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-adrenergic signaling results
in myocardial TNF- expression and contractile dysfunction
Division of Vascular Surgery, University Health Network and Department of Surgery, University of Toronto, Toronto, Ontario, Canada M5G 2C4
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemorrhagic
shock (HS), secondary to major blood loss, frequently precedes multiple
organ dysfunction and is accompanied by a surge in circulating
catecholamine levels. Expression of the cardiodepressant cytokine,
tumor necrosis factor-
(TNF-), has been observed in the heart
after HS and resuscitation (HS/R) and 1-adrenergic
blockade prevented translocation of the nuclear transcription factor,
NF-
B, to the nucleus. We hypothesized that 1-adrenergic stimulation induces myocardial TNF-
expression, which results in depressed cardiac function after HS/R. The
role of 1-adrenergic stimulation in myocardial TNF-
expression and depressed cardiac function after HS/R was assessed by
treatment with the 1-adrenergic inhibitor, prazosin
hydrochloride (1 mg/kg ip), for 1 h before the onset of
hemorrhage. In addition, TNF- was neutralized with a specific
antibody (600 µl/kg iv) 5 min before hemorrhage. HS was induced by
the withdrawal of blood to a mean blood pressure of 50 mmHg for 1 h. Contractile function was measured with the use of a Langendorff
apparatus 2 h after the end of HS. HS/R led to significant
decreases in left ventricular developed tension and in the maximal rate
of pressure increase over time during both contraction and relaxation.
Myocardial expression of TNF- measured by enzyme-linked
immunosorbent assay increased significantly after 30 min of hemorrhage
and peaked after 60 min of HS and 45 min of resuscitation. Depression
in cardiac function after HS/R was reversed by 85% in hearts from rats
treated with a TNF- neutralizing antibody and by 90% in hearts from
rats treated with prazosin hydrochloride. We conclude that HS activates
a 1-adrenergic pathway, resulting in TNF- expression
in the heart and depressed myocardial contractile function.
hemorrhagic shock; left ventricular function; cytokines; adrenergic
stimulation; tumor necrosis factor-
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HEMORRHAGIC SHOCK (HS) is a common complication of blunt and penetrating trauma, gastrointestinal bleeding, and the rupture of a major blood vessel. HS and resuscitation (HS/R) has been described to be a "whole body" ischemia-reperfusion (I/R) injury contributing to the development of multiple-organ dysfunction (38). Both hemorrhage alone and hemorrhage combined with a second injury have been shown to induce myocardial, hepatic, respiratory, renal, and intestinal dysfunction (33). Two hours of HS without resuscitation to a mean arterial blood pressure (MAP) of 30 mmHg reduced cardiac contractile function by 40% (15). The mechanisms by which hemorrhage induces such profound depression in cardiac contractility have not been well characterized.
Tumor necrosis factor- (TNF-), a pleiotropic cytokine, has been
implicated as a mediator in various cardiac pathologies, including
acute myocardial infarction, congestive heart failure, atherosclerosis,
viral myocarditis, and sepsis-induced cardiac dysfunction (24,
25, 30, 39). The cardiomyocytes in the myocardium have recently
been implicated as a rich source of TNF- (7, 11, 19).
The role of TNF- in the myocardium after HS/R was first described by
Meldrum et al. (31), when 20 min of HS and 20 min of
resuscitation resulted in a significant elevation of myocardial TNF-
and translocation of the nuclear transcription factor, NF-B, to the
nucleus. In a rat model of HS, combined with lower-torso
ischemia (simulating ruptured abdominal aortic aneurysm
repair), a significant depression in cardiac contractile function was
noted, which was primarily mediated by HS. Immunoneutralization of
TNF- in this model significantly improved cardiac contractile function by 50% (36). Thus TNF- may play a significant
role in mediating the depressed cardiac contractile function that we observed after HS/R.
The mechanism by which TNF- is expressed in the myocardium after HS
and the length of HS required to induce myocardial TNF- expression
also remain undefined. Meldrum et al. (27) has studied the
potential of HS to induce preconditioning of the myocardium for
subsequent global myocardial ischemia.
1-Adrenergic receptor blockade abolished the
preconditioning effect of HS, resulting in a significant reduction in
cardiac contractile function after myocardial I/R. Subsequently,
1-adrenergic stimulation was shown to play a role in
inducing NF-B translocation to the nucleus after HS
(28). NF-B is widely accepted as a potent transcription factor for TNF- (35). Previous studies (8)
showed that HS results in activation of autonomic pathways, resulting
in a significant release of catecholamines into the circulation.
