularly the paraventricular nucleus of the hypothalamus have emerged as sites that sense humoral signals generated
peripherally in response to the stresses of heart failure and
contribute to the altered volume regulation and augmented sympathetic
drive that characterize the heart failure syndrome. This brief review
summarizes recent studies from our laboratory supporting the concept
that the forebrain plays a critical role in the pathogenesis of
ischemia-induced heart failure and suggesting that the
forebrain contribution must be considered in designing therapeutic
strategies. Forebrain signaling by neuroactive products of the
renin-angiotensin system and the immune system are emphasized.
angiotensin; aldosterone; cytokines; tumor necrosis factor; immune system; renin; vasopressin; sympathetic; extracellular fluid
volume; baroreflex
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INTRODUCTION |
THE IMPORTANCE OF AUTONOMIC dysfunction
to the progression of heart failure is firmly established (55,
113, 120, 152). The most effective treatments for heart failure
specifically target the peripheral manifestations of neurohumoral
activation (86, 113). Yet the understanding of the
mechanisms leading to neurohumoral excitation in heart failure is still
quite limited.
Over the last several decades, substantial evidence has been
amassed to support the concept that peripheral afferent systems innervating the heart and vascular tree are altered in heart failure. Dysfunction has been described in all components of the reflexes mediated by these cardiovascular afferent systems
the afferent fibers
themselves, the central processing of the afferent signals, the
efferent innervation of the end organs, and the end organs themselves.
In general, the influence of low- and high-pressure baroreceptors
(40, 42, 191) that normally restrain sympathetic drive and
vasopressin release is diminished, whereas the excitatory influences of
arterial chemoreceptors (161) and cardiac sympathetic afferent fibers (100) are enhanced.
Central nervous system (CNS) neurons affecting cardiovascular
regulation respond to humoral as well neural signals. Blood-borne neuroactive peptides, too large to readily cross the blood-brain barrier, may influence the brain by activating sensory neurons at
specific sites in hindbrain and forebrain that lack a blood-brain barrier (15, 18) or by inducing the release of mediators
that do penetrate the barrier (135). These neuroactive
substances are released in excess by peripheral tissues under the
stress of heart failure and signal the brain to alter volume regulation and autonomic function. Interestingly, the cardiovascular regions of
forebrain that sense and respond to circulating peptides (19, 81,
110) also process the signals originating in cardiovascular afferent nerves (88, 107, 162) and are capable of
modulating cardiovascular reflexes (11).
This brief review summarizes recent and emerging observations from our
laboratory that emphasize the potential importance of humoral
heart-brain signaling in the pathogenesis of heart failure. Previous
reviews have dealt extensively with other aspects of autonomic
dysfunction in heart failure (55, 113, 120), including the
altered function of cardiovascular sensory afferents (191)
and altered function of critical forebrain mechanisms, particularly
within the paraventricular nucleus of hypothalamus (PVN)
(122).
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THE NEUROHUMORAL MILIEU OF HEART FAILURE |
It is useful to consider the neurohumoral manifestations of heart
failure (86) in terms of their peripheral vs. central origins. In the periphery, after myocardial infarction (MI), a number
of vasoactive and neuroactive humoral factors are released (55). Among these are ANG II and aldosterone (Aldo),
products of the renin-angiotensin-aldosterone (RAAS) system response to a state of reduced tissue perfusion, and the pro-inflammatory cytokines, products of immune system activation in response to myocardial injury (65). These two systems are the
principal focus of this review. Both ANG II and the cytokines act
peripherally to induce effects that may be beneficial (52)
in the short-term but are ultimately detrimental as myocardial injury
progresses to heart failure. Countering these influences are the
prostaglandins PGE2 and PGI2, whose release may
be facilitated by the combined action (4) of ANG II and
the pro-inflammatory cytokine tumor necrosis factor-
(TNF-), and
the atrial natriuretic peptides, which generally oppose the adverse
effects of the RAAS (26) in heart failure.
Among neurohumoral responses in heart failure that clearly require the
involvement of CNS neurons are increased thirst and sodium appetite
(82), release of adrenocorticotropic hormone with
consequent increase in circulating corticosterone (25), release of AVP (104) with accompanying vasoconstriction
(105, 134), water retention (23), and
hyponatremia (87), and augmented sympathetic nerve
activity (91, 191) with associated increases in
circulating norepinephrine (49). Increased sympathetic
drive in heart failure is strongly associated with ventricular
remodeling (17, 53) and myocardial depression
(17), cardiac arrhythmias (159), and
vasoconstriction (53), and is an adverse prognostic indicator (49).
The heart failure syndrome is characterized by a dynamic interplay
among these centrally and peripherally driven neurohumoral responses.
For example, the responses that can be attributed to activation of
cardiovascular and autonomic centers of the brain are stimulated by
peptides released from peripheral tissues and by altered sensory inputs
from the cardiovascular systemall consequences of impaired left
ventricular function. In this regard, the central sympathetic drive and
the peripheral RAAS appear to be locked into a feedforward
relationshipblood-borne ANG II acts on AT1 receptors in
the forebrain to increase sympathetic nerve activity, which in turn
acts on the kidneys to stimulate the renin release, the rate-limiting
step in the production of more ANG II. Interestingly, central
manipulations of AT1 receptors, or of brain ouabain-like activity, which also contributes to augmented sympathetic drive in
heart failure (92), inhibit the progression of left
ventricular dysfunction after MI (93). Presuming
sympathetic mediation of this effect, the detrimental effects of
sympathetic stimulation on left ventricular function are well described
(17). Thus, whereas augmented RAAS in heart failure
activity has direct detrimental effects on left ventricular function
(36, 139, 168, 179), it is clear from this study
(93) that heart-brain signaling via neurohumoral
mechanisms is also an important determinant of left ventricular
remodeling after ischemic myocardial injury. A similar
relationship between the centrally mediated autonomic influences of
circulating ANG II and the progression of heart failure has been
suggested in the rapid pacing model (97). A hypothesis to
be tested is that in ischemia-induced heart failure blood-borne
cytokines amplify the effects of the RAAS on sympathetic drive,
compounding this compromising interaction between heart and brain.
