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Introduction
Increased oxidative stress has been reported in vascular
diseases and is implicated in the alteration of vascular
function. Clinical and experimental studies have shown that
endogenous or exogenous reactive oxygen species (ROS)
can modulate vascular tone and perhaps mediate signal
transduction[1_4]. In different vascular beds and under different
conditions, ROS has been reported to mediate varied
vascular functions, such as vasoreactivity, vascular proliferation,
and vascular cell signaling[4_7]. Such actions depend on the
particular pathophysiological condition. In cardiovascular
diseases, increased oxidative stress and the increased
production of vasoconstrictor agents, such as catecholamine,
angiotensin, thromboxane, and endothelin-1 (ET-1) have
been reported and implicated in the pathogenesis of
vascular dysfunction[3,4,7_10]. Under such pathological conditions,
there is the possibility that vasoactive agents can recruit
different ROS components to modulate distinct vascular
functions. Such interactions will depend on the vascular
environment, type, and levels of vasoactive agents
(cons-trictors/dilators) present in that particular vascular
bed[10_14]. The origin of ROS produced in activated vascular cells,
including superoxide and
H2O2 has been a subject of several
studies and the use of different oxidase inhibitors and/or
substrates have identified membrane-associated oxidase
inhibited by flavin oxidase inhibitors and stimulated by
NADH or NADPH, suggesting that NAD(P)H oxidases are
an important source of superoxide production in the
vascular system of several
animals[3,6,15,16]. In the cardiovascular
system, NAD(P)H oxidases are membrane-associated
enzymes which catalyze reduction of oxygen using electrons
donated by NADH or NADPH. Upon stimulation by
vasoactive agents, O2_ is produced
within minutes to hours by endothelial cells and vascular smooth
muscle cells. Recent evidence further
indicates that lipoxygenase, cyclooxy-genase, mitochondrial oxidases, xanthine oxidase, and
nitric oxide (NO) synthases are also sources of
ROS[3,4,6,16_18].
Bradykinin (BK) is an important vasoactive agent which
is released by the vascular system especially during
inflammatory processes, including ischemia reperfusion and other
conditions which may involve the generation of ROS. BK
can modulate vascular functions via numerous mechanisms,
including the release of prostanoids, NO, the regulation of
intracellular calcium ions, the activation of potassium
channels, and ROS generation[9,19_23]. The varied vascular
actions of BK and the mechanisms by which they are
accomplished are vascular
bed-dependent[19_24]. For example, in the brain, BK has been reported to cause cerebrovascular
dilation through the activation of Ca2+-activated potassium
channels, the endothelium-derived hyperpolarizing factor, and
NO[22_24], while in the peripheral vessels it acts through the
release of NO, prostanoids, activation of
K+ channel, ROS generation, or the release of hyperpolarizing
factors[19_22].
In this study, we investigated the hypothesis that ROS
contributes to BK relaxation and that the relaxation is
differentially modulated in the presence of phenylephrine (PE)
and ET-1-induced contractions.
Superoxide dismutase (SOD; a superoxide scavenger),
catalase (CAT; a hydrogen peroxide scavenger), and
vitamin C (a non-selective antioxidant) were used to test the
working hypothesis. We characterized the involvement of
ROS in the BK relaxation of ET-1- and PE-induced
contractions and compared the contribution of ROS to PE- and
ET-1-generated tension.
Materials and methods
Drugs and chemicals SOD, CAT, vitamin C, bradykinin,
PE, acetylcholine, and ET-1 were purchased from
Sigma-Aldrich (St Louis, MO, USA).
Experimental animals Male Sprague-Dawley rats
(250_300 g; purchased from Harlan, Houston, TX, USA), were
used for this study and maintained according to the
National Institute of Health NIH guidelines on
the care and use of laboratory animals (Texas Southern University, Houston,
TX, USA). The protocol used for this study was approved
by the Animal Care Committee of the Texas Southern
University.
Tissue preparation Following anesthesia with urethane
(2 g/kg; ip), the chest cavity was opened and the thoracic
aorta was removed and placed in a petri dish containing
cold Kreb's (4 oC) solution (in mmol/L, NaCl 113, KCl 4.7,
NaHCO3 25.0,
CaCl2 2.5, KH2PO4 1.2,
MgSO4 1.2, and glucose 5, pH
7.4) and continuously gassed with 95%
O2 and 5% CO2. The aorta was cleansed of connective tissues and cut into 3_4
mm rings. The aortic ring was then mounted in a 10 mL
jacketed bath (World Precision Instruments, Sarasota, FL,
USA) at 37 °C. The ring was suspended in the bath solution
by 2 hooks; the lower one fixed to the bottom of the bath
while the upper one was connected via a transbridge (model
TBM4, World Precision Instruments, USA) data-acquisition
system (DataQ Instruments, Akron, OH, USA) for the
recording of isometric tension developed to the application
of vasoactive agents. The rings were subjected to a resting
tension of 2 g and allowed to equilibrate for a period of 90
min while being rinsed every 15 min. During the
equilibration period, the rings were subjected to 2 challenges of
1×10-7 mol/L PE 30 min apart and relaxed with
1×10-5 mol/L acetylcholine to test the functionality of the tissues. Tissues that
did not produce 70%_80% relaxation of the tension
generated were considered non-responsive and were excluded from
the study. Changes in tension were monitored via a force
displacement transducer connected to a DI-720 system
(DATAQ software, USA).
