(Hypertension. 1997;30:830-836.)
© 1997 American Heart Association, Inc.
Articles |
Reversal of Endothelin-1 Release by Stimulation of Endothelial 
2-Adrenoceptor Contributes to Cerebral Vasorelaxation
From The Totman Laboratory for Human Cerebrovascular Research, Department of Pharmacology, Given Building, University of Vermont (Burlington).
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Abstract |
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Abstract Agonists acting on the vascular endothelium can modulate the release of a number of factors that interact with the surrounding smooth muscle cells and influence their tone. One such factor is the vasoconstricting agent endothelin-1 (ET-1), which has been implicated in several disease states, including stroke. However, very little is known about the physiological role of ET-1 in the cerebral circulation. We demonstrate that activation of
2-adrenoceptors in human pial artery
endothelial cells reduces both constitutive and
agonist-stimulated release of immunoreactive ET-1. That this has
physiological relevance is supported by our
demonstration that in segments of rabbit middle cerebral arteries,
2-adrenoceptor activation reduces the release of
endothelium-derived ET-1 and causes an
endothelium-dependent relaxation. The
adrenoceptor-dependent relaxation was not blocked by combined addition
of indomethacin and
N
-nitro-L-arginine in 25
mmol/L KCl-depolarizing physiological solution but
was selectively antagonized by a subthreshold concentration of
exogenous ET-1. Our data suggest that activation of
endothelial 2-adrenoceptor would favor a
decrease in ET-1 production and possibly promote vascular
relaxation.
Key Words: endothelium • artery, cerebral • receptors, adrenergic • endothelin-1 • human • rabbits
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Introduction |
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The endothelium reacts to a variety of hormonal and physical stimuli1 2 by releasing local regulators of vascular function. These include vasodilators such as EDRF/NO,3 prostacyclin,4 and EDHF,5 as well as a potent vasoconstrictor, ET-1.6 Although ET-1 is thought to be involved in several diseases, including acute cerebrovascular insufficiency, vasospasm due to subarachnoid hemorrhage, and stroke,7 8 it is only recently that a physiological role for ET-1 has been suggested in the control of cerebral blood flow by the demonstration that injection of BQ123, a selective ETA receptor antagonist, dilated dog cerebral arteries in vivo.9 The release of ET-1 is stimulated by agonists including angiotensin II and thrombin,1 10 11 but linkage with adrenergic mechanisms has not been described in cerebral arteries. Activation of endothelial
2-adrenoceptor induces NO release, triggering relaxation
of large conductance arteries.12 13 In rat cerebral
arteries, NO has been shown to have a permissive role in the relaxation
induced by 2-adrenoceptor agonists.14
However, NO is not the only factor contributing to the
2-adrenoceptor–mediated relaxation.13 In
this study, we show that 2-adrenoceptor agonists reduce
ET-1 release from the endothelium and demonstrate the
physiological consequence of this effect on the
rabbit MCA tone. |
Methods |
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Reactivity Studies
The study of resistance artery reactivity on isometric or isobaric (Living System) myographs has been described previously.15 Segments of second-order rabbit MCAs (outer diameter, 311±4 µm; n=50) were used. In some experiments (n=3), the endothelium was removed by injecting air through a micropipette inserted into the arterial segment using a 5-mL syringe. After 1 hour of recovery, the segment was constricted with serotonin (1 µmol/L) and histamine (1 µmol/L); acetylcholine-induced, endothelium-dependent relaxation was suppressed without affecting the relaxation induced by sodium nitroprusside (0.1 µmol/L; 75±16% versus 88±18% relaxation in the presence of an intact endothelium).