Catecholamines have been linked with the impaired cardiac contractile
function noted after HS (22). These data suggest that the
1-adrenergic pathway may be responsible for the
induction of myocardial TNF- expression after HS.
We hypothesized the 1-adrenergic pathway is activated by
HS leading to myocardial TNF- expression and depressed contractile function. Therefore, the time course of myocardial TNF- expression after HS/R and the role of 1-adrenergic stimulation in
the expression of myocardial TNF- were studied. The effect of
TNF- neutralization and 1-adrenoreceptor blockade on
cardiac contractile function was also assessed.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials. Adult male Sprague-Dawley rats weighing 350-400 g (Charles River; Wilmonton, MA) were allowed to acclimatize for 5 days and given water and rat chow ad libitum. All of the experiments were carried out in accordance with the requirements of the Animals for Research Act of Ontario and the regulations of the Toronto Hospital Animal Care Committee. Unless otherwise specified, all chemicals and reagents were obtained from Sigma (St. Louis, MO).
Surgical procedure. Rats were anesthetized intraperitoneally with pentobarbital sodium (50 mg/kg). Catheters (22 gauge) were placed in the tail vein and carotid artery, and a tracheostomy (14-gauge catheter) was inserted. Venous access was used for administration of supplemental anesthetic, return of withdrawn blood, and fluid resuscitation (lactated Ringer solution). The carotid artery was utilized for measurement of MAP (model 78304A, Hewlett-Packard; Palo Alto, CA) and removal of blood for the induction of HS. The animal was allowed to stabilize for 30 min until hemorrhage was induced.
HS model. Hemorrhage was induced by the removal of blood through the carotid artery over a 5-min period to reduce the MAP to 50 mmHg. MAP was maintained at 50 mmHg for predetermined time intervals by continuous removal of blood and no systemic anticoagulant was given. The blood was removed into a 10-ml syringe that contained 1 ml of saline and 100 U of heparin sodium to prevent clotting in the syringe. After the HS period, animals were resuscitated with the shed blood and additional lactated Ringer solution over a 5-min period to return the MAP to preshock levels. Animals were maintained for up to 2 h, when supplemental lactated Ringer solution was given as required.
Time course of myocardial TNF- expression.
To determine the time-course of TNF- expression in the myocardium
after HS/R, rats underwent either sham operations or increasing periods
of HS/R (0, 5, 10, 15, 20, 30, and 60 min of hemorrhage and 60 min of
HS, followed by 30, 45, and 60 min of resuscitation; n = 3 at each time point). At the appropriate time, hearts were excised
and the coronary circulation was flushed free of residual blood,
flash-frozen in liquid N2, and stored at 
80°C for
subsequent TNF- quantification.
Myocardial TNF- quantification.
Myocardial TNF- levels were quantified as described previously
(36). Briefly, the samples (75 mg) were suspended in
phosphate-buffered saline (0.45 ml) containing phenylmethylsulfonyl
fluoride (1.49 mM), leupeptin (475.6 µM), and aprotonin (0.31 µM),
and homogenized for 2 min in a Polytron (setting 7, Kinematic).
Homogenates were centrifuged for 20 min at 60,000 rpm, 4°C. The
pellet was solublized by resuspension in an equal volume of PBS
containing 1 mM of phenylmethylsulfonyl fluoride, 50 µl of aprotonin,
and 1% Triton X-100. After 1 h of incubation at 4°C, the
solubilized protein was centrifuged for 20 min at 60,000 rpm. The
supernatants were analyzed in duplicate with the use of Cytoscreen rat
TNF- enzyme-linked immunosorbent assay kit (Biosource International;
Camarillo, CA). This assay is linear in between 0 and 1,000 pg/ml.
TNF- levels were standardized to total soluble protein content,
determined with the use of a bicinchoninic protein assay (Pierce;
Rockford, IL).
Role of 1-adrenergic stimulation in HS.
Sprague-Dawley rats (n = 6) were pretreated with
prazosin hydrochloride (0.5 mg/kg ip 1 h before hemorrhage).
Animals then underwent 30 min of hemorrhage (determined to be the
minimum time for significant TNF- expression after HS), after which
the heart was excised, flushed free of residual blood, and flash-frozen in liquid N2. Myocardial TNF- levels were subsequently
quantified. A group of sham-operated control animals was pretreated
with prazosin hydrochloride to determine the baseline tolerance to
1-adrenergic blockade.