Cumulative dose-response curves Following a 90 min
equilibration, the aortic rings were preconstricted with PE
(1×10-7 mol/L) or ET-1
(1×10-9 mol/L). The concentration of
PE or ET-1 used was shown in preliminary experiments to
produce about 70% of maximal contraction. The contraction
to PE or ET-1 was allowed to reach a plateau and stabilize
(5_10 min) before the relaxation studies com-menced. The
relaxation responses to the cumulative concentrations of BK
(1×10-9_1×10-5 mol/L) were determined in the absence or
presence of antioxidants: SOD (300 U/mL; a superoxide
scavenger), CAT (300 U/mL; a hydrogen peroxide scavenger),
or vitamin C (1×10-4 mol/L; a scavenger of superoxide,
hydroxyl radicals, and hydrogen peroxide). The
concentrations of the antioxidants and other agents used were
consistent with those reported by us and
others[4,14,25].
The contribution of ROS to the contraction induced by
PE or ET-1 was investigated by evaluating the
dose-dependent contraction of the aortic ring to PE or ET-1
(1×10-10_1×10-6 mol/L) in the absence or presence of SOD, CAT, or
vitamin C.
Statistical analysis Vascular relaxation responses are
presented as percentage change in the relaxation of the
aortic ring from preconstricted values following the addition of
BK. The contraction responses to PE or ET-1 are presented
as tension in grams. Data are reported as mean±SEM and
subjected to two-way ANOVA followed by
Student-Newman-Keul's post-hoc test.
P<0.05 was considered statistically significant.
Results
The application of PE (1×10-7 mol/L) to the aortic ring
preparation resulted in the development of tension that
attained a plateau in 3_5 min. The average tension
developed to PE application was 1.69±0.19 g
(n=10). ET-1 (1×10-9 mol/L) application resulted in slow-developing tension which
attained plateau in 7_10 min with an average tension of
1.82±0.18 g (n=10).
BK
(1×10-9_1×10-5 mol/L) dose-dependently relaxed PE-
and ET-1-induced tension. BK-induced relaxation was
significantly greater in the rings precontracted with ET-1
(1×10-9 mol/L) compared to those with PE
(1×10-7 mol/L). For example, the maximum relaxation of ET-1- and PE-induced tension
mediated by BK (1×10-5 mol/L) application was 75%±5% for
ET-1 versus 35%±4% for PE, respec-tively.
Role of ROS in BK-induced relaxation of PE or ET-1
contraction
Incubation of aortic rings with SOD, CAT, or vitamin
C did not have any significant effects on PE or
ET-1-induced tension In Figure 1, BK
(1×10-9_1×10-5 mol/L)
dose-dependently relaxed PE-induced tension. Pretreatment of
the ring with SOD (300 U/mL), CAT (300 U/mL), or vitamin C
(1×10-4 mol/L) for 15 min significantly enhanced the BK
relaxation of PE contraction. At the highest concentration of
BK (1×10-5 mol/L) employed, the relaxation to BK was
significantly increased from 35%±4% relaxation in the control
to 56%±9%, 60%±5%, or 49%±6%, respectively, for SOD,
CAT, or vitamin C (Figure 1, P<0.05,
n=8, ANOVA).
BK dose-dependently relaxed ET-1-induced
contraction Unlike PE, the BK relaxation of ET-1 tension was
significantly attenuated by pretreatment with SOD, CAT, or
vitamin C (Figure 2). Thus, at the highest concentration
(1×10-5 mol/L), BK-induced relaxation was reduced from 75%±5%
(control) to 37%±9% (SOD), 63±3% (CAT), or 39%±7%
(vitamin C) following 15 min pre-incubation (Figure 2,
P<0.05, ANOVA, n=8).