Cell Culture
Human pial arterial segments otherwise discarded
(external diameter, 350 to 500 µm; length, 2 mm) were
collected from three patients (18, 30, and 40 years old; free of
metabolic disease, hypertension, and
atherosclerosis) undergoing neurosurgery for skull
fracture or tumor removal. In this latter case, the
arterial segment used was not feeding the tumor. The cell
lines studied have been characterized previously.16 Each
arterial segment was cleaned of connective tissue under
sterile conditions and cut into small fragments that were placed in a
culture dish containing growth medium (Dulbecco's modified Eagle's
medium supplemented with 20% [vol/vol]
heat-inactivated fetal bovine serum, 1 mmol/L
neomycin, and 2 mmol/L L-glutamine) as
described previously.16 After 4 to 7 days, cells started
to proliferate. Trypsin-EDTA (0.05%, 0.53 mmol/L) was
added to harvest the cells, which were then seeded at a low
concentration (100 cells/mL) in large culture dishes. Cells were seen
dividing 48 hours later. Endothelial cells were
isolated under the microscope by scraping away any contaminant. If
contaminating cells were still present after 48 hours, this
operation was repeated. When confluent, a second trypsinization was
performed, and the cells were seeded in large culture flasks. After 2
to 4 weeks, the cells were trypsinized and seeded in 6-well plates for
ET-1 quantification and glass coverslips for immunocytochemical
characterization.
Endothelial Cell Characterization
Subconfluent endothelial cells established on
20x20-mm glass coverslips were incubated with anti-factor VIII/von
Willebrand factor (vWF) antibody (1:20 dilution) in PBS
overnight at 4°C. After a washing, the coverslips were incubated with
fluorescein-labeled goat anti-rabbit IgG (factor VIII/vWF)
for 2 hours at 37°C. The cells were examined using
fluorescence microscopy (Zeiss IM35 inverted microscope with
fluorescein excitation and emission wavelengths of 340 and
510 nm, respectively).
ET-1 Quantification
Appearance of immunoreactive ET-1 (ir-ET-1) in the culture
medium of endothelial cells was quantified using
anti-ET-1 antibody as described previously.16 The
experiments were performed in triplicate. After a 30-minute washout
period, cells were incubated for 30 minutes in 2 mL of serum-free
medium 199 (Life Technologies, Inc) at 37°C and 5% CO2.
The medium (100 µL) was immobilized on nitrocellulose
membrane (0.1-µm pore size) using a slot-blot apparatus
(Schleicher & Schuell). The membrane was incubated for 1 hour at room
temperature in 5% nonfat dry milk in 0.1% Tween 20 in Tris-saline
buffer (500 mmol/L NaCl, 20 mmol/L Tris-HCl, pH
7.4) to block nonspecific protein binding. After a washing with 0.05%
Tween 20 in Tris-saline buffer (Tween-Tris-saline buffer), the
nitrocellulose paper was incubated for 1 hour at room temperature with
rabbit anti-ET-1 primary antiserum (Peninsula Laboratories;
cross-reactivity of 17%, 7%, and 7% with big ET, ET-2, and ET-3,
respectively) diluted 1:1000 in 5% nonfat milk in Tween-Tris-saline
buffer. The paper was washed again and incubated for 1 hour with
horseradish peroxidase–conjugated second antibody (Bio-Rad; 1:2000
dilution in Tween-Tris-saline buffer supplemented with 5% nonfat dry
milk). The paper was washed, and detection was accomplished using the
enhanced chemiluminescence method (ECL, Amersham). ET-1 was quantified
using Optimas Imaging software (Bioscan).
For direct measurement of ET-1 released from isolated rabbit MCAs, 2-mm-long arterial segments were isolated and cleaned from connecting tissues before being mounted on a wire attached to the mobile foot of the myograph. The tissues were first equilibrated in 1 mL of Medium 199 at 37°C and 5% CO2 for 30 minutes. The medium was replaced, and the samples were incubated for a second period of 30 minutes. At the end, the medium was collected and frozen (-80°C), and the tissues were incubated in fresh medium alone or containing oxymetazoline (10 µmol/L), combined or not with serotonin (1 µmol/L) and histamine (1 µmol/L) and with or without yohimbine (30 µmol/L) for a third and last 30-minute period. ET-1 was quantified as described above. No intrinsic difference in ET-1 release was observed between the second and the third incubation periods.
Statistical Analysis
Results were expressed as mean±SEM. The pD2 value
is the negative log of the half-maximum effective concentration
(EC50) of 2-adrenoceptor agonists
(clonidine, UK 14,304, and oxymetazoline). The EC50 was
determined individually in each ring of each vessel using a logistic
curve-fitting program. Comparisons were made using Student's
t test or one-way ANOVA, followed by Fisher's correction
for multiple comparisons when appropriate. Differences between means
were considered significant at P<.05.
