Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia
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ABSTRACT |
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Thromboxane A2 (TxA2) preferentially constricts
the renal afferent arteriole. Nitric oxide (NO) modulates
vasoconstriction and is rapidly degraded by superoxide radical
(O2). We investigated the roles of NO and
O2
in rabbit isolated, perfused renal afferent
arteriole responses to the TxA2/prostaglandin
H2 (TP) receptor agonist U-46,619. U-46,619 (10
10-10
6 M) dose-dependently reduced
afferent arteriolar luminal diameter (ED50 = 7.5 ± 5.0 nM), which was blocked by the TP receptor antagonist ifetroban (10
6 M). Tempol (10
3 M)
pretreatment, which prevented paraquat-induced vasoconstriction in
afferent arterioles, blocked the vasoconstrictor responses to U-46,619.
To test whether U-46,619 stimulates NO and whether tempol prevents
U-46,619-induced vasoconstriction by enhancing the biological activity
of NO, we examined the luminal diameter response to U-46,619 in
arterioles pretreated with
Nw-nitro-L-arginine methyl ester
(L-NAME, 10
4 M) or L-NAME + tempol. During L-NAME, the sensitivity and maximal responses of the afferent arteriole to U-46,619 were significantly (P < 0.05) enhanced. Moreover, L-NAME
restored a vasoconstrictor response to U-46,619 in vessels pretreated
with tempol. In conclusion, in isolated perfused renal afferent
arterioles TP receptor activation stimulates NO production, which
buffers the vasoconstriction, and stimulates O2
production, which mediates the vasoconstriction, in part, through interaction with NO.
thromboxane A2; nitric oxide; superoxide; afferent arteriole; tempol
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INTRODUCTION |
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THROMBOXANE A2 (TxA2) produced in the endothelium constricts vascular smooth muscle cells through activation of thromboxane A2/prostaglandin H2 (TP) receptors. In the kidney, TxA2 reduces renal blood flow and glomerular filtration rate through preferential action on the afferent arteriole and glomerulus (3, 15, 25). Some of these effects are mediated via the tubuloglomerular feedback (TGF) response (41), whereas others are apparent in hydronephrotic kidneys that lack a TGF response and therefore must be due to direct action on afferent arterioles (15,25). Several studies implicate TxA2 to be an important mediator of the renal hemodynamic and blood pressure effects of angiotensin II (ANG II) under normal conditions (42, 43) and in ANG II-dependent forms of hypertension (28). However, the mechanisms by which TP receptor activation causes vasoconstriction remain to be fully elucidated.
Nitric oxide (NO) produced by the endothelium is a ubiquitous vasodilator and modulator of vascular tone. NO buffers the vasoconstrictor action of TxA2 in the isolated aorta (5, 7), coronary artery (37), and pulmonary artery (40). NO also modulates vasoconstriction induced by ANG II and endothelin-1 but not by norepinephrine in the renal afferent arteriole (18, 19). Whether NO plays an important role in modulating vasoconstriction induced by TxA2 in the renal afferent arteriole remains unknown.
Several studies suggest that the oxygen radical superoxide
(O2) interacts with NO and thus limits its
bioavailability. The affinity of NO for O2
is so high
that its rate of reaction is limited only by diffusion (31). Since O2
effectively degrades NO,
the biological activity of NO may be determined by the availability of
O2
(13, 31). NO-mediated
vasodilation is impaired in aorta with enhanced generation of
O2
(12) and can be restored by blockade
of TP receptors (2, 33, 38).
This led us to the hypothesis that TP receptor activation may be a
potent source for the generation of O2
and hence for
degrading NO in resistance vessels. The objectives of this study were
to 1) determine the role of O2
in TP
receptor activation, 2) to examine the role of NO in TP receptor activation, and 3) to investigate the interaction
between NO and O2
in TP receptor activation in renal
afferent arterioles. The response to the stable TP receptor agonist
U-46,619 was studied in rabbit isolated, perfused renal afferent
arterioles. The role of NO was assessed from the responses to
inhibition of NO synthase with Nw-nitro-L-arginine methyl ester
(L-NAME). The stable nitroxide 4-hydroxy-[2,2,6,6]-tetramethylpiperidine-1-oxyl
(tempol) was used to scavenge O2
. Tempol is a
metal-independent, membrane-permeable superoxide dismutase mimetic that
scavenges O2
to hydrogen peroxide
(H2O2) and oxygen. Tempol has been validated as
an electron paramagnetic resonance spin-label molecule specifically for
O2
(16, 29) and
does not donate NO or scavenge H2O2
(16, 29). In vivo studies have shown that
tempol reduces damage caused by oxygen radicals in ischemia/reperfusion
injury (8), inflammation (21), and radiation
(27).