Contribution of ROS to PE- and ET-1-induced contraction of the aortic
ring The effects of pre-incubation with SOD, CAT, or vitamin C on PE-induced contraction of
the aortic ring was determined (Figure 3). PE
dose-dependently contracted the aortic rings and pre-incubation with
SOD (300 U/mL) significantly enhanced PE contraction by
36%. PE tension increased from 1.69±0.19 g (control) to
2.30±0.14 g (SOD) (Figure 3A, P<0.05,
n=10, ANOVA). Pre-incubation with CAT (300 U/mL) had no significant effects
on PE-induced contraction (1.69±0.19 g) in the control
versus 1.72±0.25 g in CAT (Figure 3B,
P>0.05, n=10). However, pre-incubation with vitamin C significantly
attenuated PE-induced tension by 50%. Tension was reduced from
1.69±0.19 g in the control rings to 0.84±0.26 g in the vitamin
C-treated rings (Figure 3C, P<0.05,
n=8, ANOVA).
The effects of pre-incubation of the aortic ring with SOD,
CAT, or vitamin C on ET-1-induced contraction was
determined (Figure 4). Pre-incubation with SOD or vitamin C did
not have any significant effects on ET-1 contraction. The
tension generated by ET-1 (10 nmol/L) was 1.82±0.18 g
(control), 1.48±0.27 g (SOD), or 1.57±0.52 g (vitamin C) (Figure
4A,4C, P>0.05, n=9). However, pre-incubation with CAT
significantly attenuated ET-1-induced tension at higher (5
and 10 nmol/L), but not at the lower concentrations (Figure
4B, P<0.05, n=9, ANOVA). The tension generated by ET-1
after CAT treatment was reduced by 66% (from 0.92±0.15 g in
the control to 0.31±0.16 g by 5 nmol/L) and by 44% (from
1.82±0.18 g in the control to 1.03±0.21 g by 10 nmol/L).
Discussion
This study revealed that: (i) BK evoked dose-dependent
relaxation of ET-1- and PE-contracted aortic rings,
producing a greater relaxation of ET-1-induced tension than that by
PE; (ii) pretreatment with antioxidants enhanced BK
relaxation of PE tension, but attenuated its relaxation of
ET-1 tension; (iii) PE-induced contraction was enhanced by
pretreatment of aortic rings with SOD, but not vitamin C or
CAT; and (iv) ET-1-induced contraction was attenuated by
pretreatment of the aortic rings with CAT, but not SOD or
vitamin C. The results presented generally support a
differential role for ROS in BK-induced vascular relaxation of PE-
and ET-1-induced contraction and that the contribution of
free radical species for the generation of tension by ET-1 or
PE is agonist specific. O2_ negatively modulated PE
contraction while H2O2 positively modulated ET-1-induced
contraction.
It is now well established that various stimuli can induce
increased production of ROS in vascular
cells[4,6,10,26,27]. ROS produced in activated vascular cells can come from different
oxidases, for example, xanthine/xanthine oxidase,
mitochondrial oxidase, and arachidonic acid oxygenases, including
the NADPH oxidase in the vascular
wall[3,6,7,28,29]. The ROS usually produced primarily is superoxide which undergoes
dismutation to H2O2, another potent ROS. Results from
various laboratories support the role of ROS in vascular
function in response to different vasoconstrictors and
vasodilators. For example, PE via its activation of
α1-receptors or ET-1 via the activation of
ETA receptors could potentially generate ROS via the stimulation of protein kinase C
(PKC), Ca2+ channels, or arachidonic acid
metabolites[4,7,10,27,30,31]. In view of the similarity in signaling mechanisms between
different constrictor and relaxant agents, it is difficult to
specifically identify the exact source(s) of ROS or their
qualitative effects in a particular preparation. In the cardiovascular
system, NAD(P)H oxidases are membrane-associated
enzymes which catalyze the reduction of oxygen using
electrons donated by NADH or NADPH. Upon
stimulation by vasoactive agents,
O2_ is produced within
minutes to hours by endothelial cells and vascular smooth
muscle cells and is considered the main source of free radical generation in the
vascular system[6,7,15,16].
In this study, we addressed the differential effects of
ROS on PE- and ET-1 contraction of the rat aorta and
characterized the relaxant effects of BK in tissues in which tension
was generated with PE or ET-1 in order to evaluate the
differential role of ROS. In the PE-contracted preparations, ROS
appeared to contribute to BK-induced relaxation inasmuch
as antioxidant treatment with SOD, CAT, or vitamin C resulted in enhanced relaxation. Although the exact
mechanism by which this occurs is not clear, the observation tends
to support the hypothesis that the
O2_ and SOD-facilitated conversion of
O2_ to
H2O2 subserves a contractile function.
