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Departments of 1 Anesthesiology and 2 Physiology, University of Regensburg, 93042 Regensburg, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The reduced pressure
response to vasopressin during acute sepsis has directed our interest
to the regulation of vasopressin V1A receptors. Rats were
injected with lipopolysaccharide for induction of experimental
gram-negative sepsis. V1A receptor gene expression was
downregulated in the liver, lung, kidney, and heart during endotoxemia.
Inasmuch as the concentrations of proinflammatory cytokines such as
interleukin-1
, tumor necrosis factor-
, and interferon-
were
highly increased during sepsis, the influence of these cytokines on
V1A receptor expression was investigated in primary
cultures of hepatocytes and in the aortic vascular smooth muscle cell
line A7r5. V1A receptor expression was downregulated by the
cytokines in a nitric oxide-independent manner. Blood pressure dose-response studies after injection of endotoxin showed a
diminished responsiveness to the selective V1 receptor
agonist Phe2,Ile3,Orn8-vasopressin.
Our data show that sepsis causes a downregulation of V1A
receptors and suggest that this effect is likely mediated by
proinflammatory cytokines. We propose that this downregulation of
V1A receptors contributes to the attenuated responsiveness of blood pressure in response to vasopressin and, therefore,
contributes to the circulatory failure in septic shock.
blood pressure; hepatocytes; vascular smooth muscle; A7r5 cell line; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SHOCK DUE TO SEPSIS HAS
INCREASED in incidence during the past 50 years and is now one of
the most common causes of death in intensive care units. Despite
considerable therapeutic advances, mortality from septic shock remains
high. Pathogenetically, sepsis and septic shock are characterized by
systemic vasodilation, leading to arterial hypotension, multiple organ
dysfunction, and death (21). The pathogenetic mechanism of
this vasodilation is multifactorial and not clearly understood. Nitric
oxide (NO) production due to induction of NO synthase isoform II (NOS
II) has been assumed to mediate sepsis-induced vasodilation (16,
21). However, findings that arterial hypotension, as well as
vascular hyporeactivity, is only slightly alleviated by NOS II
inhibition suggest that other or additional pathways may be involved in
septic circulatory failure (5, 22, 27, 31). Alterations in
vasoconstrictor mechanisms have been reported. Inappropriate low plasma
vasopressin levels have been suggested to contribute to the hypotension
in advanced vasodilatory septic shock (14). In models of
acute sepsis, vasopressin is markedly increased (26, 32,
33); in addition, a reduced pressor response to the exogenous
hormone has been shown (8, 26, 30). The pathogenetic
mechanisms of this phenomenon, called vasoplegia, are not clearly
understood. One could imagine that the receptors for vasoconstrictors
could be altered during sepsis, leading to diminished pressor effects in response to the respective agonist. We previously demonstrated that
sepsis leads to a systemic downregulation of ANG II type 1 receptors
(4). Therefore, we were interested also in the regulation
of the receptor mediating the vasoconstrictive response to vasopressin,
which is thought to be the vasopressin subtype 1A (V1A)
receptor (17), during experimental endotoxemia. For this
purpose, we determined V1A receptor gene expression in
different organs of rats with acute gram-negative sepsis. In addition,
the regulation of V1A receptors was investigated at a
cellular level in response to typical endogenous mediators of sepsis.
It is well known that the proinflammatory cytokines interleukin-1
(IL-1), tumor necrosis factor- (TNF-), and interferon-
(IFN-), as well as NO, are predominantly active during inflammation
(21). Therefore, the effect of these mediators on the
expression of V1A receptors was determined in vitro in rat
hepatocytes and aortic vascular smooth muscle cells (VSMCs).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal experiments.
All animal experiments were conducted in accordance with the National
Institutes of Health guidelines and German laws relating to the
protection of animals and were approved by the local ethics committee.
Male Sprague-Dawley rats (200-250 g) were injected intravenously
with Ringer solution (control rats) or lipopolysaccharide (LPS;
Escherichia coli, 10 mg/kg iv; Sigma) and killed by
decapitation 3, 6, 12, or 24 h (n = 6 per group)
after injection. Blood was collected, and organs were rapidly
extirpated, weighed, frozen in liquid nitrogen, and stored at 
80°C.