Experimental design and groups.
Rats were divided into the following six groups: 1)
sham-operated control rats; 2) HS/R + anti-TNF-
antibody, polyclonal rabbit anti-mouse TNF- neutralizing antibody,
600 µl/kg iv, 5 min before hemorrhage (Genzyme Diagnostics;
Cambridge, MA); 3) HS/R + isotype control antibody
molecule, 500 µl/kg of rabbit IgG iv, 5 min before hemorrhage (Zymed
Laboratories; San Francisco, CA); 4) sham-operated control
rats + prazosin hydrochloride (1 mg/kg ip 60 min before
hemorrhage); 5) HS/R + prazosin hydrochloride; and
6) HS/R + diluent (1 ml of saline ip 60 min before hemorrhage).
Assessment of 1-blockade.
Another group of animals was stabilized and the heart rate and blood
pressure were measured. After 20 min, phenylephrine was administered
(10 µg/kg) and the response observed. Animals were then treated with
prazosin hydrochloride (0.05 mg/kg ip). The challenge with
phenylephrine was repeated 1 and 2 h later to simulate the onset
and termination of the HS period. The blood pressure and heart
responses were recorded.
Assessment of left ventricular function.
After the rats underwent 60 min of hemorrhage and 2 h of
reperfusion, heparin sodium (200 IU iv) was given to prevent
coagulation, and the hearts were rapidly excised and placed in 4°C
Krebs-Henseleit bicarbonate (KHB) buffer. The KHB buffer used in this
study is similar to the one reported (1) with isolated
heart muscle preparations. The solution contained (in mM) 118 NaCl, 4.7 KCl, 21 NaHCO3, 1.25 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, and 11 glucose. All of the solutions were prepared daily with deionized water and
bubbled with 95% O2-5% CO2. The pH of the
solution was 7.4, and the temperature was maintained at 37°C. The
ascending aorta was cannulated with an 18-gauge cannula that was
subsequently connected through glass tubing to a KHB buffer reservoir
for perfusion of the coronary circulation at a constant pressure of 120 cm of water. Intraventricular pressure was measured with a
saline-filled latex balloon attached to a polyethylene tube and
threaded into the left ventricular chamber through the left auricle.
Left ventricular pressure was measured with a mini pressure transducer
(Gould Electronics; Valley View, OH) attached to the balloon cannula.
Left ventricular maximal rate of pressure contraction over time
(+dP/dtmax) and maximal rate of pressure
relaxation over time (dP/dtmax) values were
obtained using an electronic differentiator (model
13-4615-17, Gould Electronics) and recorded with the use of a
chart-recording system (Windo-Graph, Gould Electronics)
(23).
dP/dtmax
against the physical parameter of increasing left ventricular volume.
As a second method of determining cardiac contractile function
independent of alterations in ventricular volume, the isolated heart
was stimulated with the 
-adrenergic agonist, isoproterenol, as
previously described (36). Left ventricular end-diastolic
pressure was maintained at 5 mmHg, whereas the heart was stimulated
with isoproterenol at a concentration of 50 ng/ml (we have noted that
maximal cardiac stimulation occurs at this concentration).
The relationship between left ventricular capacity and balloon volume
was determined by plotting the pressure-volume relationship of the
isolated balloon. All experiments were performed on the flat portion of
the balloon pressure-volume curve.
Statistical analysis. All values are expressed as means ± SE. Statistical comparisons were performed with the use of statistical software (version 9.0 for Windows, SPSS; Chicago, IL). Analyses include Student's t-test and one-way analysis of variance (ANOVA), followed by Student-Newman-Keuls post hoc test for multiple pair-wise comparisons. For repeated measurements in individual animals, we used repeated-measures ANOVA (RM-ANOVA), followed by a Tukey-Kramer multiple comparison test to isolate differences. A probability of <0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Time course of myocardial TNF- expression.
The first elevation in myocardial TNF- expression was observed 20 min after the onset of HS. After 30 min of HS, a sixfold increase in
TNF- was observed (P < 0.001; ANOVA) (Fig.
1). TNF- levels reached a maximum of
393.2 pg/mg of protein after 60 min of HS and 45 min of resuscitation
(P < 0.0001 vs. sham-operated control group at 60 min
of HS and 45 min of resuscitation), after which myocardial TNF-
levels began to decline.
