|
Effect of endothelin-1
(1-31) on the renal resistance vessels
Yuichi Ozawa, Toyoshi Hasegawa,
Koichiro Tsuchiya, Masanori Yoshizumi, and Toshiaki Tamaki
|
Department of Pharmacolgy, The University of
Tokushima School of Medicine, Tokushima, Japan
Abstract: Human chymase produces not only angiotensin II but
also endothelin(ET)-1(1-31). We previously reported that ET-1(1-31)
had several biological activities in vascular smooth muscle
cells. In this study, we investigated the vasoconstrictor
effect of ET-1(1-31) on the renal resistance vessels using
in vitro microperfused rabbit afferent and efferent arterioles.
ET-1(1-31) decreased the lumen diameter of the afferent and
efferent arterioles dose-dependently. ET-1(1-31)-induced afferent
arteriolar vasoconstriction was not affected by phosphoramidon,
an ET converting enzyme inhibitor. ET-1(1-31)-induced renal
arteriolar vasoconstriction was inhibited by BQ123, an ETA
receptor inhibitor, but not by BQ788, an ETB receptor inhibitor.
These results suggest that ET-1(1-31)-induced renal arteriolar
vasoconstriction may be mediated by ETA-like receptors. J.
Med. Invest. 50:87-94, 2003
Keywords:ET-1(1-31), ET-1, afferent arteriole, efferent arteriole,
INTRODUCTION
Human endothelin(ET)-1is a 21-amino acid polypeptide, and
is generated from the 38-amino acid precursor, big ET-1, through
cleavage of Trp21-Val22 bound via the action of a membrane-bound
metalloprotease, ET-converting enzyme (ECE) (1, 2). ET-1 induced
powerful and long-lasting vascular smooth muscle cell contractile
responses in various systems with particularly potent actions
on renal vascular beds (1, 3-6). ET-1 also exhibits various
physiological actions, such as cardiac hypertropyh (7), vascular
thickening (4) and mitogenesis (8). On the other hand, Nakao
et al. (9) reported that human mast cell chymase, unlike rat
mast cell chymases, selectively cleaves big ETs at the Tyr31-Gly32
bond to produce novel trachea-constricting 31 amino acid ETs,
ETs(1-31), without any further degradation products. ET-1(1-31)
was found in human blood (10), granulocytes (11) and lung
(12). ET-1(1-31) also exhibits various physiological actions,
such as vascular contraction (3), cell proliferation (10,
13), and chemotactic effects (14).
Exogenous ET-1 caused potent vasoconstriction and prolonged
the elevation of blood pressure. Thus, endogenous ET-1 is
assumed to modulate vascular tone and regional blood flow
as a circulating hormone, or to exert its actions locally
within the vascular wall and on the endothelium in an autocrine
or paracrine fashion. ET-1(1-31) may also modulate vascular
tone and regional blood flow. However, the effect of ET-1(1-31)
on the resistance vessels, which regulate the organ circulation,
has not yet been examined. In renal circulation, preglomerular
afferent and post glomerular efferent arterioles are crucial
vascular segments to the control of glomerular hemodynamics
(5). The balance of vascular tone between the afferent and
efferent arterioles critically affects glomerular capillary
pressure, and thereby the glomerular filtration rate, as well
as renal excretory function. In this study, we examined the
effects of synthetic ET-1(1-31) on the lumen diameter of isolated
microperfused rabbit afferent and efferent arterioles.
MATERIALS AND METHODS
Materials
Human ET-1 and phosphoramidon (N-(α-rhamnopyran-osyloxyhydroxyphosphinyl)-L-Leucyl-L-tryptophan)
were obtained from the Peptide Institute (Osaka, Japan). ET-1(1-31)
was synthesized using a solid-phase procedure at the Peptide
Institute. Bovine albumin fraction V was purchased from Seikagaku
Kogyo Co., Ltd.(Tokyo, Japan). Medium 199 was purchased from
Nissui Pharmaceutical Co., Ltd. (Tokyo, Japan). BQ123(cyclo-(D-Try-D-Asp(ONa)-Pro-D-Val-Leu))
(15) and BQ788(N-cis-2,6-dimethylpiperidinocarbonyl-L-&ganma;MeLeu-D-Trp(COOMe)-D-Nle-ONa)
(16) were gift from Banyu Pharmaceutical Co (Tsukuba, Japan).