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THE HYPOTHALAMUS AND PVN IN HEART FAILURE |
The particular constellation of centrally driven autonomic
abnormalities that define end-stage heart failure, augmented
sympathetic drive in the face of vasoconstriction, salt, and water
retention in the presence of volume overload, immediately suggests
dysfunction of the forebrain neurons that regulate these systems under
normal conditions. In a pioneering study focusing on the role of the forebrain in heart failure, Patel and colleagues (124)
demonstrated that metabolic activity was increased in the parvicellular
and magnocellular regions of the PVN in rats with
ischemia-induced heart failure. More recently, Vahid-Ansari and
Leenen (167) demonstrated that Fra-like immunoreactivity,
an indicator of long-term neuronal activation, was increased in these
same regions in rats with a large MI. Other studies (41, 78, 79,
145, 181, 185) demonstrated that manipulations within the
forebrain region affect the regulation of sympathetic drive in the rat
model of ischemic heart failure.
The anatomy and relevant physiological functions of the hypothalamus
and PVN under normal conditions (19, 82, 111, 149, 163)
and the potential involvement of this region in the pathogenesis of
heart failure (121-123) have been reviewed in detail
by others. Particularly pertinent to the heart failure syndrome are
those PVN neurons that produce and release AVP and CRF
(146) and those that project to the principal centers of
sympathetic drive, the rostral ventrolateral medulla (RVLM) and the
intermediolateral cell column (IML) of the spinal cord
(148). PVN neurons receive and integrate ascending signals
from the hindbrain regions related to pressure and volume within the
cardiovascular system (107) and signals from forebrain
regions including the circumventricular organs of the lamina
terminalis, which lack a blood-brain barrier and thus sense the
presence of blood-borne neuroactive peptides (108). Figure
1 illustrates this concept, showing that
the discharge rate of a single PVN neuron is increased by blood-borne
ANG I or ANG II administered into the ipsilateral carotid artery (ICA) but also by a reduction in arterial pressure induced by intravenous sodium nitroprusside. A fall in arterial pressure and an increase in
circulating angiotensin in response to a fall in arterial pressure would elicit the same excitatory response from this neuron. In this
instance, the angiotensin affects the neuron secondarily, via an
influence on neurons of the circumventricular organs of the lamina
terminalis. However, angiotensin can also be produced within the
blood-brain barrier (51) to activate angiotensin type-1
(AT1) receptors on PVN neurons (33, 117).
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Fig. 1.
Neural and humoral modulation of neurons in paraventricular nucleus
of hypothalamus (PVN). Single-unit recordings of PVN neuronal activity
(discharge rate, spikes/s) and arterial pressure (AP, mmHg) taken from
a normal rat. Top: unit activity increases in response to
intracarotid artery (ICA) administration of ANG II (left)
and ANG I (right). Both elicit an increase in AP. Response
to ANG I implies conversion of ANG I to ANG II in forebrain to activate
angiotensin type 1 receptors. Bottom: unit activity is
unchanged by an increase in AP induced by intravenous phenylephrine
(PE) but increases in response to lowering AP with intravenous sodium
nitroprusside (SNP). The majority of PVN neurons tested demonstrated
increased activity in response to a hypotensive challenge.
[Borrowed with permission (186).]
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In normal rats, the PVN and related forebrain nuclei play a
prominent role in thirst, sodium appetite, and humoral release (19). The role of the PVN in driving the sympathetic
nervous system, however, is less clear. In the anesthetized rat, for
example, electrical stimulation of the PVN elicits only a small pressor response (130). Similarly, the cardiovascular response of
normal rats to activation of the forebrain region with angiotensin is small (8, 173) and is restrained by baroreceptor input
(Fig. 2). Normally, the PVN is under the
potent inhibitory influence of GABA and nitric oxide, as demonstrated
by the striking increases in sympathetic drive that can be elicited by
local injection of bicuculline or inhibitors of nitric oxide synthase
(182, 183). In certain disease conditions, however,
heightened sympathetic drive emanating from the PVN may become an
important pathophysiological determinant. PVN lesions in the young
spontaneously hypertensive rat, for example, inhibit the development of
hypertension and augmented sympathetic drive (164). The
augmented humoral drive and diminished baroreceptor influence favor a
prominent pathophysiological role for the PVN in heart failure as well.
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Fig. 2.
Baroreceptor regulation of sympathetic responses to humoral
stimulation of forebrain in a normal rat. Heart rate (HR, beats/s,
bps), AP (mmHg), and renal sympathetic nerve activity (RSNA) as
integrated voltage (mV) and windowed multifiber spike activity
(spikes/s) are shown in an intact (A) and a
baroreceptor-denervated (B) rat. In the baroreceptor-intact
rat, ANG I injected centrally via the carotid artery (ICA) elicits an
increase in AP but a baroreceptor-mediated decrease in HR and RSNA.
After baroreceptor denervation, ANG I induces a parallel increase in
AP, HR, and RSNA, consistent with a centrally driven response.
[Borrowed with permission (173)].
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MI AND PROGRESSION TO HEART FAILURE IN THE RAT |
To further define the mechanisms activating the forebrain and PVN
in heart failure, our laboratory has used a multifaceted approach,
combining venous sampling of circulating peptides, metabolic cage
measurements of salt and water consumption and excretion, and
electrophysiological recording from central neurons and from sympathetic nerves in rats with a large MI produced by ligation of the
left anterior descending coronary artery and confirmed by
echocardiography. All studies were performed in accordance with the
"Guiding principles for research involving animals and human
beings" (1a).
Animals with ischemia-induced heart failure already have
significantly reduced left ventricular systolic function and an
enlarged left ventricle when evaluated by echocardiography within
24 h after coronary ligation (62). Serial
echocardiographic measurements demonstrate that the injured myocardium
thins and the left ventricle dilates further over the ensuing 6 wk, but
ejection fraction (0.36, vs. 0.82 in sham-operated controls, 2-3
wk post-MI) remains about the same (63). These heart
failure rats have increased levels of plasma renin activity, AVP, and
atrial natriuretic factor (63), and of TNF-
(61) (Fig. 3). They consume
more sodium than sham-operated control rats, and their urinary
excretion of sodium and water is reduced (63).
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Fig. 3.
Humoral milieu of ischemia-induced heart failure in the
rat. Circulating levels of plasma renin activity (PRA; A),
atrial natriuretic factor (ANF; B), AVP (C), and
tumor necrosis factor- (TNF-; D), sampled weekly from
conscious rats via a chronically implanted jugular venous cannula.
Time 0 indicates baseline control values, and the remaining
times are weeks (wks) after coronary ligation (CL). All 4 peptides had
increased 1 wk after CL. At week 3, PRA had peaked and begun
to stabilize at a lower but still increased level, but TNF- was
still rising. [Modified from Ref. 63, with
additional data from Ref. 61.]