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Role of 1-adrenergic stimulation in hemorrhagic
shock.
Treatment with the 1-adrenergic receptor inhibitor,
prazosin hydrochloride, before the onset of HS, significantly reduced the amount of TNF- in the heart. Myocardial TNF- levels after 30 min of hemorrhage was 231.2 pg/mg of protein in the shock group compared with 34.5 pg/mg of protein in the sham-operated control group
(P < 0.001 vs. sham-operated control) (Fig.
2). Prazosin hydrochloride reduced the
myocardial TNF- expression by 65% to 82.0 pg/mg of protein
(P < 0.05 vs. HS alone group).
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1-adrenergic blockade alone did not result in
an increase in myocardial TNF- expression compared with
sham-operated control animals that did not receive prazosin
hydrochloride (32.8 pg/mg of protein in the prazosin-treated
sham-operated control group and 34.4 pg/mg of protein in the
sham-operated control group alone).
Assessment of 1-blockade.
Responses to phenylephrine and subsequent prazosin blockade with
phenylephrine challenge are shown in Table
1. A significant increase in blood
pressure and compensatory decrease in heart rate was noted during the
first dose of phenylephrine. After prazosin treatment, subsequent doses
of phenylephrine did not produce significant alterations in blood
pressure or heart rate.
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In vivo response to HS/R.
HS to a MAP of 50 mmHg for 60 min, followed by 2 h of
resuscitation, resulted in a significant change in the demand for
resuscitation fluid. Although the volume of blood withdrawn in the four
hemorrhage groups was equivalent (ANOVA, P = 0.96), the
volume of supplemental lactated Ringer solution required to resuscitate
the animals differed among the six groups (Table
2). The resuscitation volumes in the
sham-operated control group (16.1 ml/kg) and the sham-operated group
receiving prazosin (16.4 ml/kg) were equivalent. Animals undergoing
hemorrhage, either treated with the control antibody (71.0 ml/kg) or
with the saline vehicle (70.1 ml/kg), required a significantly greater
amount of resuscitation fluid volume (P < 0.002 vs.
sham-operated control group). TNF- neutralization (50.2 ml/kg) and
1-adrenergic inhibition (54.0 ml/kg) reduced the demand
for supplemental fluid significantly (P = 0.035 vs. control antibody and diluent-treated groups, respectively). Previous experiments using this anti-TNF antibody demonstrated that lung and
liver neutrophil sequestration was significantly reduced (data not
shown). This confirms the expected action of this intervention in a
second system (36).
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Assessment of left ventricular function.
HS to a MAP of 50 mmHg for 60 min, followed by 2 h of
resuscitation, resulted in a significant reduction in baseline left ventricular DP, +dP/dtmax and
dP/dtmax, compared with sham-operated control
animals (Fig. 3). Cardiac contractile
function was reduced by 35% in hearts from animals treated with the
control antibody. The reduction in contractile function persisted as
left ventricular volume (preload) was increased. Administration of the
anti-TNF- antibody before HS resulted in an 85% improvement in DP
(Fig. 3A), +dP/dtmax (Fig.
3B) and dP/dtmax (Fig.
3C) at baseline volumes. As preload was increased, cardiac
contractile function in the anti-TNF--treated group paralleled the
sham-operated control group, whereas hearts from animals receiving the
control antibody remained significantly depressed (P < 0.05 vs. sham-operated control group and HS/R + anti-TNF-
antibody). Treatment with prazosin hydrochloride
(1-adrenergic blocker) significantly improved cardiac contractile function to 90% of sham-operated controls at baseline and
on increasing preload (Fig. 4). Control
animals pretreated with either the saline vehicle (for prazosin) or the
control antibody had similar reductions in myocardial contractile
function to untreated hemorrhaged animals.
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-adrenergic stimulation
of the isolated heart from animals undergoing HS, remained depressed
(Fig. 5). Isoproterenol stimulation
increased DP in the sham-operated control group to 150% of
prestimulated levels, whereas DP in the HS/R group treated with the
control antibody rose by only 120% of prestimulated levels
(P < 0.03 vs. sham-operated control group).
Neutralization of TNF- restored the -adrenergic responsiveness
(DP increased to 150% of prestimulated levels; P = NS
vs. sham-operated control group). Similarly, DP in hearts from animals
receiving prazosin hydrochloride returned to sham-operated levels after
isoproterenol stimulation, whereas hearts from diluent-treated HS/R
animals remained significantly depressed (P < 0.03 vs.
sham-operated control + prazosin and HS/R + prazosin groups).