All other chemicals used were commercial products of reagent
grade.
Isolation and microperfusion of the rabbit afferent and efferent
arterioloes.
We used a method similar to that described previously (17,
18). Briefly, male New Zealand white rabbits were anesthetized
with intravenous sodium pentobarbital (25 mg/kg) and given
an intravenous injection of heparin (500U). The kidney was
exposed through a retroperitoneal flank incision, and the
renal pedicle was clamped and cut. The kidney was quickly
removed and placed in iced medium 199. Then, the kidney was
sliced along the corticomedullary axis. A thin slice was transferred
to a dish containing chilled medium 199 and microdissected
under a stereoscopic microscope (SZH, Olympus, Tokyo, Japan)
using thin steel needles and sharpened forceps (No. 5, Dumont,
Basel, Switzerland) at 4°C. The superficial glomerulus,
with afferent and efferent arterioles, was dissected free
from the surrounding tissue and all tubular fragments were
removed. Great care was taken to avoid touching the vessels
and exerting longitudinal or transverse tension on them. An
afferent arteriole, with its glomerulus and efferent arteriole,
was severed from the interlobular artery by cutting it with
a disposable 27-gauge injection needle (TOP, Tokyo, Japan).
The final preparation was transferred with a micropipette
to a temperature-regulated chamber (ITM, San Antonio, TX,
USA) and the camber was mounted on the stage of an inverted
microscope with Hoffman modulation (Diaphot, Nikon, Tokyo,
Japan). The volume of the chamber was 1 ml. For drainage,
fresh bath medium (medium 199) was supplied to the bottom
right side of the chamber at 0.5 ml/min, and the medium was
gently aspirated from the top of left side of the chamber.
During the experiment, water-saturated gas (90% O2 and 10%
CO2) was gently blown over the surface of the bath to maintain
the pH at 7.4.
The afferent arteriole was cannulated with a pipette system
as illustrated (Fig. 1). The method used for cannulating the
afferent arteriole into the micropipette system was similar
to that reported by Osgood et al. (19) and by Ito and Carretero
(20). The afferent arteriole was drawn into the holding pipette,
which had a constriction. The tip of the perfusion pipette
was advanced into the lumen of the afferent arteriole. A strong
vacuum was then applied to the holding pipette to pull the
afferent arteriole further toward the constriction in the
holding pipette, and thereby seal it between the two pipettes.
The pressure pipette, which was filled with 0.9% NaCl solution
containing FD & C green and 4% KCl, was then advanced
into the afferent arteriole through the opening of the perfusion
pipette. The intraluminal pressure was measured by Landis'
technique (19) using this pressure pipette. The afferent arteriole
was microperfused with oxygenated medium 199 containing 5%
bovine albumin fraction V (Fig. 2). After the completion of
cannulation, the intraluminal pressure was set at 60 mmHg
and maintained throughout the experiment. The intraluminal
pressure was continuously monitored with a pressure transducer
and monitor(Digic VPC, Valcom, Tokyo, Japan). Microdissection
and cannulation of the afferent arteriole was completed within
90 minutes. The temperature of the bath was gradually raised
to 37°C and monitored during the experiment (E5CS,
Omron, Tokyo, Japan). A 30-minute equilibration period was
allowed before the experiment. The image of the afferent arteriole
during the experiment was recorded with a video system consisting
of a CCD camera and control unit (CCD-10, Olympus, Tokyo,
Japan), a monitor (NV-0930Z, Mitsubishi, Tokyo, Japan), and
a video recorder (Timelapse BR-9000, JVC, Tokyo, Japan). The
effect of ETs was evaluated on the basis of the change in
the lumen diameter of the microperfused afferent or efferent
arterioles. The lumen diameter of the arteriole was measured
directly on the video monitor screen. At the end of the experiment,
the viability of the vessel was assessed by the response to
10-5M norepinephrine.