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In heart failure rats monitored continuously by telemetry over a 6-wk
period, heart rates (HR) were higher and blood pressures lower than
sham-operated controls (Fig. 4).
Sympathetic nerve activity in conscious heart failure rats is
increased, with a characteristic pattern of unsuppressed yet still
pulse-related bursting, suggesting some degree of continued
baroreceptor modulation. As shown in Fig.
5, however, the pulse-triggered average
of sympathetic discharge is higher in the heart failure rats.
Baroreflex regulation of renal sympathetic nerve activity (RSNA) is
blunted. Studied 1 wk after coronary ligation, they exhibit signs of
psychological depression (69). Consistent with other
studies using this model, left ventricular end-diastolic pressure is
elevated when checked terminally. At postmortem exam, 6-8 wk after
coronary ligation, heart weight-to-body weight and lung weight-to-body
weight ratios are increased and pleural and/or ascitic fluid is
sometimes present. Thus rats with ischemia-induced heart
failure express many features typical of human heart failure.
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Fig. 4.
Altered hemodynamics in rats with
ischemia-induced heart failure. Data were accumulated by
telemetry from conscious rats in their home cages over a 6-wk period.
Samples acquired every 10 min were averaged to obtain the single value
shown for each week. A: systolic (circles) and diastolic
(triangles) AP are shown for sham-operated rats (SHAM, open symbols)
and rats that had undergone CL to induce heart failure (HF; filled
symbols). Before CL or sham operation, the baseline pressures (Pre)
were the same in both groups. Both systolic and diastolic pressures
were significantly (P < 0.05) lower in the HF rats at
all subsequent time points. B: HR, derived from the AP
pulse, was the same at baseline (Pre) in both groups but was
significantly (P < 0.05) higher in the HF rats at all
time points except week 6.
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Fig. 5.
RSNA is increased in
ischemia-induced HF. Tracings of integrated RSNA (mV) and AP
(mmHg) taken from conscious rats 6 wk after coronary ligation (HF) or
sham operation. Top insets show raw tracings of RSNA. TRIG,
trigger generated by the peak of the AP tracing, used to obtain a
triggered average of the integrated RSNA voltage over a 2-min interval.
Bottom insets show the triggered average of RSNA voltage for
these 2 rats. Note the pulse-locked quality of the integrated RSNA
signal in both conditions, indicating that some degree of baroreceptor
modulation persists in heart failure but the loss of a more general
modulatory influence that may be respiratory related (respiration was
not monitored in these experiments). Triggered average shows that RSNA
is increased in the HF rat on a beat-by-beat basis, unrelated to
differences in HR. [Borrowed with permission (63)].
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TESTS OF THE FOREBRAIN HYPOTHESIS |
Using this rat model of ischemia-induced heart failure, we
have performed both acute and chronic interventions to address specific
questions regarding the contribution of the forebrain to the
progression to heart failure after MI.
How important is forebrain activation to the course of heart
failure after MI?
There is no question that the forebrain is a point of access for the
variety of neuroactive substances, including ANG II, endothelin, atrial
natriuretic peptides, and cytokines, that are produced by peripheral
organs responding to the stresses associated with a large MI and heart
failure. However, the importance of the forebrain as an active
participant in the pathophysiology of heart failure, as opposed to a
passive sensor of adverse peripheral events, is less certain.
To study this question, we created MI in rats that had fully recovered
6 wk after a lesion in the anteroventral third ventricle (AV3V) region
(21), which included the organum vasculosum as well as the
pathways connecting the circumventricular organs of the lamina
terminalis to PVN. Several important findings emerged from this study,
the details of which have been published elsewhere (59).
First, the characteristic features of heart failure that were present
in MI rats with sham AV3V lesion, increased sodium appetite, the
decreased sodium and water excretion, and augmented sympathetic drive
with blunted baroreflex, were dramatically attenuated in animals with
an AV3V lesion. Second, the expected increase in plasma renin activity
did not occur in the AV3V-lesioned MI rats. These findings clearly
implicate the forebrain as an active participant in the progression of
heart failure and further suggest that the renin response to renal
underperfusion after MI may be largely dependent on sympathetic
efferent regulation emanating from the forebrain. There is some
precedent for that suggestion in previous work demonstrating that
electrical stimulation of PVN can increase renin release from the
kidney (129) and facilitate the renin response to other
usual stimuli (128). But perhaps most important was a
third finding, the survival of the AV3V-lesioned MI rats was
compromised to the extent that most had died 3 wk after MI, in contrast
to MI rats with sham-AV3V lesion and AV3V-lesioned rats with sham MI
(Fig. 6).
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Fig. 6.
Survival after myocardial infarction (MI) is compromised
in rats with a forebrain lesion. Data indicate numbers of rats
surviving a lesion of the anteroventral 3rd ventricle
(AV3V-x) or sham lesion (AV3V-s), a MI induced by coronary ligation or
a sham MI (MI-s) performed 6 wk later, and the subsequent 3 wk (Wk3) of
the study protocol. Rats with AV3V lesion had a decidedly poorer
survival after MI, compared with all other groups.  ,
AV3V-s/MI;  , AV3V-x/MI;  , AV3V-x/MI-s;
 , AV3V-s/MI-s. (Data from Ref. 59.)
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Thus the AV3V lesion identified the forebrain as important not only to
the centrally mediated (e.g., thirst, sodium appetite) mechanisms in
heart failure but to remote peripheral manifestations (e.g., renal
sodium and water handling, renin release) as well. Furthermore,
forebrain mechanisms appear to confer a survival benefit in heart
failure that cannot be ascribed simply to the ability to muster a
stress response. Work by others has shown that AV3V-lesioned rats have
elevated plasma corticosterone levels and exaggerated corticosterone
responses to volume depletion (12) and that CRF-producing
neurons PVN can be activated by circulating cytokines despite knife cut
lesions in this same general region (46). Interestingly,
because plasma renin activity did not rise after MI in the
AV3V-lesioned rats, this study did not actually address the
contribution of the peripheral RAAS as a factor activating the
forebrain in heart failure.
Does excessive activity of the RAAS drive forebrain mechanisms in
heart failure?