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antibody before hemorrhage did not significantly improve the diastolic
compliance after HS/R (P < 0.05 vs. sham-operated
control animals) (Fig. 6A). However, pretreatment with
prazosin resulted in a significant improvement in left ventricular
diastolic function, compared with the diluent-treated group
(P < 0.05 vs. HS/R + diluent) (Fig.
6B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The aim of this study was to define the mechanism by which
hemorrhage induces depressed cardiac function. Previous studies have
shown that HS/R results in depressed cardiac contractile function
(15) and significant TNF- expression in the heart (31). However, the role that TNF- plays in the cardiac
dysfunction after HS remained undefined. Giroir et al.
(10) showed that the depressed cardiac function seen after
burn shock was mediated primarily by TNF- (10). Our
laboratory has used an anti-TNF- antiserum to define the role of
TNF- on cardiac dysfunction in a rat model of ruptured abdominal
aortic aneurysm repair, which combines both HS and lower-torso
ischemia (36). This is the first study to
demonstrate that myocardial TNF- mediates a significant component of
the depressed cardiac function observed after uncomplicated hemorrhage.
The results of this subsequent study, directed at defining the effects
of hemorrhage alone on cardiac function, indicate that
1-adrenergic stimulation induces myocardial TNF- expression, which subsequently induces depressed cardiac contractile function.
In this model of HS/R, TNF- levels significantly increased by 30 min
of HS and peaked after 60 min of hemorrhage and 45 min of
resuscitation. The elevation in myocardial TNF- was associated with
a significant reduction in contractile function. Immunoneutralization of TNF- returned the depressed myocardial systolic contractile function to 85% of sham-operated controls (at baseline and on increasing preload).
We hypothesized that the rapid rise in myocardial TNF- observed
after HS, combined with the significant depression in cardiac contractile function, was the result of 1-adrenergic
receptor stimulation. Previous studies (6) have shown that
stimulation of isolated cardiomyocytes with phenylephrine, an
1-adrenergic agonist, resulted in the translocation of
NF-B, a potent transcription factor for TNF-, which induced a
significant depression in cardiac contractile function. TNF- is
known to have cardiodepressant effects in both isolated cardiomyocyte
and whole heart preparations (26, 40). Others have shown
that isolated cardiomyocytes produce TNF- on stimulation (with
H2O2 and lipopolysaccharide) and up to 50% of
the total TNF- found within the heart can be produced by
cardiomyocytes, with endothelial cells and resident macrophages also
producing TNF- (11, 19, 29). To investigate the
signaling pathways responsible for TNF- expression after HS, we used
a selective inhibitor of the 1-adrenergic pathway,
prazosin hydrochloride, before the onset of hemorrhage. Prazosin
significantly reduced the TNF- expression in the heart seen after HS
by 65%, without altering basal myocardial TNF- levels, suggesting
that 1-adrenergic stimulation plays a role in the rapid
rise in TNF- that occurs during HS. In addition,
1-adrenergic blockade restored cardiac contractile
function to 90% of sham-operated control levels, similar to that seen
after TNF- neutralization. Thus the mechanism by which
1-adrenergic stimulation induces depressed cardiac
contractile function after HS/R may occur through TNF- expression in
the heart.
TNF- neutralization and 1-adrenergic blockade
improved -adrenergic responsiveness in animals undergoing HS. While
inotropic stimulation increased DP in the anti-TNF- and
prazosin-treated groups to a similar degree as sham-operated controls
(150% of baseline DP), the response to isoproterenol was blunted in
the HS group treated with the control antibody or diluent. Studies (13) showed that TNF- reduces -adrenergic
stimulation without altering the density of -adrenergic receptors.
The reversal of the reduced inotropic response with either the
anti-TNF- antibody or with prazosin suggests that the pronounced
depression in cardiac function in hearts from animals undergoing
hemorrhage may be due to an inhibition of -adrenergic
responsiveness, secondary to myocardial TNF- expression.
A significant impairment of diastolic compliance was also observed
after HS/R. In contrast to the improved systolic contractile function
observed after TNF- neutralization, no improvement in diastolic
function was observed with the anti-TNF- therapy. However, prazosin
pretreatment returned diastolic function to sham-operated control
levels. Activation of the -adrenergic pathway is known to stimulate
various kinase pathways, including p38 mitogen-activated protein
kinase, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p42 and p44 extracellular signal-regulated protein kinase
in the heart (21). Activation of these kinases may
phosphorylate regulatory or contractile proteins or alter calcium
transients (5). Thus the effect of prazosin treatment on
diastolic function is likely the result of direct influence on the
contractile mechanism of the heart.