Experimental Protocols
Effect of ETs on the lumen diameter of microperfused afferent
and efferent arteriole.
Following a 30-minutes equilibration, ET was applied to the
bath in increasing concentrations, to determine its dose-response
curve. The control measurements of the lumen diameter were
made at 1-min intervals for 3 minutes, and the control value
was the mean value of three measurements. During the control
measurements, we confirmed that the lumen diameter was stable.
The continuous bath exchange was stopped and the bath medium
was rapidly exchanged for the medium containing the lowest
concentration of ET. The bath exchange was resumed with medium
containing the same concentration of ET, and the arteriole
was observed for 5 minutes. Every 5 minutes, the concentration
of ET was increased by one order of magnitude, up to 10-6M.
The effects of ET-1(1-31) on the lumen diameter of afferent
and efferent arterioles were evaluated using different sets
of microperfused glomeruli. The effects of ETs on the lumen
diameter of arterioles were measured 5 minutes after the addition
of ETs.
Effect of phosphoramidon on the ET-1(1-31)-induced afferent
arteriolar vasoconstriction.
We investigated the possibility that ET-1(1-31)-induced afferent
arteriolar vasoconstriction may be due to further degradation
of ET-1(1-31) to ET-1 by endothelin-converting enzyme in the
medium or microdissected glomerulus with afferent and efferent
arterioles. We examined the effect of an inhibitor of endothelin-converting
enzyme, phosphoramidon (21), on the ET-1(1-31)-induced afferent
arteriolar vasoconstriction.
After the microperfusion of the isolated afferent arteriole
was completed, we added phosphoramidon to the perfusate and
bath medium. After preincubation with 10-5M phosphoramidon,
ET-1(1-31) and 10-5M phosphoramidon were added to the bath
medium, and the effect of ET-1(1-31) was evaluated in the
manner as described above.
Effects of endothelin receptor antagonists on the ET-1(1-31)-induced
arteriolar vasoconstriction.
We examined the effects of endothelin receptor antagonists
on the ET-1(1-31)-induced arteriolar vasoconstriction to
determine whether the effect of the ET-1(1-31) is a receptor-mediated
phenomenon. There are at least two subtypes of endothelin
receptors, termed endothelin ETA and ETB (22). We examined
the effects of a specific endothelin ETA receptor antagonist,
BQ123(15), and a specific endothelin ETB receptor antagonist,
BQ788(16),on the ET-1(1-31)-induced arteriolar vasoconstriction.
After the microperfusion of the isolated afferent arteriole
was completed, we added an endothelin receptor antagonist
to the perfusate and bath medium. Following preincubation
with an endothelin receptor antagonist, the effect of ET-1(1-31)
was evaluated in the manner described above.
Data Analysis
Values are expressed as means±SEM. The data were
analyzed by one-way analysis of variance, followed by a
least significant different test. P<0.05 was considered
to be a statistically significant difference.
RESULTS
Effect of ET-1(1-31) on the lumen diameter of microperfused
afferent and efferent arterioles.
The basal lumen diameter of microperfused afferent arterioles
was 13.4±0.7 µm (n=7), and the basal
lumen diameter of microperfused efferent arterioles was9.8±0.4µm
(n=7) (Fig. 3). ET-1(1-31) decreased the lumen diameter of
afferent and efferent arterioles dose-dependently (Fig. 3).
In some experiments, we examined the duration of the constrictor
effect of ET-1(1-31). Five minutes after the addition of 10-6M
ET-1(1-31), 10 exchanges of the bath medium were made to remove
residual ET-1(1-31). ET-1(1-31)-induced renal arteriolar vasoconstriction
lasted for 60 minutes at least (data not shown).
Effect of phosphoramidon on the ET-1(1-31)-induced afferent
arteriolar vasoconstriction.