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Results |
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Isolated Middle Cerebral Artery Mounted Isometrically
Preliminary Experiments
Histamine and phenylephrine (1 to 10 µmol/L) when added alone induced only a small and unsustained contraction (8±1%, n=8 and 3±1%, n=14, respectively, of the maximum contractile response [Emax] obtained in the presence of PSS containing 127 mmol/L KCl). In agreement with previous studies, serotonin (1 µmol/L) did not produce a stable contractile response.17 18 Because a stable contraction was critical to our study of vasorelaxation, we tested a combination of agonists. Combined addition of serotonin (1 µmol/L) and histamine (1 µmol/L; n=19) or serotonin (1 µmol/L) and phenylephrine (10 µmol/L; n=33) induced stable constrictions (54±6% and 24±3% of Emax, respectively). Acetylcholine (1 µmol/L) decreased the preconstricted tone by 96±15%. In the presence of 100 µmol/L N
-nitro-L-arginine
(inhibitor of NO synthase19 ), the
preconstricting tone induced by serotonin and histamine was
potentiated (89±17% of Emax; n=8,
P<.05), whereas the relaxation induced by acetylcholine was
partially inhibited (45±7% relaxation; n=8, P<.05).
Indomethacin (10 µmol/L), which prevents
the formation of dilator prostaglandins,4 had
no significant effect on acetylcholine-induced relaxation.
2-Adrenoceptor Agonist-Induced Relaxation
As shown by Fig 1
(top
recording), oxymetazoline (0.1 to 30 µmol/L)
induced a concentration-dependent relaxation of rabbit MCA segments
isometrically preconstricted by combined addition of
serotonin (1 µmol/L) and histamine (1
µmol/L). After removal of the endothelium
(middle trace), the 2-adrenoceptor–dependent relaxation
was abolished. Other 2-adrenoceptor agonists, clonidine
and UK 14,304, also completely relaxed the artery preconstricted with
serotonin (1 µmol/L) and
phenylephrine (10 µmol/L) (Fig 2A). pD2 values for clonidine
and UK 14,304 were 5.96±0.03 (n=8) and 5.94±0.04 (n=5), respectively,
and were significantly less than that for oxymetazoline (6.98±0.02;
n=8, P<.05, ANOVA, Scheffé's F test). The
relaxation to these agonists was inhibited by the
2-adrenoceptor antagonists rauwolscine and
yohimbine but not the 1-adrenoceptor
antagonist HEAT20 21 (Fig 2B). These data
indicate that activation of the endothelial
2-adrenoceptor in the MCA induces vasorelaxation.
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Relaxation Mechanisms
Early studies of noncerebral arteries have reported that
endothelial 2-adrenoceptor–induced
relaxation was only partially mediated by NO.13 The
possible involvement of other endothelial factors in
the 2-adrenoceptor–mediated relaxation of rabbit MCA
was assessed. Although the acetylcholine-mediated relaxation was
reduced by 100 µmol/L
N-nitro-L-arginine and 10
µmol/L indomethacin (see "Preliminary
Experiments"), the relaxant effect of oxymetazoline (n=4) was
unaffected (Fig 3A), indicating that the
mediator was neither NO nor dilator prostanoids.
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EDHF has been proposed to make a significant contribution to the
regulation of cerebrovascular tone.22 23 24 PSS containing
25 mmol/L KCl, which changes the membrane potential of the
smooth muscle cells from -66.1±0.6 to -34.8±0.6 mV (n=6; N. Gokina,
unpublished observations, 1995), would be expected to antagonize the
effect of EDHF.5 25 To investigate the possible
involvement of EDHF in 2-adrenoceptor agonist–induced
relaxation, the following experiments were undertaken and performed in
the presence of indomethacin (10 µmol/L).
The addition of 25 mmol/L KCl PSS raised the tone by
25±5% of Emax (n=4). After incubation with
100 µmol/L
N-nitro-L-arginine for 45
minutes, the addition of 25 mmol/L KCl PSS induced a
contraction that was strongly potentiated, representing
78±10% of Emax (P<.05; n=4).