After synthesis, TNF- is incorporated into the cell membrane and
then is cleaved by the activity of a metalloprotease enzyme, TNF-
converting enzyme (TACE) to result in a soluble 17-kDa form (25). After secretion, TNF- acts via membrane-bound
TNF- receptors to activate intracellular signaling cascades
(3). On binding of TNF- to its receptor, sphingosine
and nitric oxide may be produced (2, 32, 34), which have
been shown to induce early and late depression in cardiac function,
respectively (9, 12, 20). After 24 h of stimulation
with phenylephrine, production of NO was observed in cultured
cardiomyocytes (18). The improvement in contractile
function observed after immunoneutralization of TNF- suggests that
TNF- is released into the extracellular space to act on myocyte cell
surface receptors, because the anti-TNF- antibody employed in this
study is unable to traverse the cell membrane and no breach of the cell
membrane is observed during hemorrhage (36). Thus
neutralizing TNF- in the extracellular space in this model of HS/R
may inhibit the production of downstream mediators, preventing the
reduction in cardiac contractile function.
The mechanism by which 1-adrenergic stimulation induces
myocardial TNF- expression remains unknown. Phenylephrine
stimulation of cardiomyocytes has been shown (17) to
induce hydrolysis of phosphatidylinositol 4,5-bisphosphate to release
diacylglyerol and D-myo-inositol
1,4,5-trisphosphate (4), and diacylglycerol subsequently
activates protein kinase C (PKC) in the heart (17). Horton
et al. (16) showed that PKC plays a significant role in
burn-induced cardiac dysfunction, and PKC stimulation has been linked
to activation of TACE (37). This may suggest that
1-adrenergic stimulation induces proteolytic cleavage
and release of TNF- in the heart. Thus release of preformed TNF-
may be responsible for the early expression of TNF- during HS, and
this elevation in myocardial TNF- levels may induce a "positive
feedback" loop to induce new TNF- transcription and synthesis
(35).
Other potential mechanisms may also contribute to the
1-adrenergic-induced depression in cardiac contractile
function, including a reduction in sarcoplasmic reticulum calcium
release, due to D-myo-inositol
1,4,5-trisphosphate hydrolysis (14). However, TACE
activity has been shown to increase within 15 min of PKC stimulation
(37). The rapid rise in myocardial TNF- levels, which
are observed during hemorrhage, was significantly blunted with prazosin
pretreatment and combined with improved cardiac function lends support
to the notion that after HR/S, 1-adrenergic stimulation
results in myocardial TNF- expression, leading to depressed cardiac
contractile function.
The results of this study indicate that TNF- plays a significant
role in inducing cardiac dysfunction after HS. Neutralization of
TNF- before the onset of hemorrhage significantly reversed the
depressed systolic cardiac contractile function. This study has also
defined a relationship between 1-adrenergic stimulation and myocardial TNF- expression, as myocardial TNF- levels were reduced after prazosin pretreatment, and myocardial function improved to a similar degree as that observed after TNF- neutralization. More
importantly, these studies have begun to elucidate the mechanisms by
which HS results in TNF- expression in the heart and induces depressed cardiac contractile function. Ultimately, further studies may
lead to the design of new therapeutic strategies that have the
potential to reduce the morbidity and mortality associated with HS.
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ACKNOWLEDGEMENTS |
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This research was supported by the Physicians of Ontario through Physician Services.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. F. Lindsay, 200 Elizabeth St., EN 5-306, Toronto, Ontario, Canada M5G 2C4 (E-mail: thomas.lindsay{at}uhn.on.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 June 2000; accepted in final form 23 February 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs. shock at 20, 30, and 60 min and 15 min
of resuscitation.
, Sham-operated
control group. 
, Hemorrhagic shock + anti-TNF-
, hemorrhagic shock + control antibody-treated group. All values are means ± SE.
,
Sham-operated control + prazosin group. 
, Hemorrhagic
shock + prazosin-treated group. 
, Hemorrhagic
shock + diluent-treated group. All values are means ± SE.
*P < 0.05 vs. hemorrhagic shock + diluent-treated
group.