ANG II and Aldo, active products of the RAAS, can both act on receptors
in the forebrain to induce changes in volume regulation (82) and sympathetic drive (67, 90). In heart
failure, the circulating levels of these peptides are increased. Both
peptides can also be produced within the blood-brain barrier (22,
66). Furthermore, Aldo increases the binding of ANG II to
AT1 receptors in the subfornical organ and the PVN
(35) and also increases mRNA for vasopressin in PVN and
vasopressin release (144). In another context
(73), Aldo has been shown to promote the activity of
angiotensin converting enzyme (ACE), which produces ANG II from its
precursor ANG I. ACE is present in the forebrain and is particularly
abundant in the circumventricular organs of the forebrain (140,
143). Thus it is possible that Aldo may amplify the influences
of circulating and intrinsically produced ANG II. Whereas most of these
potential interactions have yet to be tested in the brain in heart
failure, there is evidence for increased AT1 receptors in
the forebrain of rats with high-output heart failure
(177).
We examined the influences of the RAAS on forebrain neurons in rats
with chronic heart failure (186). Single-unit recordings were made from PVN neurons in anesthetized rats 4-6 wk after MI. Heart failure was documented by echocardiography. Drugs were
administered by the intracarotid (ICA) route, directed centrally, an
approach that has been shown to preferentially influence the
ipsilateral forebrain and to spare the hindbrain (75).
The activity of PVN neurons was on average increased in rats with heart
failure, although the discharge rate of some neurons remained within
the range of normal (Fig. 7). Neurons
with high discharge frequencies were tested for the effects of
selectively blocking several components of the RAAS. The effects of the
AT1 receptor blocker losartan, the ACE inhibitor captopril,
and the mineralocorticoid (MC) receptor antagonist spironolactone were tested. Both losartan and captopril substantially and transiently reduced the discharge rate of PVN neurons and arterial pressure (Fig.
8). Spironolactone also reduced the
discharge rate of PVN neurons but with a longer latency and without
affecting arterial pressure.
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Fig. 7.
Neuronal activity in PVN is augmented in rats with
ischemia-induced HF. Baseline discharge rates from normal
Sprague-Dawley rats (NORM), rats with HF 6-8 wk after MI, and rats
that underwent sham-coronary ligation are shown. SHAM resemble NORM,
but HF rats have a generally higher discharge frequency. However, there
was overlap among groups in the lower discharge frequencies, not all
PVN neurons from HF rats had increased discharge frequency. Projection
sites for neurons with higher vs. lower firing frequencies have not yet
been determined. Values are means ± SE. [Borrowed with
permission (186).]
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Fig. 8.
Increased PVN neuronal activity in HF can be reduced by
AT1 receptor blockade or by inhibition of angiotensin
converting enzyme. Top: recordings from HF rats treated with
forebrain directed ICA injections of losartan (A) and
captopril (B). Bottom: change in PVN neuronal
activity for each unit studied, represented as %change from baseline
firing rate. Losartan (C) and captopril (D)
induced comparable significant (P < 0.05) reductions
in PVN firing rate in the HF rats; PVN neurons from sham-operated rats
showed no consistent change from baseline.  , Data from
baroreceptor intact rats; , data from baroreceptor
denervated rats. Horizontal bars indicate mean values for the groups.
Values are means ± SE. (Modified from Ref. 186.)
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Several new insights emerged from these studies. First, as predicted by
previous work (124), neuronal activity in the PVN is
generally (but not uniformly) increased in rats with
ischemia-induced heart failure. The specific types of cells
that have augmented activity, e.g., sympathetic premotor vs.
neurosecretory, remain to be determined. Second, the RAAS, whether
intrinsic or circulating, contributes importantly to this increased
activity. Third, the captopril data indicate that intrinsic ACE
activity in the forebrain is increased in the heart failure rats. In
theory, because increased ANG II can upregulate AT1
receptors (175), the losartan data and the captopril data
might both be explained by a common mechanism, augmented CNS production
of ANG II by ACE in heart failure, perhaps facilitated by Aldo, rather
than an independent increase in both components of central RAAS. This
hypothesis remains to be tested. Finally, despite a chronic high
discharge rate in heart failure, PVN neurons remain responsive to acute
manipulations of the RAAS. This latter point has important implications
for the clinical treatment of heart failure, suggesting that acute
interventions can have substantial impact on central neural mechanisms
despite the chronic nature of the heart failure syndrome.
Will chronic manipulation of the RAAS at the forebrain level alter
the course of heart failure after MI?
In another set of experiments (62), we examined the effect
of a selective intervention in the RAAS at the CNS level. At the time
this study was designed there was increasing interest in the role of
aldosterone as an untreated element in heart failure (125,
157). The recently published RALES trial (127)
demonstrated that the addition of a small dose of the MC receptor
antagonist spironolactone to the medical regimen of patients already
optimally treated for heart failure resulted in substantial reductions
in morbidity and mortality. MC receptors have well-known effects in
brain to increase sodium appetite (34), ANG II binding in subfornical organ and PVN (35), vasopressin production and
release into the circulation (144), and sympathetic drive
(67). However, none of these central influences had been
directly examined in the heart failure setting. We therefore elected to
test the effect of chronic central administration of spironolactone on
volume regulation and sympathetic drive in rats with heart failure
induced by MI.
In these experiments, rats underwent echocardiography the day after MI
or sham MI to verify their left ventricular function and to assign them
to treatment groups. MI and sham-MI rats were assigned to treatment
with a chronic infusion of spironolactone or its ethanol vehicle
administered either intracerebroventricularly or intraperitoneally. The
dose chosen for intracerebroventricular administration was known to
have CNS effects (176), and the intent of the identical
intraperitoneal dose was to control for potential effects of leakage
from the CNS.
Central MC receptor blockade produced the expected behavioral effect of
reducing salt intake in the heart failure rats. Surprisingly, however,
within the first week of treatment urinary sodium and water excretion
had normalized in the MI rats treated with intracerebroventricular spironolactone, whereas these variables remained abnormally low in the
MI rats treated with intraperitoneal spironolactone. However, 2 wk into
the protocol, rats receiving intraperitoneal spironolactone also
experienced normalization of sodium appetite and renal handling of
sodium and water. After 4 wk of treatment by either route, the
spironolactone-treated MI rats had a reduction in sympathetic discharge
(Fig. 9) and some, but not complete,
improvement in baroreflex function. The impact of spironolactone
treatment on survival could not be evaluated because rats were
euthanized at the conclusion of the study to obtain anatomical evidence
of myocardial injury and heart failure. However, at the 2-wk time
point, at which most AV3V-lesioned rats from the above study were dying post-MI, the spironolactone-treated rats appeared to be in satisfactory condition. In a follow-up study (60), we found that a
reduction in sympathetic drive occurs as early as 2 wk after starting
central spironolactone treatment of MI rats, an effect not seen in the MI rats treated with peripheral spironolactone. Thus, although in
theory amelioration of the baroreflex effects of high circulating aldosterone (170) may have contributed to the reduced
sympathetic drive and HR in the rats treated with intraperitoneal
spironolactone, the results of our studies indicate that spironolactone
acts centrally on MC receptors to reduce sympathetic drive in heart
failure. This mechanism may account at least in part for the beneficial effect of spironolactone in the clinical setting. In our studies, the
intraperitoneal dose of spironolactone was intentionally low to allow
us to identify a CNS effect; at higher doses, one might anticipate an
early centrally mediated effect of the peripherally administered drug
as well.