Cell culture.
Primary cultures of hepatocytes were obtained from collagenase-perfused
rat livers as previously described (7). Hepatocytes were
cultured in medium containing insulin (660 U/l), hydrocortisone (1 mg/l), 10% fetal calf serum (FCS), and antibiotics for 4 h. Then
cells were incubated as listed below with medium containing insulin
without hydrocortisone, FCS, and antibiotics. Aortic VSMCs (A7r5 cell
line) were obtained from the American Type Culture Collection
(Manassas, VA) and cultured in medium with 10% FCS and antibiotics.
Incubation experiments were performed in medium without FCS and
antibiotics. Cells were incubated for 8 h with medium (control),
IL-1 (50 ng/ml; Sigma), TNF- (100 ng/ml; R & D Systems), IFN-
(500 U/ml; Life Technologies), a mixture of these cytokines, a mixture
of these cytokines with
N
-nitro-L-arginine methyl ester
(L-NAME; 1 mmol/l) in arginine-free medium (cytokines + L-NAME), or the NO donor
S-nitroso-N-acetyl penicillamine (SNAP; 500 µmol/l). Rat recombinant cytokines were used for the experiments. The
dose of the cytokines was chosen from data taken from the literature
(2-4, 9, 10, 19, 25, 29).
Determination of V1A receptor and -actin mRNA.
Total RNA from tissues and cells was extracted and the RNase protection
assays for V1A and -actin mRNA were carried out as described previously (4). For V1A mRNA
detection, a 32P-labeled antisense RNA probe was generated
by in vitro transcription of the plasmid vector TOPO (Clontech)
containing a PCR fragment, targeted against the published mRNA sequence
(bp 267-420) of the rat V1A receptor
(17). Identity of the PCR fragment was confirmed by
sequencing. The -actin probe is targeted against bp 108-393 of
the published mRNA sequence (20). Performing the RNase
protection assay with this complementary RNA produces a 154-bp
protected fragment of the V1A receptor gene transcript.
Radioligand binding assays. Binding assays in 24-well culture plates were carried out on whole cells as described previously (4). Hepatocytes (3 × 105 cells/well) were pretreated as described above, washed three times with PBS, and incubated with 125I-vasopressin (50 or 500 pmol/l, 2,000 Ci/mmol; Amersham) in NaCl (100 mmol/l), Tris (25 mmol/l), 5 mM MgCl2 (4.5 mmol/l), and 0.1% BSA (pH 7.4) in the absence or presence of unlabeled vasopressin (10 µmol/l for nonspecific binding). After incubation at 37°C for 15 min, the cells were washed three times with ice-cold PBS and solubilized with 1 N NaOH, and radioactivity was measured. Accordingly, aortic VSMCs (A7r5 cell line, 3.5 × 105 cells/well) were incubated with 125I-vasopressin (100 pmol/l or 1 nmol/l). All binding data were related to total cellular protein content.
Cytokine assays.
Concentrations of IL-1, TNF-, and IFN- in the liver were
determined using enzyme-linked immunosorbent assay kits (R & D Systems). Measurements for each cytokine were carried out in one assay.
Statistics. Data were analyzed by ANOVA with multiple comparisons followed by t-test with Bonferroni's adjustment. P < 0.05 was considered significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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V1A receptor gene expression in vivo.
V1A receptor gene expression was determined in major rat
organs before and after injection of LPS. V1A mRNA was
abundantly expressed in the liver. In the lung, kidney, and heart,
V1A mRNA was expressed to a much lower extent (Fig. 1,
inset). In the liver, V1A mRNA was downregulated to ~2% of the control level
6 h after LPS injection and increased thereafter to 5 and 16% of
the control level 12 and 24 h after injection, respectively (Fig.
1). Also, in the lung, kidney, and heart, V1A mRNA was
downregulated to 31, 75, and 84% of the control level after 6 h
of endotoxemia, respectively. In the lung and heart, V1A
mRNA was also depressed after 12 and 24 h, whereas in the kidney,
V1A mRNA had returned to control values at this time point.