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METHODS |
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Isolation and Microperfusion of Afferent Arterioles
Male New Zealand White rabbits (1.4-1.8 kg) were maintained on tap water and standard chow. Protocols were approved by the Institutional Animal Care and Use Committee of Georgetown University Medical Center and were performed according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health as well as the guidelines of the Animal Welfare Act. Rabbits were anesthetized with xylazine (9 mg/kg im), ketamine (47 mg/kg im), and pentobarbital sodium (11 mg/kg iv) followed by heparin (1,000 USP iv) for anticoagulation. Microdissection and microperfusion of the afferent arteriole were performed as previously described (18, 19). Briefly, the right kidney was extracted via an abdominal incision and immediately placed in ice-cold preservation solution (24). Slices of the kidney were made along the corticomedullary axis and replaced in the preservation solution. A single superficial afferent arteriole with glomerulus attached was microdissected under a stereomicroscope (model SZ40, Olympus) on a temperature-controlled stage maintained at 4°C. The arteriole was transferred to a temperature-regulated chamber mounted on the stage of an inverted microscope (model IX70, Olympus) modified with micromanipulators. The afferent arteriole was cannulated with a series of concentric glass pipettes including holding, perfusion, and exchange pipettes and perfused with alpha modification of minimum essential media (MEMProtocol
Rabbit microperfused afferent arterioles were gradually warmed to 37°C and allowed to equilibrate for 30 min. Drugs were added to the superfusion solution, and measurements of luminal diameter were made after 10-15 min. To test the viability of the tissue at the completion of the studies, norepinephrine (10
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Experimental Design
Series 1.
The aim of this series was to assess the specificity of tempol as a
superoxide dismutase mimetic in the isolated, perfused afferent
arteriole. We used the classic quinoline agent paraquat to stimulate
intracellular production of O2 in afferent
arterioles. Paraquat redox cycles with cellular diaphorases and
molecular oxygen to generate superoxide (30). This occurs at doses that do not affect cell viability (9). Luminal
diameter was measured during graded doses of paraquat
(10
7-10
3 M) in normal vessels
(n = 4) and in vessels pretreated with tempol (10
3 M, n = 4). To assess the stability
of the response to tempol, the luminal diameter response to tempol
(10
3 M) alone was examined in microperfused afferent
arterioles after 15 and 60 min of superfusion (n = 4).
Series 2.
The aim of this series was to determine the afferent arteriolar
response to TP receptor activation. Luminal diameter was measured during basal conditions and after increasing doses of U-46,619 (1010-10
6 M, n = 6).
To determine whether the arteriolar response to U-46,619 was mediated
through activation of TP receptors, the dose response was repeated in
separate vessels pretreated with the TP receptor antagonist
ifetroban (10
6 M, n = 4).
Series 3.
The aim of this series was to investigate the role of
O2 in TP receptor activation. The luminal diameter
response to U-46,619 (10
10-10
6 M) was
determined in afferent arterioles pretreated with tempol (10
3 M, n = 6).
Series 4.
The objective of this series was to assess the role of NO on the
afferent arteriolar response to TP receptor activation. The NO synthase
inhibitor L-NAME was used at a dose which has previously been shown to block acetylcholine-induced, endothelium-dependent vasodilation of the rabbit afferent arteriole (19). The
luminal diameter response to U-46,619
(1010-10
6 M) was determined in
afferent arterioles pretreated with L-NAME (10
4 M, n = 6).
Series 5.