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Fig. 9.
Chronic mineralocorticoid receptor blockade reduces sympathetic
drive and HR in rats with ischemia-induced HF. A: HF
rats were treated with continuous infusion of spironolactone (SL) or
the ethanol vehicle (VEH) into the cerebral ventricles for 4 wk,
beginning the day after left coronary artery ligation. Compared with
the vehicle-treated HF rats (n = 6, hatched bars), the
SL-treated HF rats (n = 7, solid bars) had
significantly (P < 0.05) lower HR and RSNA,
quantitated as integrated voltage (Int Volt) or as area under the curve
(mV-sec) of the waveform average of the integrated voltage signal
triggered by the peak of the AP pulse over a 2-min interval (see Fig.
5). MAP was not different in the 2 treatment groups. B: HF
rats were treated with continuous intraperitoneal infusion of SL or the
ethanol vehicle for 4 wk, beginning the day after left coronary artery
ligation. Compared with vehicle treatment (n = 7),
intraperitoneal SL (n = 6) also resulted in
significantly (P < 0.05) lower HR and RSNA at 4 wk,
again without a significant difference in MAP. These findings suggest a
beneficial influence of mineralocorticoid receptor blockade on
autonomic regulation in heart failure. Other data from the same study
groups (62) and data from an additional study of early
effects of ICV SL (60) suggest that the SL acts centrally
to reduce sympathetic drive in HF rats.
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THE CYTOKINE CONNECTION |
In a retrospective analysis of humoral variables from this chronic
spironolactone study (62), a surprising discovery was made: the circulating levels of TNF- were normal in the MI rats treated with central infusion of spironolactone. Vehicle-treated MI
rats had the anticipated increase in TNF- (Fig.
10). Whether the brain produces less
TNF- or signals peripheral tissues to reduce cytokine production
remains to be determined. However, the observation suggests a
previously unrecognized central link between the immune system and the
RAAS in heart failure and yet another reason why MC receptor blockade
might be beneficial in heart failure.
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Fig. 10.
Central blockade of mineralocorticoid receptors reduces
blood-borne TNF-. Measurements obtained from conscious rats with
chronically implanted jugular venous catheters before and at weekly
intervals after CL. SL or its vehicle ethanol was administered
continuously into the cerebral ventricles via osmotic minipump. HF
induced by CL resulted in the expected increase in TNF- (HF-VEH). In
HF rats treated with SL (HF-SL), this increase did not occur. TNF-
levels did not change in the rats subjected to sham CL (SHAM-SL;
SHAM-VEH). Values are means ± SE. (Data from Ref.
62.)
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The immune system is activated by injury or inflammation. Both MI
(65) and heart failure (151) are associated
with immune system activation. In the heart failure and MI literature,
the most studied of the proinflammatory cytokines are TNF-,
interleukin-6, and interleukin-1
(6, 38, 39, 84, 118,
131). In our rat model (61), blood-borne TNF-
increases as early as 30 min after coronary artery ligation.
"Resident" monocytes and macrophages within the heart
(64), and myocytes themselves (32), are
likely sources of circulating proinflammatory cytokines early after MI (112). However, because one of the effects of the
proinflammatory cytokines is to promote further cytokine production,
the sources of circulating cytokines in established heart failure are
likely ubiquitous (10).
The persistence of proinflammatory cytokines in the circulation has
numerous potential deleterious peripheral effects (10, 112), including depression of myocardial function
(16), activation of reactive oxygen species
(32), and stimulation of the renin-angiotensin system by
impairing feedback regulation by circulating ANG II (3).
The cytokines also act on the CNS (77, 135, 166). Although
too large to readily cross the blood-brain barrier, they nevertheless
activate the hypothalamic-pituitary-adrenal (HPA) axis
(135) to augment sympathetic drive (116, 141)
and increase the release of vasopressin and ACTH (27, 43, 106,
166), all components of a feedback inhibitory mechanism that
restrains the peripheral inflammatory response. In a series of
functional anatomical studies, Ericsson and colleagues (45,
46) provided evidence that acutely administered IL-1 elicits
these responses indirectly by activating its receptors on endothelial
cells in cerebral circulation that in turn release PGE2.
PGE2 diffuses across the blood-brain barrier and appears to
preferentially activate receptors on neurons in the ventrolateral
medulla (45). These investigators further demonstrated
that an ascending pathway from the ventrolateral medulla is a critical
element of the PVN response to systemically administered IL-1
(46) and that stimulation of C1 catecholaminergic neurons
in RVLM with PGE2 provides excitatory input to PVN,
simulating the response to intravenous cytokine administration
(45). Subsequent studies have supported this general
concept (116) but have further suggested that
PGE2 might activate sympathetic drive directly at the
forebrain level (2), perhaps even via prostaglandin
synthesis inside the blood-brain barrier (102).
This model of immune activation of the forebrain is particularly
interesting when considered in the context of heart failure. In heart
failure, cytokine production persists (38) despite this
combined HPA and sympathetic feedback pathway, and the pro-inflammatory cytokines act on the same general classes of neurons, CRF, AVP, and
presympathetic, that mediate the central effects of the RAAS. Moreover,
PGE2 production is increased generally in heart failure, in
which its vasodilator properties counterbalance the vasoconstrictor effects (44) of such peptides as ANG II, vasopressin, and endothelin.
This remarkable convergence of immune system mediators and RAAS
mediators, seemingly affecting the same general populations of neurons
in the forebrain, led us to test several elements of the proposed
mechanism (Fig. 11) of cytokine-induced
HPA axis activation, but in the context of cardiovascular regulation.
