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European Journal of Pharmacology 385 1999 209–216
www.elsevier.nlrlocaterejphar
Renal interstitial concentration of adenosine during endotoxin shock
Akira Nishiyama
a
, Katsuyuki Miura
b
, Akira Miyatake
c
, Yoshihide Fujisawa
c
, Wang Yue
a
,
Toshiki Fukui
a
, Shoji Kimura
a
, Youichi Abe
a,)
a
Department of Pharmacology, Kagawa Medical UniÕersity, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
b
Department of Pharmacology, Osaka City UniÕersity Medical School, Osaka, Japan
c
Research Equipment Center, Kagawa Medical UniÕersity, Kagawa, Japan
Received 27 May 1999; received in revised form 4 October 1999; accepted 12 October 1999
Abstract
The present experiments were designed to measure the renal interstitial concentration of adenosine in an attempt to determine whether
adenosine participates in the regulation of renal hemodynamics during endotoxin shock. The renal concentration of adenosine in response
Ž.
to lipopolysaccharide LPS administration was measured in anesthetized dogs using a microdialysis method. Renal hemodynamic
Ž.Ž. w Ž w
responses to LPS were also determined with and without the adenosine A receptor antagonist, E - R -1- 3- 2-phenylpyrazolo 1,5-
1
x . x Ž. Ž .
a pyridin-3-yl acryloyl pyperidin-2-ylacetic acid FK352 . Intravenous administration of LPS 0.5 mgrkg significantly decreased renal
blood flow and mean arterial pressure. These parameters reached the minimum level at 5–10 min after the LPS administration and then
returned to their respective preinjection levels. The renal interstitial concentration of adenosine increased from 118 "18 to 381 "46 nM.
During treatment with FK352, LPS decreased renal blood flow and mean arterial pressure, however, these reductions were significantly
attenuated. LPS also increased adenosine concentration, but its rise was reduced along with the attenuation of LPS-induced renal blood
flow reduction. These results suggest that adenosine was involved in LPS-induced renal hemodynamic changes and that FK352 has a
protective effect against renal dysfunction during endotoxin shock. Since the adenosine concentration was inversely proportional to renal
blood flow levels, it can be assumed that adenosine plays an important role as a mediator, but not as an initiator of renal hemodynamic
changes during endotoxin shock. q1999 Elsevier Science B.V. All rights reserved.
Keywords: Adenosine; Lipopolysaccharide; Endotoxin shock; Renal hemodynamics; Microdialysis; Adenosine A receptor antagonist
1
1. Introduction
Acute renal failure is a serious and common complica-
tion of endotoxin shock and produces a high mortality rate
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Groeneveld et al., 1991; Levy et al., 1996 . The mecha-
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nisms of lipopolysaccharide LPS -induced renal dysfunc-
tion have been studied extensively but remain elusive. The
administration of a lethal dose of LPS results in an imme-
diate decrease in renal blood flow and glomerular filtration
rate along with a fall in cardiac output and mean arterial
pressure during the initial phase of experimental endotoxin
Ž
shock Hinshaw et al., 1961; Petrucco et al., 1972; Gul-
.
lichsen, 1991 . Various vasoactive mediators such as the
sympathetic nervous system, catecholamine, thromboxane,
and the renin–angiotensin system have been implicated in
)
Corresponding author. Tel.: q81-87-891-2125; fax: q81-87-891-
2126.
Ž.
E-mail address: yakuri@kms.ac.jp Y. Abe
the renal hemodynamic changes in the initial stage of
Ž
endotoxin shock Nykiel and Glaviano, 1961; Isakson et
al., 1977; Keeler, 1981; Henrich et al., 1982; Badr et al.,
.
1986 , however, the mechanism by which this occurs is
poorly understood.
A possible candidate mediator of LPS-induced renal
dysfunction is adenosine, which has been shown to play an
important role in the regulation of renal hemodynamic
changes during various forms of acute renal failure
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Churchill and Bidani, 1987 . In fact, Churchill et al.
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1987 have proposed that adenosine mediates renal hemo-
dynamic changes during endotoxin shock. This hypothesis
is supported by the finding that treatment with a non-selec-
tive antagonist prevented LPS-induced renal vasoconstric-
Ž.
tion. Moreover, Knight et al. 1993 have reported that
blocking A adenosine receptors prevents LPS-induced
1
reduction in renal blood flow and reduces the severity of
acute renal failure during endotoxin shock. This indicates
that adenosine induces renal vasoconstriction via the
0014-2999r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.
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PII: S0014-2999 99 00716-5