The objective of this series, was to assess whether the effect of
tempol on the response to TP receptor activation could be ascribed to
potentiation of the effects of NO. The arteriole response to U-46,619
was measured during blockade of NO synthesis and scavenging of
O2. The luminal diameter response to graded
concentrations of U-46,619 (10
10-10
6
M) was measured in vessels pretreated with tempol (10
3
M) + L-NAME (10
4 M, n = 6).
Drugs and Solutions
U-46,619 (Cayman Chemical) was evaporated under N2 and reconstituted using 97% ethanol and 55 mM Tris. After further evaporation with nitrogen, aliquots of U-46,619 (10Statistics
All values are reported as means ± SE. Overall significance between dose responses was determined from repeated measures analysis of variance and the Scheffé post hoc test where appropriate. A Student's t-test was used to determine significance between groups. P < 0.05 was determined to be significant. ![]() |
RESULTS |
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Series 1
Figure 2 shows the luminal diameter response to paraquat (10
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Series 2
Figure 3 illustrates the luminal diameter response to TP receptor activation with U-46,619 in microperfused afferent arterioles in the presence and absence of ifetroban. From a baseline of 15.63 ± 0.89 µm, U-46,619 (10
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Series 3
Figure 4 illustrates the luminal diameter response to U-46,619 (10
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Series 4
Figure 5 illustrates the luminal diameter response to low (10
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Series 5
Figure 6 shows the luminal diameter response to U-46,619 (10
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DISCUSSION |
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The stable TP receptor agonist U-46,619 vasoconstricts isolated
rabbit microperfused afferent arterioles. This response can be
attributed to activation of TP receptors because it is blocked by
ifetroban. These results are similar to those previously reported for
TP receptor-mediated vasoconstriction of isolated aorta
(7), pulmonary arteries (40), and afferent
arterioles of the hydronephrotic rat kidney preparation
(25). The new findings in the present study are that the
vasoconstrictor response to U-46,619 is abolished by a
membrane-permeable superoxide dismutase mimetic and is enhanced by NO
synthesis blockade. We conclude that TP receptor activation leads to
generation of O2, which is permissive in the
vasoconstriction, and to NO, which buffers the vasoconstriction.
L-NAME restored a vasoconstrictor response to U-46,619 in
vessels pretreated with tempol. This suggests an important role for the
interaction between NO and O2
in TP receptor-mediated
vasoconstriction in the afferent arteriole.
NO is a powerful endothelium-derived vasodilator that maintains basal vascular tone and modulates the vasoconstrictor actions of several agonists within the kidney. Ito et al. demonstrated that NO blunts the vasoconstriction caused by ANG II (19) and endothelin-1 (18) of isolated, microperfused afferent arterioles. The present study confirms that blockade of NO synthesis significantly reduces basal luminal diameter, indicating that NO is produced tonically in rabbit isolated, perfused afferent arterioles (19). The data show, for the first time, that TP receptor activation stimulates NO, which buffers the vasoconstrictor action of U-46,619 in afferent arterioles.
The mechanism by which U-46,619 stimulates NO in afferent arterioles remains unknown. One possible mechanism may involve a TP receptor located on the endothelium. Kent et al. (22) identified a TP receptor on isolated human endothelial cells that stimulates increases in intracellular calcium, which can activate endothelial-derived NO synthase. The importance of the endothelium in modulating the vasoconstrictor actions of TP receptor activation depends on the vascular site. For example, removal of the endothelium or blockade of NO synthesis in the aorta (7) and coronary artery (37) enhances U-46,619-induced vasoconstriction. However, blockade of NO synthase in the pulmonary vasculature either enhances (40) or has no effect (20) on U-46,619-induced vasoconstriction. Endothelial NO synthase may also be activated indirectly by a rise in intracellular calcium generated in response to a primary action of TP receptors on vascular smooth muscle cells where TP receptors are readily expressed. Dora et al. (6) have shown such electromechanical coupling between vascular smooth muscle and endothelial cells of the hamster cheek pouch. Activation of TP receptors in afferent arterioles of the hydronephrotic kidney increases intracellular calcium (25). However, the role of electromechanical coupling or endothelial TP receptors in mediating the stimulation of NO in the afferent arteriole remains to be elucidated.
O2 is scavenged extracellularly by copper-zinc
superoxide dismutase (CuZnSOD) and intracellularly by CuZnSOD and
manganese SOD. Mehta et al. (26) showed that inhibition of
TxA2 synthesis decreases the production of
O2
in activated human neutrophils. They suggested
that TxA2 stimulates the production of
O2
. Griendling et al. (10) provided
direct evidence that ANG II stimulates O2
production
in vascular smooth muscle cells via activation of NADPH oxidase. We
selected the nitroxide tempol in our studies. It is a stable,
membrane-permeable, metal-independent SOD mimetic (16,
29). U-46,619 caused a dose-dependent vasoconstriction of
afferent arterioles. This response was completely prevented in vessels
pretreated with tempol. We conclude that U-46,619 stimulates the
production of O2
, which is permissive for TP
receptor-induced vasoconstriction of the afferent arteriole.
The source of O2 production in the renal afferent
arteriole remains unknown. O2
is produced by cellular
electron transport chains such as those in mitochondria and endoplasmic
reticulum (14), NO synthase (4,
32), cyclooxygenase (23), lipoxygenase
(23), xanthine oxidase (12), and NADPH
oxidase (10). All of these enzymes are expressed in the
kidney. NO synthase and cyclooxygenase are known to be expressed in the
afferent arteriole. The importance of these enzymes in mediating
U-46,619-induced stimulation of O2
in the afferent
arteriole remains to be determined.