The attenuation by O2_ in BK relaxation of PE contraction
suggests that PE may activate the production of
O2_ which may reduce the availability of NO that is potentially released
by BK. Consistent with this observation is the reported
involvement of ROS in vascular signaling via
α1-adreno-ceptors in which the inhibition by
the SOD mimetic was
accompanied by a decrease in ROS generation and release in
vascular tissue as well as
tone[31]. Also, it is possible that
BK-induced relaxation may be blunted by a PE-induced
increase in the O2_ level leading to the neutralization of
NO[1,3,7,10,31]. Thus, SOD mitigated this effect and preserved
NO leading to the enhanced relaxation (Figure 1A).
Consistent with this notion is the enhanced BK relaxation of PE
tension following treatment of the aortic ring with vitamin C,
an antioxidant and the reported attenuation of BK relaxation
during high oxidative stress[3,4,19,22]. This observation finds
support in the finding that vitamin C via its antioxidant
properties can stabilize cofactors for eNOS (tetrahydrobiopterin)[7,32], thereby preserving NO bioavailability and
promoting relaxation. The degree of enhancement of the
relaxation evoked by BK was similar in the tissues treated with
SOD or CAT indicating that both
O2_ and
H2O2 in the PE-contracted aorta are equally effective and negatively coupled
to BK relaxation. Vitamin C, a non-selective antioxidant,
enhanced the BK-induced relaxation of PE tension, but
surprisingly, to a lower extent than that observed in the
presence of SOD or CAT. The reason for this is not clear.
How-ever, as ROS are known to produce contraction and/or
relaxation in the same
preparation[17,28,29,33_35], and because of its
non-selective effects, we speculate that the final effect on
vascular response will be the net effect of vitamin C on ROS
that produces contractile or relaxant effects.
In the ET-1-contracted aorta, ROS produced effects
opposite to that in the PE-contracted aorta and attenuation
rather than enhancement of relaxation resulted when the
ET-1-contracted aorta was challenged with antioxidants.
Comparing the degree of attenuation,
O2_ exerted a greater role than
H2O2 as SOD produced a greater (38%) attenuation of BK
relaxation than CAT (10%). On the other hand, the effects
produced by vitamin C were similar in magnitude to that
produced by SOD (36%), suggesting that
O2_ is the predominant ROS playing a greater role in the BK relaxation of
ET-1-contracted aorta. The minimal effect of CAT is consistent
with the studies of Ellis et
al[14] in the mouse isolated aorta.
It thus appears that in an ET-1-contracted tissue,
O2_ produced relaxation while
H2O2 produced contraction, a notion
supported by studies that demonstrated relaxation and
contractile effects to O2_ or
H2O2,
respectively[17,33,34]. This being the case, BK may have produced relaxation via
O2_ in the process of a cyclooxygenase (COX)-dependent
prostaglandin production, a known mechanism for the relaxant effects
of BK. In preparations incubated with SOD and challenged
with ET-1, the dismutation of
O2_ to a contractile
superoxide anion may therefore have accounted for the
enhanced tone to ET-1. Also, the vasoconstrictor actions of
H2O2 has been attributed to its ability to increase
intracellular Ca2+, the generation of arachidonic acid metabolites with
vasoconstrictor activity, and to its direct
Ca2+-independent tonic effects on
vascular smooth muscle contractile
apparatus[11,33,34,36,37].
Apart from relaxation of the aortic ring, the contribution
of ROS to PE- or ET-1-induced contraction was also
inves-tigated. Pretreatment with antioxidants resulted in the
selective regulation of tension generated by PE and ET-1. Thus,
PE-induced contraction was enhanced by an
O2_ scavenger (SOD) indicating that
O2_ contributes a negative tone to
vessels challenged with PE. On the other hand, increased
H2O2 level resulting from the SOD-induced dismutation of
O2_ did not influence PE contraction. However, ET-1-induced
contraction was attenuated by CAT, but not by SOD or vitamin
C, indicating that H2O2 contributed to ET-1-induced
contraction, but not PE-induced contraction. This is
consistent with studies that have reported that
H2O2 causes
vasoconstriction[17,34,35]. Thus, the contribution of free radical
species to the generation of tension by ET-1 or PE is agonist
specific and the contribution of free radicals to BK relaxation
is also agonist specific, resulting in a differential modulation
of its relaxation. This differential effect may be a reflection of
the interaction of the multiple signaling processes, for
example, phospholipase C, PKC, mitogen-activated protein
kinases, and intracellular Ca2+ involved in BK relaxation, PE
or ET-1 contraction, and ROS generation. These mechanisms
are further complicated by the fact that PE and ET-1 are
potent stimulators of vascular superoxide generation[6,26,28,29,31,37,38]. It therefore appears that different
mechanisms involved in ROS generation and agonist-induced
signaling mechanisms will define the resulting vascular
responses to vasoconstrictors and dilators in a particular
tissue.
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