Subsequent addition of serotonin and histamine produced a
maximal constriction (118±13% of Emax;
P<.05). Although the preconstricting level of tone was more
than doubled by the combined addition of 25 mmol/L KCl PSS
and N-nitro-L-arginine,
oxymetazoline (100 µmol/L) still induced a complete
relaxation of the arterial segment (Fig 3B
). In contrast,
acetylcholine (1 to 10 µmol/L) did not relax segments
preconstricted in the presence of 25 mmol/L KCl PSS and
N-nitro-L-arginine (n=4;
P<.05). These data suggest that EDHF is not involved in the
2-adrenoceptor–mediated relaxation.
ET-1 is another potent endothelium-derived factor that
may regulate tone. Basal release of ir-ET-1 by intact isolated segments
of rabbit MCAs (Fig 4) was 0.76±0.07
pmol/mg tissue (n=5). Oxymetazoline (10 µmol/L)
decreased the appearance of ir-ET-1 in the medium to 0.49±0.09
pmol/mg tissue (P<.05, Student's t
test). In the absence of endothelium, no ir-ET-1 was
detectable. In a second series of experiments, combined addition of
serotonin (1 µmol/L) and histamine (1
µmol/L) increased the release of ir-ET-1 to 1.64±0.14
pmol/mg tissue (n=6; P<.05, ANOVA, Scheffé's
F test). Oxymetazoline (10 µmol/L) decreased
the appearance of ir-ET-1 in the medium (0.49±0.09 pmol/mg
tissue; P<.05, ANOVA, Scheffé's F test),
an effect reversed by yohimbine (30 µmol/L; 0.80±0.08
pmol/mg tissue).
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To further elucidate the role of endogenous ET-1 in the
regulation of cerebral arterial tone, we studied the
effects of a subthreshold exogenous concentration of ET-1 or exposure
either to an antibody to ET-1 or the ETA receptor
antagonist BQ123 in isolated vessels. Although a
subthreshold concentration of ET-1 (0.1 nmol/L) did not affect
the relaxation elicited by acetylcholine (1 µmol/L, data
not shown), it did reduce 2-adrenoceptor–dependent
relaxation (Fig 5). The relaxation to
oxymetazoline (10 µmol/L) was decreased from 60±4%
(n=19) to 11±7% (n=5, P<.05, Student's t
test) by 0.1 nmol/L ET-1. ET-1 (0.1 nmol/L) potentiated
tone development to serotonin (1 µmol/L) and
histamine (1 µmol/L) by 38% (from 36±3% to 49±4% of
Emax; n=5, P<.05, Student's
t test). A subthreshold concentration of
angiotensin II (10 nmol/L), which caused an
equivalent potentiation of the tone, did not affect relaxation (Fig 5).
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In the presence of anti-ET-1 antibody (1:1000 dilution, 2 hours,
37°C, n=3), the peak arterial contraction induced by
serotonin (1 µmol/L) and histamine (1
µmol/L) was reduced from 56±10% to 12±6% of
Emax (P<.05, Student's t
test). Furthermore, tone was not sustained (Fig 1, lower
recording). The contraction induced by 40 mmol/L
KCl PSS was not affected by the antibody (61±5% compared with 64±6%
of Emax). An antivasoactive intestinal
polypeptide antibody (1:1000 dilution, 2 hours, 37°C, n=3; Peninsula
Laboratories), used as a control in these experiments, had no effect.
Similarly, BQ123 (1 µmol/L, 20-minute preincubation
period, n=4; American Peptide Co), a selective ETA
endothelin receptor antagonist,11 decreased
the contraction induced by serotonin (1
µmol/L) and histamine (1 µmol/L) from 36±8% to
16±3% of Emax (P<.05, paired
Student's t test). In parallel experiments performed in the
absence of BQ123, no decrease in responsiveness was observed between
the first and the second applications of serotonin (1
µmol/L) and histamine (1 µmol/L) after 30
minutes (25±4% and 32±1% of Emax,
respectively; n=4).