To exclude the possibility that the weak V1A mRNA signal in
the lung and heart is due to trapped blood cells in these organs, we
also assayed the total RNA yield from 2 ml of whole blood for
V1A mRNA and found no specific V1A mRNA
hybridization signal in whole blood (data not shown).
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Cytokine concentrations.
We further aimed to characterize the mechanisms along which
V1A receptors could be downregulated at a cellular level.
As possible molecular mediators of sepsis, we considered
proinflammatory cytokines, such as IL-1, TNF-, and IFN-, which
are known to mediate a variety of effects during sepsis. As shown in
Fig. 2, these three cytokines were
strongly induced in the liver in the chosen model of sepsis.
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V1A receptor expression in hepatocytes.
To investigate the possible role of proinflammatory cytokines in the
regulation of V1A receptor expression, we stimulated primary cultures of rat hepatocytes with the cytokines known to be
abundantly generated in the liver during endotoxemia and determined hepatocellular V1A mRNA as well as specific
125I-vasopressin binding to hepatocytes. Incubation of
hepatocytes with IL-1 (50 ng/ml), TNF- (100 ng/ml), or IFN-
(500 U/ml) for 8 h decreased V1A mRNA to 35, 20, and
34% of control, respectively (Fig. 3).
The combination of the cytokines additively downregulated V1A receptor gene expression to 13% of control (Fig.
3A). In parallel, 125I-vasopressin binding to
the hepatocytes was reduced after incubation with the cytokines to 46, 43, 55, and 20% of control, respectively (Fig. 3B).
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V1A receptor expression in VSMCs.
To investigate whether the cytokine-induced downregulation of
V1A receptors was restricted to hepatocytes or was a more
general effect, we also incubated the aortic VSMCs (A7r5 cell line)
with the cytokines. Incubation of VSMCs with IL-1 (50 ng/ml),
TNF- (100 ng/ml), or IFN- (500 U/ml) decreased V1A
mRNA, with TNF- having the strongest effect (Fig.
5). The combination of the cytokines produced an even stronger downregulation of V1A receptor
gene expression in aortic VSMCs (Fig. 5A) than the single
cytokines. In parallel, 125I-vasopressin binding to A7r5
cells was reduced after incubation with the cytokines (Fig.
5B).
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Blood pressure response.
Because our data suggested that V1A receptors are
downregulated in several rat organs during endotoxemia, we aimed to
determine the pathophysiological significance of this receptor
downregulation for the vascular hyporeactivity in response to
vasopressin. We therefore performed blood pressure-response studies
using the selective V1 receptor agonist
Phe2,Ile3,Orn8-vasopressin.
Inasmuch as V1A receptor gene expression was mostly downregulated 6 h after LPS injection, we performed dose-response studies after 6-8 h. In vehicle-injected anesthetized rats, mean arterial blood pressure (MAP) was 102 mmHg, and graded bolus injections of Phe2,Ile3,Orn8-vasopressin
(10-300 pmol/kg) caused a dose-related increase in MAP of 70 mmHg
after injection of 300 pmol/kg
Phe2,Ile3,Orn8-vasopressin (Fig.
7). At 6 h after injection of LPS,
MAP was decreased to 58 mmHg, and the pressure response to
Phe2,Ile3,Orn8-vasopressin was
diminished compared with nonseptic rats. Thus, at that time, MAP
increased by only 47 mmHg after injection of 300 pmol/kg
Phe2,Ile3,Orn8-vasopressin.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Several in vivo and in vitro studies demonstrate a diminished pressor response to vasopressin during acute experimental sepsis (8, 26, 30). Despite its potential pathophysiological significance with regard to circulatory failure during sepsis, the factors responsible for the diminished vascular reactivity in response to vasopressin remain undefined. The vasoconstrictive response to vasopressin is mediated through the V1A receptor (17). We speculated that an altered expression of this receptor subtype could be involved in the diminished pressor response to vasopressin during acute sepsis. Therefore, we investigated V1A receptor expression in LPS-injected rats as one of the most common models of gram-negative sepsis. This maneuver caused an arterial hypotension and an increase in cytokine concentrations in various organs, indicating the efficacy of our model. We found a pronounced downregulation of V1A receptor mRNA in the liver as well as in the lung, kidney, and heart during experimental sepsis. These results are in good agreement with a study reporting diminished hepatic [3H]vasopressin binding in the rat after endotoxin infusion (23).