ICA TNF- increases RSNA, mean arterial pressure (MAP), HR, and the
discharge rate of anesthetized RVLM neurons in PVN rats
(187). The cardiovascular and sympathetic responses to
TNF- were not different in rats that had undergone bilateral
cervical vagotomy 1 h before testing, confirming that the acute
cardiovascular responses to blood-borne TNF- are not dependent upon
vagal afferent activation (188). We then compared the
effects of intravenous TNF- on RSNA, MAP, and HR in intact rats and
rats that had undergone a mid-collicular decerebration 1 h before
study. The decerebrate rats had no response to TNF-, suggesting the
involvement of higher centers, but a significant increase in the
baseline values rendered these data inconclusive (188).
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Fig. 11.
A model for cytokine activation of the
central nervous system in HF after MI, based on work cited in
text. Injured heart itself is a site of early cytokine production,
recruiting other cytokine-producing organs. Blood-borne cytokines
activate their receptors in blood vessels at the blood-brain barrier,
stimulating the production of prostaglandins (PGE2) that
can cross blood-brain barrier (BBB). A principal target is
catecholaminergic neurons (CA) in the rostral ventrolateral medulla
that project to PVN to activate neurons containing CRF and AVP and
presympathetic neurons. CRF neurons regulate release of ACTH and AVP
into the circulation, but some of these neurons also project to brain
stem and spinal cord where they may contribute to sympathetic
activation. The outcome of cytokine activation of PVN is an increase in
circulating corticosterone and AVP and an increase in sympathetic
drive, all feeding back to inhibit the peripheral immune system. In HF,
however, cytokine production persists despite these feedback
mechanisms. SNA, sympathetic drive; IML, intermediolateral cell column
of the spinal cord.
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We subsequently examined the effects of the putative diffusible
cytokine mediator PGE2 on sympathetic nerve discharge,
arterial pressure, and HR, and simultaneously recorded PVN or RVLM
neuronal activity (188). PGE2 administered
intracerebroventricularly increased the activity of PVN neurons and all
three measures of sympathetic drive; PGE2 microinjected
into PVN increased the activity of RVLM neurons and the indexes of
sympathetic drive. These studies suggest that if PGE2 is
produced in the forebrain region during cytokine stimulation, it may
directly activate sympatho-excitatory PVN neurons. Finally, the
cyclooxygenase inhibitor ketorolac, administered intracerebroventricularly, blocked the increases in PVN neuronal discharge and RSNA and the pressor response to ICA TNF-
(188). These results strongly support the general
hypothesis that PGE2 is a critical mediator of central
influences of TNF- on sympathetic drive, but also suggest that the
cardiovascular and autonomic responses to TNF- may ultimately be
dependent on prostaglandin production by cyclooxygenase within the CNS
rather than in perivascular cells of the blood-brain barrier (45,
135). A similar mechanism has also been proposed for activation
of splenic nerve activity by peripheral endotoxin (102), a
stimulus to cytokine production. We have not yet tested this hypothesis
with antagonists for PGE2 in the key CNS sites (RVLM and PVN).
Extrapolating these concepts and findings to the heart failure setting,
one might speculate that cytokine signaling of the HPA, which under
normal circumstances serves to regulate the immune system, targets a
population of PVN neurons that are already strongly driven in heart
failure by excessive activity of the RAAS. Are these two systems
redundant or facilitatory? In preliminary studies (unpublished data)
the acute administration of entanercept to rats with heart failure
appears to decrease PVN neuronal activity, presumably by reducing
circulating TNF-. This observation suggests that circulating TNF-
affects PVN neurons independently of RAAS. Further studies will be
required to address the relative contributions of cytokines and RAAS to
the altered central regulation of fluid volume and sympathetic drive in
heart failure.
It is important to note that our preliminary results (187, 188)
regarding the central effects of TNF- and PGE2, and much of the data cited from the pertinent literature regarding cytokine mechanisms and effects (2, 45, 46, 101, 102), are derived from acute immune challenges or interventions. In the chronic, established heart failure setting, other mechanisms may be operative. Thus, although the passage of cytokines is restricted by the
blood-brain barrier, active transport mechanisms exist (7)
that may facilitate their entry under conditions such as heart failure
that are characterized by chronically elevated circulating cytokine
levels. Signaling via vagal afferents (103) may play a
more prominent role. The brain itself is capable of producing cytokines
(119), and neuronal content of cytokines is increased in
certain chronic disease states (138). Interestingly, mice
treated with continuous infusion of high dose PGE2,
simulating the high levels in heart failure, demonstrate increased
brain cytokine content (169). In our preparation, using immunohistochemistry and real time RT-PCR, mRNA for TNF- is
increased in hypothalamic neurons as early as 60 min after MI
(56).
The potential production of proinflammatory cytokines in the brain
itself raises interesting untested possibilities for interactions between the RAAS and cytokines. Does TNF- promote renin production in the brain as it does in the kidney (3), stimulating
brain RAAS? Does TNF- upregulate the message for AT1
receptors in the brain after MI, as it does in heart (71)?
Does TNF- stimulate prostaglandin synthesis within the blood-brain
barrier, providing an excitatory input to forebrain neurons? Both
TNF- (32) and RAAS (68) can stimulate
reactive oxygen species, which may also drive sympathetic activity
(189). Does the presence of both in forebrain contribute
to the increased sympathetic drive in heart failure? If TNF-
production increases in the forebrain early after MI in rats
(56), and brain is a potential source of circulating TNF- (132), to what extent is brain a source of the
high circulating levels of TNF- in heart failure vs. a command
center signaling peripheral tissues to produce cytokines? These and
related questions are fertile ground for future studies of the
contribution of pro-inflammatory cytokines to the progression of heart failure.
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SYMPATHETIC DRIVE IN HEART FAILURE: A HYPOTHETICAL CONSTRUCT |
The PVN is clearly emerging as a pivotal site in the forebrain
that responds to the peripheral signals of homeostatic imbalance in a
manner that is at once both essential to survival and detrimental if
perpetuated over time. Some of the peripheral signals that may impact
the function of this region of the brain in heart failure are
illustrated in Fig.
12A, in
the context of sympathetic regulation. PVN neurons directly innervate
preganglionic sympathetic neurons in the IML, as well as presympathetic
neurons in the RVLM and neurons in the nucleus of the solitary tract
(NTS), the site of first termination for cardiovascular afferent nerve
fibers (31, 74, 96, 158, 163).
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Fig. 12.