Cultured Cells
To further substantiate the effect of
2-adrenoceptor agonists on ET-1 release, we isolated
human cerebral endothelial cells from pial
arterial segments obtained during neurosurgery (Fig 6A and 6B). Constitutive release of ir-ET-1 (Fig 6C) was 7.1±0.8 pmol/µg protein (n=6). Oxymetazoline (10
µmol/L) decreased the appearance of ir-ET-1 to 5.2±0.8
pmol/µg protein (P<.05, ANOVA, Scheffé's
F test), an effect reversed by yohimbine (30
µmol/L; 6.9±0.8 pmol/µg protein). In a second series
of experiments (n=6), combined addition of serotonin
(1 µmol/L) and histamine (1 µmol/L)
increased the appearance of ir-ET-1 in the medium from 7.5±0.7
pmol/µg protein to 9.6±1.0 pmol/µg protein
(P<.05, ANOVA, Scheffé's F test).
Oxymetazoline (10 µmol/L) strongly decreased the
appearance of ir-ET-1 to 4.0±0.7 pmol/µg protein
(P<.05, ANOVA, Scheffé's F test). This
effect was antagonized by yohimbine (30 µmol/L; 6.8±0.6
pmol/µg protein).
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Isolated Posterior Cerebral Artery Mounted Under Isobaric
Conditions
Isolated resistance arteries studied in isobaric conditions have
been shown to be more sensitive to agonist than when mounted
isometrically, largely because of a pressure-dependent depolarization
of the smooth muscle cells that occurs when the former technique is
used.15 In these conditions, oxymetazoline relaxed the
rabbit posterior cerebral artery. Although acetylcholine-mediated
dilation was abolished by
N-nitro-L-arginine (100
µmol/L) and indomethacin (10
µmol/L), oxymetazoline-mediated relaxation was unaffected (Fig 7). Removal of the
endothelium by air flow prevented the response to
acetylcholine (10 µmol/L) and oxymetazoline (10
µmol/L).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The aim of this study was to investigate the endothelium-dependent pathway associated with the relaxant effect of
2-adrenoceptor stimulation in rabbit
MCAs (Figs 1 and 2). Our results suggest that inhibition of ET-1
production by 2-adrenoceptor agonists may be
responsible for the relaxation of preconstricted rabbit MCAs.
In this study, we used the most selective 2-adrenoceptor
agonists and antagonists available.12 26 27
The effective dose range (0.1 to 30 µmol/L) of the
agonists (Fig 2A) that induced vasorelaxation is characteristic of
functional 2-adrenoceptors.26 28 Both
yohimbine and rauwolscine antagonized this response at concentrations
typical for functional
2-adrenoceptors,12 26 27 whereas the
1-adrenoceptor antagonist HEAT was without
effect (Fig 2B). Furthermore, no functional
1-adrenoceptors have been identified so far on the
endothelium. Taken together, we conclude that the data
demonstrate that the vasorelaxation is mediated by
2-adrenoceptors. The greater potency of oxymetazoline
compared with clonidine and UK 14,304 suggests that this receptor is of
the A subtype.12
Combined addition of serotonin and histamine, like several
other factors,10 11 29 30 31 32 increased ET-1
production both in cultured cells and isolated vessels (Figs 4 and 6). Because BQ123 and anti-ET-1 antiserum antagonized contractions
induced by serotonin/histamine, it is likely that
endothelium-derived ET-1 is partly responsible for the
response. On the basis of these data and other
reports,33 34 35 we suggest that ET-1 sensitizes the
contractile apparatus of the underlying smooth muscle
cells, thus potentiating responses to contractile agonists. By
contrast, 2-adrenoceptor agonists reversed
endothelium-derived ET-1 release to prestimulated
levels (Figs 4 and 6). It is well established that
endothelial cells secrete ET-1.6 36 37
Most stimuli, such as thrombin,29 insulin,30
oxidized LDL,31 and hemodynamic shear
stress,32 regulate ET-1 release at the level of gene
transcription. However, our findings that
serotonin/histamine and 2-adrenoceptor
agonists have an immediate effect on ET-1 release are not without
precedent. Angiotensin II is reported to have a similar
effect in the isolated tail artery11 and various
resistance arteries.10 Furthermore, preproendothelin-1 and
ET-1 are stored in intracellular vesicles in cultured bovine aortic
endothelial cells,38 suggesting that this
could be a target for some stimuli. It is therefore likely that
regulation at the level of the mRNA and release represent two
different mechanisms involved in chronic and acute responses,
respectively.