Proinflammatory cytokines and NO are known to be abundantly generated mediators during sepsis (21). Therefore, we were interested in the influence of these mediators on the expression of V1A receptors. Because of the multiplicity of factors that can influence the regulation of receptor expression, it has been impossible to examine the specific and independent effect of one mediator in vivo. For this purpose, we used two in vitro cell culture systems to exclude other variables and uniquely demonstrated an NO-independent effect of proinflammatory cytokines to downregulate V1A receptors in hepatic and vascular tissue.
To investigate whether the downregulation of V1A receptors is of relevance for the vascular hyporeactivity to vasopressin during experimental sepsis, we performed blood pressure-response studies with a selective V1 receptor agonist 6 h after injection of vehicle or LPS, when V1A receptor gene expression was mostly depressed in all organs investigated. The diminished pressure responsiveness to the V1 receptor agonist suggests the relevance of the V1A receptor for the vascular hyporeactivity to vasopressin during acute endotoxemia. These results fit with previous reports showing decreased blood pressure response (26, 30) as well as decreased microvascular vasoconstrictive responses (8) to vasopressin during acute experimental sepsis. An increased pressor sensitivity to vasopressin has been reported in advanced vasodilatory septic shock. That study demonstrated a blood pressure-elevating effect of vasopressin in five septic patients, but the effect has not been compared with a nonseptic control group (15). These results are not in contrast to our findings, because we also found a blood pressure responsiveness to a V1 receptor-selective vasopressin analog during endotoxemia, which, however, was attenuated compared with normal rats.
The downregulation of V1A receptors in the liver may also be of relevance for some metabolic aberrations during sepsis. Alterations in glucose metabolism occur frequently during sepsis and include hyper- and hypoglycemia. It has been shown that vasopressin-stimulated glycogen phosphorylase a activation is less responsive in isolated rat hepatocytes after continuous infusion of endotoxin (23). The diminished expression of hepatic V1A receptors during sepsis could account for this observation.
Characteristics similar to those we suggest for the regulation of
V1A receptor expression in this study have been observed for the ANG II type 1 receptor, which mediates the vasoconstrictor action of ANG II. So we have shown that a combination of IL-1, TNF-, and IFN- downregulates not only V1A receptor
expression but also ANG II type 1 receptor expression in vitro
(4). Therefore, proinflammatory cytokines seem to play a
key role in the pathogenesis of septic shock. On one hand, these
cytokines mediate a significant tissue production of the vasodilatory
molecule NO, which causes the cardiovascular collapse during sepsis. On
the other hand, these cytokines lead to a pronounced downregulation of
pressor receptors for ANG II and vasopressin, resulting in a decreased vasoconstrictor responsiveness to these agonists. Consequently, ANG II
and vasopressin are not able to counteract the overshooting vasodilatory action of NO during acute sepsis. It is not known along
which signaling pathways the V1A receptor gene expression is downregulated by proinflammatory cytokines at the cellular level.
The expression of functional receptors for IL-1, TNF-, and IFN-
has not been investigated in this study, but data from the literature
indicate that these cytokine receptors should be expressed in
hepatocytes and VSMCs, with the exception of IFN- receptors, which
are only weakly or not expressed in normal hepatocytes (1, 6,
11-13, 18, 24, 28). Which downstream signaling pathways are
involved in the downregulation of vasopressin receptors requires
further investigation.
Together, our data suggest that proinflammatory cytokines downregulate V1A receptor expression during sepsis, causing an attenuation of the V1A receptor-mediated vasoconstriction. This downregulation of V1A receptor gene expression likely contributes to the development of cardiovascular failure during sepsis.
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ACKNOWLEDGEMENTS |
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The expert technical assistance of A. Seefeld and G. Wilberg is gratefully acknowledged.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Bucher, Dept. of Anesthesiology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany (E-mail: michael.bucher{at}klinik.uni-regensburg.de).
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.
First published November 29, 2001;10.1152/ajpregu.00520.2001
Received 30 August 2001; accepted in final form 24 November 2001.
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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MAP) from the same experiments; n = 6 animals per group. *P < 0.05 vs. vehicle.