Extrinsic factors affecting regulation of SNA
by the PVN in heart failure. A: descending pathways from PVN
are shown in double lines. PVN neurons project monosynaptically to
rostral ventrolateral medulla (VLM), the nuclei of the solitary tracts
(NTS), and the IML, all of which may affect SNA. In HF, peripheral
sensory receptors that project centrally to modulate sympathetic drive
are altered, with reduced arterial baroreceptor restraint of SNA and
increased arterial chemoreceptor stimulation of SNA. These signals
(dashed lines) initially impinge on neurons in the NTS and from there
are relayed rostrally either directly or indirectly (e.g., via VLM) to
affect the activity of PVN neurons. Blood-borne products of the
renin-angiotensin-aldosterone system (RAAS) may activate the forebrain
directly (e.g, aldosterone) or via effects on circumventricular organs,
and intrinsic components of RAAS may be stimulated to generate these
peptides locally within the forebrain. Influences of the RAAS are
illustrated as squiggly lines. B: putative influences of the
cytokines in HF are shown superimposed on the schema A.
There are several mechanism, shown as dotted lines, by which cytokines
might activate PVN neurons driving sympathetic activity. By binding to
receptors on vascular endothelium or other elements of the BBB,
circulating cytokines stimulate the production of PGE2,
which diffuses readily across BBB. With respect to acute activation of
the hypothalamic-pituitary-adrenal (HPA) axis, it has been suggested
that PGE2 preferentially stimulates catecholaminergic (CA)
neurons in the RVLM that then ascend to activate neurons in the PVN. In
HF, in which cytokine levels are chronically elevated, other mechanisms
may come into play. These include peripheral activation of vagal
afferent fibers, activation of circumventricular neurons with secondary
projections to PVN, passage of cytokine across BBB via active transport
mechanism, and production of cytokines by neurons and glial cells
within the BBB. The mechanism for cytokine activation of SNA, their
interactions with altered peripheral afferent systems and RAAS, and
their contribution to the augmented SNA in heart failure are still
poorly understood.
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We know that cardiovascular afferent systems are altered in heart
failure (192). The activity of sympatho-inhibitory
systems, such as the high-pressure arterial baroreceptors
(190) and low-pressure cardiac mechanoreceptors
(192), is reduced, whereas the activity of
sympatho-excitatory systems, such as arterial chemoreceptors (161) and cardiac sympathetic afferent fibers
(171), is increased. The central processing of these
afferent signals is also altered (99, 100). The
cardiovascular afferent signals entering the NTS ultimately affect the
discharge of PVN neurons, via direct projections from NTS or a more
circuitous route involving a synapse in the ventrolateral medulla
(29, 107, 147). For example, the majority of PVN neurons
responding to ICA ANG II also respond to changes in arterial pressure
(186), and baroreceptor regulation of vasopressin release
is a well recognized phenomenon (165). Thus the increased
activity of PVN neurons in heart failure likely reflects the
compromised state of cardiovascular afferent systems, whether at the
sensory ending, in the afferent fiber, or in the hindbrain processing
of the afferent signal.
The excessive activity of the peripheral RAAS in heart failure may
influence PVN neurons indirectly, via actions of circulating ANG II on
neurons in the circumventricular organs (110) of the forebrain. With chronic elevation of ANG II, one might also anticipate an influence from area postrema, a circumventricular organ in the
medulla (54). In addition, there is suggestive evidence that the activity of the intrinsic brain RAAS may be upregulated in
heart failure (177). As mentioned above, Aldo may
facilitate the forebrain actions of the peripheral or intrinsic RAAS
(35).
Finally, as illustrated in Fig. 12B, immune system
activation may influence PVN neurons indirectly via the production
prostaglandin mediators (45, 136), directly via transport
of cytokines across blood-brain barrier (7), or by as yet
poorly understood effects of cytokine production within the blood-brain
barrier itself (56, 119, 169). In our studies
(188), vagal afferent activation (103) did
not seem to affect PVN or sympathetic responses to the acute
administration of TNF-, but a role for this afferent pathway in
established heart failure, in which cytokines are chronically elevated,
cannot be excluded.
Multiple interactions among these three regulatory systems are possible
within PVN. For example, the connections ascending from NTS and
ventrolateral medulla that convey afferent signals generated by
cardiovascular afferent inputs (147) are predominantly catecholaminergic. The cytokine influence on PVN neurons is also mediated at least in part by catecholaminergic neurons ascending from
RVLM (46). A cytokine-mediated increase in norepinephrine release into PVN has also been demonstrated after peripheral injection of endotoxin (58). ANG II has a pronounced effect on
norepinephrine release within the PVN (156). All three
systems, cytokines, cardiovascular afferents, ANG II, influence the
activity of CRF neurons, AVP neurons, and presympathetic neurons in
PVN, which are modulated by catecholaminergic inputs (20, 27, 30,
70, 76, 80). Moreover, norepinephrine is critical to the
regulation of autonomic functions by this region of the brain
(13, 24). For example, catecholamine depletion in ventral
lamina terminalis blocks drinking and pressor effects of ANG II, via
effects on adrenergic neurons (14). Thus a parsimonious
unifying hypothesis to explain the coordinated excesses of neurohumoral
drive emanating from this region of the brain in heart failure might be
intense catecholaminergic stimulation of PVN neurons, perhaps
overwhelming local regulatory systems (see below). In rats with
ischemia-induced heart failure, an in vivo microdialysis study
(9) demonstrated a striking increase in norepinephrine
release into PVN compared with sham-operated control animals. In humans
with heart failure, excessive catecholamine turnover in the brain
correlates with augmented sympathetic drive (89).
Finally, although this review has focused on the convergence of neural
and humoral signals that might drive the activity of PVN neurons, it is
important to remember that altered neurotransmitter mechanisms within
the PVN itself contribute to altered PVN neuronal function and
sympathetic drive in heart failure. GABA and nitric oxide clearly play
an important role in regulating PVN neurons in normal rats
(183). The potential contribution of the altered function
of these mechanisms within PVN to the augmented sympathetic drive in
heart failure has been extensively examined and reviewed by Patel and
colleagues (122). The influence of inhibitory mechanisms within PVN is substantially diminished in rats with heart failure (180, 181, 184), and the influence of excitatory mediators is increased (94). In part, these changes may reflect
altered neural inputs to PVN. For example, GABA is involved in the
baroreceptor modulation of neurosecretory PVN neurons
(85); a reduction in baroreceptor function in heart
failure might well result in a reduction of GABA levels in PVN.
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TRANSLATIONAL ASPECTS |
Despite recent advances in the treatment and the primary
prevention of heart failure (1, 115, 168, 178), the
long-term prognosis for patients who present with this diagnosis
remains dismal and the economic burden to the health care system is
huge (47, 133). In this perspective, a consideration of
the role of the brain may be critically important in the development of effective therapeutic strategies.