As illustrated in Fig. 4, phosphpramidon (10-5M), an inhibitor
of endothelin-converting enzyme, did not affect on the ET-1(1-31)-induced
afferent arteriolar vasoconstriction. These results suggest
that the vasoconstrictor effect of ET-1(1-31) is not due to
the conversion of ET-1(1-31) to ET-1.
Effects of endothelin receptor antagonists on the ET-1(1-31)-induced
afferent arteriolar vasoconstriction.
BQ123(10-7M), a specific endothelin ETA receptor antagonist,
completely abolished the ET-1(1-31)-induced afferent arteriolar
vasoconstriction (Fig. 5). On the other hand, pretreatment
with BQ788(10-7M), a specific endothelin ETB receptor antagonist,
did not affect the ET-1(1-31)-induced vasoconstriction (Fig.
5). These results suggest that ET-1(1-31) decreased the lumen
diameter of the isolated microperfused afferent arteriole
via ETA receptor or ETA like receptor.
Effect of ET-1 on the lumen diameter of the microperfused
afferent arteriole.
As shown in Fig. 6, ET-1 decreased the lumen diameter of isolated
microperfused afferent arterioles dose-dependently. ET-1 was
more potent than ET-1(1-31). BQ123(10-7M), a specific endothelin
ETA receptor antagonist, inhibited ET-1-induced afferent arteriolar
vasoconstriction.
DISCUSSION
ET-1 has been reported to induce powerful and long-lasting
vasocontractile responses in various vessels with particularly
potent actions on renal vascular beds (1, 3-6). Since the
afferent arteriole is not only a resistance vessel in renal
circulation, but also a major component which regulates kidney
function, it would be important to understand the action of
ETs in this vessel. In this study, we demonstrated that ET-1(1-31)
decreased the lumen diameter of microperfused renal afferent
and efferent arterioles dose-dependently. Phosphoramidon,
an ET converting enzyme inhibitor, did not affect the ET-1(1-31)-induced
afferent arteriolar vasoconstriction. ET-1(1-31)-induced renal
arteriolar vasoconstrictin was inhibited by BQ123, an ETA
receptor inhibitor, but not by BQ788, an ETB receptor.
We already reported that the plasma concentration of immunoreactive
ET-1(1-31) was similar to that of ET-1 in young healthy volunteers
(10), and that ETs(1-31) exist in human granulocytes and lungs
at similar levels to those of ETs (11, 12). We also found
that ET-1(1-31) increased [3H]-thymidine incorporation into
the cultured human coronary artery smooth muscle cells and
cell numbers to a similar extent as ET-1 (13). Nakao et al.
(9) reported that human mast cell chymase specifically converted
big ETs to the 31-amino acid peptide ETs(1-31)s, which are
different in amino acid length from the well-known 21-amino
acid ETs. These findings suggest that ET-1(1-31) is a bioactive
peptide in humans and is deeply involved in chymase-related
pathophysiological processes in humans. It has been confirmed
that human vascular tissue has a chymase-dependent angiotensin
II(Ang II)-forming pathway. Human chymase is highly efficient
in converting Ang I to Ang II (23). Miyazaki and Takai suggested
that chymase plays a major role in the vascular Ang II-generating
system, particularly in the case of vascular injuries (24).
Their conclusion was as follows. In the normal state, a vascular
angiotensin converting enzyme (ACE) regulates local Ang II
formation and plays a crucial role in the regulation of blood
pressure, whereas chymase is stored in mast cells and shows
no Ang II-forming activity. On the other hand, chymase is
activated immediately upon release into the extracellular
matrix in vascular tissue after mast cells have been activated
by a stimulus such as injury by a catheter or grafting of
vessels (24). Increased expression of chymase in mast cells
was related to the severity of interstitial fibrosis in human
transplant rejected kidneys (25). We already comfirmed that
ET-1(1-31) increased intracellular free Ca2+ concentration
(26) and stimulated the proliferation of cultured human mesangial
cells (10). Taken together, ET-1(1-31) may play an important
role in chymase-related pathophysiological processes in humans.