That the decrease in ET-1 release mediated by
2-adrenoceptor activation may be responsible for the
relaxation of preconstricted cerebral arteries (Figs 1 and 2) is
further strengthened by the demonstration that a subthreshold
concentration of exogenous ET-1 selectively antagonized the relaxation
mediated by oxymetazoline (Fig 5). This latter result supports the idea
that by decreasing ET-1 levels, 2-adrenoceptor agonists
trigger relaxation because in the presence of excess ET-1, the
2-adrenoceptor–dependent relaxation pathway is
ineffective.
The direct involvement of ET-1 in the observed responses is further
supported by the observation that blocking the release and/or formation
of known EDRFs had no antagonistic action on the relaxation
induced by 2-adrenoceptor occupation. It had previously
been demonstrated that vasoactive prostanoids were not involved in the
relaxation of various arterial beds induced by
2-adrenoceptor agonists.13 39 Our results
confirm those findings. NO, however, has been shown to be responsible
for the relaxation of large conductance arteries mediated by
2-adrenoceptor agonists12 13 and to be
released from stimulated cultured endothelial
cells.28 In Long-Evans rat cerebral arteries, NO seems to
have a permissive role in the relaxation, ie, NO is required but is not
the mediator of the relaxation.14 In Wistar-Kyoto rat
cerebral arteries, however, we failed to demonstrate a role for NO in
the relaxation mediated by clonidine.40 Similarly, in the
present study, although inhibition of NO formation potentiated
contractile responses to agonists, it did not antagonize relaxations
mediated by 2-adrenoceptor agonists (Fig 3A).
In depolarizing solution, the efficiency of oxymetazoline was decreased
but not abolished (Fig 3B). EDHF is involved in the relaxation mediated
by acetylcholine because the muscarinic agonist did not induce a
complete relaxation of depolarized tissues. The remaining component of
the relaxation was abolished by NO synthase blockade. In the same
conditions, the highest concentration of oxymetazoline still induced a
complete relaxation, suggesting that EDHF, in the presence or absence
of NO, is not the mediator of the
2-adrenoceptor–mediated dilation. The depolarization
potentiated the preconstricting tone by increasing smooth muscle
sensitivity without change in agonist concentration. Because
oxymetazoline appears to trigger the relaxation by decreasing
endothelium-derived ET-1 release, it is likely that in
depolarizing solution, a higher proportion of the
endothelial outflow of the peptide has to be decreased
to produce a similar relaxant effect to compensate for the potentiating
contractile effect of high external K+. If EDHF was the
mediator of the relaxation induced by oxymetazoline, the effect of this
factor would be blocked in depolarizing solution,5 25 as
shown with acetylcholine.
In conclusion, these results demonstrate for the first time that ET-1
released from the endothelium of human pial arteries is
inhibited by 2-adrenoceptor occupation. Studies of
rabbit cerebral arteries in vitro suggest that
endothelium-derived ET-1 significantly influences
agonist-induced contraction. Furthermore, the
endothelium-dependent relaxation mediated by
2-adrenoceptor stimulation seems to be directly
associated with the inhibition of ET-1 formation independent of other
EDRFs. We propose that by secreting ET-1 in response to selective
agonists such as serotonin, the
endothelium, predominantly vasodilator, can sensitize
the underlying smooth muscle to contractile agonists. This pathway
provides a link between sympathetic activation and the
endothelial contribution to the regulation of
cerebrovascular tone. Finally, it gives a possible pathological
significance to the increase in ET-1 observed in
atherosclerosis41 and subarachnoid
hemorrhage associated with spasm.42 43 It should
be remembered, however, that in vivo administration of
2-adrenoceptor agonists raises blood pressure; in this
context, our data suggest that regional differences may occur, leading
to vasoconstriction of most vascular territories and possibly dilation
in others. Additional studies are thus required to define the overall
importance of the endothelial
2-adrenergic pathway on the regulation of local blood
flow.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Totman Medical Research Fund.
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Footnotes |
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Reprint requests to Eric Thorin, Institut de Cardiologie de Montréal, Centre de Recherche, 5000 rue Bélanger, Montréal, Quebec, H1T 1C8 Canada.
Received February 10, 1997; first decision March 11, 1997; accepted March 25, 1997.
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