ACE inhibitors and diuretics are first-line therapy for patients with
heart failure. This same drug combination has been used for years by
physiologists to stimulate thirst in normal rats by increasing
circulating levels of ANG I, which is converted to ANG II in the
forebrain to stimulate AT1 receptors (82). The
circumventricular organs of the forebrain contain higher concentrations of ACE than any peripheral tissue (140, 143), including
the lungs, which are the principal site for conversion of circulating ANG I to ANG II. Experimentally, lower dose ACE inhibitor has been
shown to stimulate forebrain neurons, an effect blocked by higher doses
(109). Interestingly, in that study, pretreatment with an
AT1 receptor blocker prevented the low dose effect. In our
experiments, lower doses of systemically administered ACE inhibitor
reduced arterial pressure, a peripheral effect of diminished ANG
II-mediated vasoconstriction and/or increased bradykinin-mediated vasodilation, but actually increased PVN neuronal activity (Fig. 13). Because clinical dosing of ACE
inhibitor is frequently empiric, and if monitored at all is primarily
directed toward the clinical endpoint of reducing systemic vascular
resistance, it is likely that the doses used are sufficient to increase
circulating ANG I but insufficient to block the conversion of ANG I to
ANG II by ACE in the CNS. Thus it is reasonable to hypothesize that an unrecognized source of thirst, sodium appetite, and increased sympathetic drive persists despite seemingly appropriate treatment. One
might also hypothesize that the concomitant use of AT1
receptor blockers would ameliorate these potential untoward CNS effects of ACE inhibition. These hypotheses are amenable to clinical testing.
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Fig. 13.
Effects of inhibiting ACE with systemically administered captopril
are dose dependent. Top: records from a sham-operated rat
(A) and a rat with ischemia-induced HF (B). Both
low dose (A) and high dose (B) captopril lower
AP, but the higher dose is required to achieve the central effect of
reducing PVN neuronal discharge. Bottom: changes in PVN
neuronal discharge for the low dose (C) and high dose
(D) treatment groups, represented as %change from baseline
firing rat. Horizontal bars indicate means for the grouped data.
[Modified from Ref. 186].
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The addition of an MC receptor antagonist to a standard heart failure
regimen has recently been shown to have a dramatic impact on morbidity
and mortality (127). This result could not be attributed to a diuretic effect. Aldo is known to "escape," or at least to be
inadequately suppressed, in a substantial number of patients treated
with ACE inhibitor (125, 159) and has been shown to have
deleterious effects on the heart and vasculature (172) and to impair the baroreflex (170). Aldo also has CNS effects,
described above, to augment sympathetic drive (67) and
vasopressin release (144) and may facilitate the central
influences of ANG II (35, 160, 175). We have found that
the MC receptor antagonist spironolactone, acting centrally, decreases
renal sympathetic activity (62), improves renal handling
of sodium and water (62), and reduces circulating levels
of TNF- (61) in rats with heart failure. The hypothesis
that central MC receptors play a role in regulating the production of
TNF- is strengthened by the finding that deoxycorticosterone, a
precursor of Aldo, induces sodium appetite and an increase in circulating levels of TNF- (57), an effect that is
blocked by central administration of spironolactone (57).
Whether spironolactone, or the more selective MC receptor antagonist
eplerenone (37), which is currently undergoing clinical
testing (126), has similar beneficial effects in humans
remains to be determined. This, too, is a readily testable hypothesis.
New strategies directed toward treatment of the central influences of
RAAS patients with heart failure will require a reconsideration of
pharmacological properties of commonly available drugs and perhaps
development of drugs that specifically target the CNS. Although
currently used ACE inhibitors, AT1 receptor blockers and MC
receptor antagonists may act upon the CNS, either by crossing blood-brain barrier (95, 150, 174) or by acting upon the
circumventricular organs that lack a blood-brain barrier (50,
137, 140, 142), their design and clinical usage target
peripheral endpoints. Ideally, it might be possible to continue
treating the adverse peripheral consequences of RAAS, e.g.,
vasoconstriction, cardiac and vascular remodeling, while increasing the
ability of these agents to penetrate brain regions whose intrinsic RAAS
activity may actually be augmented by predominantly peripheral ACE
inhibition in heart failure. The forebrain circumventricular organs,
rich in ACE (140, 143) and AT1 receptors
(50, 142) and lacking the protection of the blood-brain barrier, would appear to be easily accessible targets for therapeutic intervention.
A limited understanding of cytokine mechanisms has precluded aggressive
clinical treatment of the immune system in heart failure. In fact,
etanercept, a fusion protein that binds circulating TNF- has
recently been withdrawn from a major clinical trial in heart failure
due to lack of efficacy (98). Etanercept has been
efficacious in the treatment of rheumatoid arthritis (83),
and both etanercept and infliximab, a monoclonal antibody to TNF-,
are both currently used in the treatment of inflammatory bowel disease
(83), two other chronic clinical conditions characterized
by increased circulating TNF-, and have beneficial effects in a
number of other inflammatory diseases (83). Considering
the wide range of adverse effects of blood-borne TNF- in heart
failure, some of which have been touched upon in this review, it seems
likely that these agents will eventually reach the clinical heart
failure arena. Whereas blood-borne TNF- seems an obvious target for
intervention, its presence in the blood indicates excessive production
of TNF- at the cellular level. In that regard, pentoxifylline, which
inhibits the production of TNF- (5) and has been used
clinically for many years to treat vascular insufficiency
(114), has shown some promise in small clinical studies of
heart failure (153, 154). Thalidomide also inhibits
TNF- production (48). In the context of the potential
CNS effects of TNF-, our data suggest that limiting tissue
production and binding circulating cytokines might both be useful
therapeutic approaches in heart failure.
Our data have also confirmed a role for prostaglandins as mediators of
the cardiovascular and autonomic effects of circulating TNF-,
resembling their effects as mediators of cytokine activation of the HPA
axis (45) and have demonstrated a beneficial effect of a
centrally administered cyclooxygenase inhibitor on these cardiovascular
endpoints. It is important to note, however, that systemic
cyclooxygenase inhibition is counterproductive in severe heart failure,
because it eliminates the beneficial compensatory vasodilator effects
of circulating PGE2 and PGI2 (72).
The demonstration that cyclooxygenase inhibition within the CNS blocks
the sympatho-excitatory influences of circu
TOP
ABSTRACT
INTRODUCTION