In this study, we demonstrated that ET-1(1-31)decreased the
lumen diameter of microperfused afferent and efferent arterioles
via ETA or ETA -like receptors of the cells. Phosphoramidon,
an inhibitor of endothelin converting enzyme (ECE), at a concentration
of 10-5M, had no effect on ET-1(1-31)-induced renal arteriolar
vasoconstriction. These results suggest that renal arteriolar
vasoconstriction caused by ET-1(1-31) is not the consequence
of conversion to ET-1 by ECE. Our results are consistent with
the finding that ECE requires the C-terminal structure of
big ET-1 for enzyme recognition and is not able to cleave
ET-1(1-31) (27). However, ET-1 was about 103-104-times more
potent than ET-1(1-31) in our experimental condition. Although
there is general agreement that the renal vasculature has
enhanced sensitivity to ET-1, the constrictor potency relative
to other physiological agonists remains controversial. Lanese
et al. reported that EC50 of ET-1-induced afferent arteriolar
vasoconstriction was 5.2±1.7×10-11M,
using isolated microperfused rat afferent arterioles (28).
In the isolated perfused hydronephrotic rat kidney preparation,
Loutzenhiser et al. (29) found that the lumen diameter of
afferent arterioles decreased by 41% to 0.3×10-9M
ET-1. Edwards et al. (30) reported similar EC50 values in
afferent arterioles to ET-1 in the order of 10-9M using isolated
rabbit afferent arterioles. Bloom et al. (31) found that 10-8M
ET-1 decreased the lumen diameter of afferent arterioles by
39±2%, using the split rat hydronephrotic kidney
preparation. The marked differences in ET-1 responses in renal
arterioles is difficult to explain. Although we found a large
difference in constrictor potency between ET-1(1-31) and ET-1
in an in vitro isolated microperfused rabbit arteriole preparation,
it should be noted that ET-1(1-31) itself has biological activity.
In previous studies, we demonstrated that ET-1(1-31) stimulated
human coronary smooth muscle cells and mesangial cell proliferation
to a similar extent as that of ET-1 (10, 13). We also demonstrated
that ET-1(1-31) caused a rapid and significant activation
of mitogen-activated protein (MAP) kinases in a concentration-dependent
manner in various cultured cells to a similar extent as that
of ET-1 (10, 13, 32, 33). These effects of ET-1(1-31) were
inhibited by BQ123, but not by BQ788. This suggests that the
cell responses induced by ET-1(1-31) are mediated through
ETA or ETA-like receptors. ET-1(1-31) increased the intracellular
free Ca2+ in cultured smooth muscle cells and this activity
of ET-1(1-31) was about 10-times less than that of ET-1 (34,
35). On the other hand, ET-1(1-31)-induced renal afferent
arteriolar vasoconstriction was about 1000 to 10000-times
less potent than ET-1 in our experimental condition. If the
cell responses induced by ET-1(1-31) are mediated through
an ETA receptor, we can not explain the large potency difference.
Although we have no evidence that the receptor of ET-1(1-31)
is different from ETA, the results suggest the existence of
a different receptor(s) that mediates ET-1(1-31)-induced cell
response.
In conclusion, ET-1(1-31) decreased the lumen diameter of
afferent and efferent arterioles dose-dependently. ET-1(1-31)-induced
renal arteriolar vasoconstriction may be mediated by ETA -like
receptors.
ACKNOWLEDGMENTS
This work was supported, in part, by Grants-in-Aid for scientific
research (No.12557008 and 13670087 to T. Tamaki) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
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Received forpublication December 17, 2002;accepted January
10, 2003.
Address correspondence and reprint requests to Toshiaki Tamaki,
M.D., Ph.D., Department of Pharmacolgy, The University of
Tokushima School of Medicine, Kuramoto-cho, Tokushima 770-8503,
Japan and Fax:+81-88-633-7062. |
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