Our data suggest that one mechanism whereby O2
mediates U-46,619-induced vasoconstriction is through interaction with
NO. Gryglewski et al. (13) first showed in vascular
endothelial cells that O2
is involved in the
inactivation of NO. Since then, several studies have demonstrated that
scavenging of O2
increases the release of bioactive
NO in the vasculature in situ (39) and in cultured
vascular endothelial cells (12). In the present study, we
show that blockade of the U-46,619-induced vasoconstriction by tempol
is largely prevented by inhibition of NO synthesis with L-NAME. This data suggests that production of
O2
after U-46,619 decreases the bioactivity of
stimulated NO and that this promotes the vasoconstriction of afferent
arterioles. However, additional mechanisms must be involved since
L-NAME augmented the response to U-46,619 in the absence of
tempol. Superoxide can also stimulate inositol 1,4,5 trisphosphate
(IP3) formation and thus increase intracellular
calcium in vascular smooth muscle cells (44). Therefore,
tempol may reduce superoxide-mediated increases in intracellular
calcium and thus block the vasoconstrictor response to U-46,619.
Tempol has been evaluated extensively as a scavenger of
O2 in vitro and in vivo. We evaluated the specificity
of tempol's actions in the rabbit isolated perfused afferent
arteriole. Tempol given alone for 60 min did not alter the diameter of
the vessel. This indicates that tempol does not have nonspecific
effects on afferent arteriole tone. Vessels treated with paraquat,
which is a O2
-generating quinoline, showed graded but
reversible vasoconstriction consistent with the contractile effects of
O2
on blood vessels (34). Vessels
pretreated with tempol were protected fully from paraquat-induced
contractions, consistent with tempol's proposed mechanism of actions
as a superoxide dismutase mimetic. Furthermore, we have previously
reported (35) that tempol given in vivo reduces a marker
for oxygen radical production. This confirms its ability to scavenge
superoxide radical. The afferent arteriole responses to norepinephrine
were unaffected by tempol (
69 ± 17% vs.
67 ± 13%,
unpublished observations), indicating that G protein coupled signal
transduction was intact in vessels treated with tempol. However, we
have not performed direct studies to exclude the possibility that
tempol impaired the vasoconstrictor response to U-46,619 by uncoupling
G proteins. We have recently reported that the elevated blood pressure
and renal vasoconstriction in the spontaneously hypertensive rat (SHR) are normalized by tempol (35, 36); however,
TP receptor antagonism is not effective in this model
(11). This suggests that tempol is not a TP receptor
antagonist. We found that the antihypertensive and renal vasodilatory
effect of tempol in the SHR is blocked when NO synthesis is reduced
(36). This suggests an important role for the interaction
between NO and O2
in genetic hypertension, similar to
what we have found for the isolated afferent arteriole stimulated by
U-46,619 in the present studies.
Metabolism of O2 by superoxide dismutase or tempol
yields oxygen and H2O2.
H2O2 can be either a vasodilator or a
vasoconstrictor in the aorta (17, 45) and
pulmonary artery (1). After blockade of NO generation with
L-NAME and scavenging of O2
with tempol,
the response of the afferent arteriole to U-46,619 was not fully
restored to the level seen with U-46,619 alone. One possible
explanation for this finding is that H2O2
generated in tempol-treated arterioles in response to U-46,619 may
contribute to vasodilation. However, the action of
H2O2 in the afferent arteriole remains to be investigated.
In conclusion, this study provides evidence that generation of
O2 contributes to the contractile response to
activation of TP receptors in afferent arterioles. TP receptor
activation also stimulates NO, which buffers the contraction. The
balance between O2
and NO is important in the
vasoconstrictor response. These results suggest a role for oxygen
radical therapy in conditions of endothelial dysfunction associated
with oxidative stress and increased TxA2 production in the
kidney such as hypertension, diabetes, and renal failure.
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ACKNOWLEDGEMENTS |
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We sincerely appreciate the assistance of Drs. Tom Pallone and Erik Silldorff from the University of Maryland Medical Center and of Drs. Oscar Carretero and YiLin Ren from Henry Ford Hospital for their technical advice on microdissection and microperfusion of the afferent arteriole.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-36079 and DK-49870 and by the George E. Schreiner Chair of Nephrology. Dr. Schnackenberg is a recipient of an American Heart Association Scientist Development Grant.
Present address of C. G. Schnackenberg and address for reprint requests and other correspondence: Renal Pharmacology, UW2521, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406-0939 (Email: Christine_G_Schnackenberg{at}sbphrol.com).
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. §1734 solely to indicate this fact.
Received 16 August 1999; accepted in final form 22 March 2000.
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