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Department of Physiology, New York Medical College, Valhalla, New York 10595
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To investigate the role of estrogen in
flow-induced dilation (FiD) in nitric oxide (NO) deficiency, FiD was
examined in isolated gracilis arterioles of ovariectomized
(OVX) and OVX rats with estrogen replacement (OVE). Both groups
of rats were treated chronically with
N
-nitro-L-arginine methyl ester.
Plasma concentration of NO2/NO3 was reduced in
both groups. Plasma concentration of estradiol was lower in OVX than in
OVE rats. FiD was similar in vessels of the two groups; calculated wall
shear stress and basal tone were significantly greater in OVX vs. OVE
rats. Indomethacin did not affect FiD in vessels from OVE rats but
abolished dilation in vessels from OVX rats. Valeryl salicylate or
NS-398 inhibited FiD by ~50%, whereas their simultaneous
administration eliminated the response in arterioles from OVX rats. In
vessels from OVE rats, miconazole or charybdotoxin eliminated FiD.
Thus, in NO deficiency, prostaglandins derived from both cyclooxygenase
isoforms mediate FiD in gracilis arterioles of OVX rats. Estrogen
replacement switches the mediation, showing dependence on
endothelium-derived hyperpolarizing factor in the
arterioles of OVE rats.
ovariectomy; estrogen replacement; potassium channels; arterioles; endothelium-derived hyperpolarizing factor; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTHELIAL
CELLS CONTRIBUTE to the control of vascular tone through the
synthesis and/or release of vasoactive agents that affect the
contractile activity of the underlying smooth muscle. This regulatory
function of the endothelium can be modulated by pharmacological agents
and mechanical forces, such as pressure and shear stress. As a
physiologically relevant stimulus in vivo, shear stress mediates
vascular dilator responses by triggering the release of endothelial
nitric oxide (NO), prostaglandins, and endothelium-derived
hyperpolarizing factor (EDHF) (19, 20, 23). The
contributions of these factors to the mediation of flow- and/or shear
stress-induced dilation are dependent not only on the different
species and vascular beds studied but also on their interactions
(3, 4, 23). Our laboratory's recently published studies
revealed a gender difference in the endothelial mediators eliciting
flow-induced dilation in NO-deficient states (13, 28, 31).
These studies showed that flow-dependent responses of arterioles are
mediated exclusively by EDHF in female endothelial NO synthase
(eNOS)-knockout mice and by prostaglandins in male littermates. This
gender-dependent compensation for NO deficiency was also demonstrated
in rats that were chronically treated with N-nitro-L-arginine methyl ester
(L-NAME). These congruent findings obtained from two
different species and models provide evidence to support our conclusion
that arteriolar responses evoked in the absence of NO are indeed gender
dependent in nature, although the specific mechanisms by which
endothelial cells sense a change in shear stress and convert it into
biochemical signals to account for the release of specific mediators
are still unknown. In line with the foregoing, we hypothesized that
estrogen is responsible for the gender-specific regulation of
flow-induced dilation of arterioles lacking eNOS. Thus we conducted
experiments on skeletal muscle arterioles of L-NAME-treated
female rats that had been ovariectomized (designated OVX) or
ovariectomized and given estrogen replacement (designated OVE).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Seven-week-old female Wistar rats (Charles River Laboratories,
Wilmington, MA) were ovariectomized (14-17) and then
received L-NAME in drinking water (50 mg/100 ml) for 4 wk.
During the period of L-NAME treatment, rats received
injections of either 17
-estradiol benzoate subcutaneously (50 µg/kg in sesame oil every 48 h) (OVE rats) or the vehicle (OVX
rats). Systolic blood pressure was monitored with a tail-cuff method.
All protocols were approved by the Institutional Animal Care and Use
Committee of New York Medical College and conform to the guidelines of
the National Institutes of Health and the American Physiological
Society for the use and care of laboratory animals.
Measurement of plasma estradiol and nitrite/nitrate. Ten milliliters of blood were withdrawn from rat abdominal aorta with a 10-ml syringe containing 0.1 ml of heparin (1,000 UPS U/ml) before the rats were killed. The blood sample was centrifuged immediately (3,000 rpm at 4°C for 30 min) to obtain the plasma, which was then divided into two parts for the measurement of estradiol and nitrite/nitrate (NO2/NO3), respectively.
Plasma estradiol concentration was measured by a radioimmunoassay with a double-antibody estradiol kit (Diagnostic Products) (15, 17). Plasma NO2/NO3 was measured by using a fluorometric assay (31).Experimental procedures. Experiments were conducted on isolated gracilis muscle arterioles of rats. The dissection of muscle, isolation of vessels, and experimental setup have been described previously (14-18, 31). Changes in diameter of arterioles in response to increases in flow were studied at 80 mmHg of intraluminal pressure. Perfusate flow was increased from 0 to 25 µl/min, in 5 µl/min steps.
In the first series of experiments, a role of prostaglandins in the mediation of flow-induced dilation was assessed by using indomethacin (Indo, 10
5M), a nonselective inhibitor of cyclooxygenase (COX).
In the second series of experiments, the specific roles of COX isoforms
(COX-1 and COX-2) in the prostaglandin-mediated flow-induced dilation
were evaluated by performing the experiments before and after
administration of valeryl salicylate (VSA, 3 × 103
M) and
N-[2-(cyclohexyloxy)
4-nitrophenyl]-methanesulfonamide (NS-398, 105 M), specific inhibitors of COX-1 and
COX-2, respectively. The inhibitors were given in different sequences,
alone and in combination.
In the third series of experiments, the role of metabolites of
cytochrome P-450 (CYP) in flow-induced dilations was
assessed by using miconazole (MCZ, 2 × 106 M), an
inhibitor of CYP/epoxygenase.
Finally, the contribution of smooth muscle K+ channels to
flow-induced dilations was evaluated by abluminal administration of
charybdotoxin (ChTX, 2 × 108 M), a blocker of
Ca2+-dependent K+-channels.
Passive diameter. At the conclusion of each experiment, the suffusion solution was changed to a Ca2+-free solution containing 1 mM EGTA. Vessels were incubated for 10 min to reach maximal diameter at 80-mmHg perfusion pressure.
Chemicals.
All chemicals were obtained from Sigma Chemical (St. Louis, MO). ChTX
was dissolved in saline. Indo, MCZ, VSA, and NS-398 were dissolved in
DMSO at a concentration of 101 M (for Indo),
102 M (for MCZ and NS-398), and 3 × 103 M (for VSA) and further diluted with physiological
salt solution. The highest concentration of DMSO in the chamber was
0.1% (vol/vol), which had no significant effect on the vessel tone.
The 17-estradiol benzoate was dissolved in pure ethanol (5 mg/ml)
with sesame oil as vehicle.
Calculations and statistics.
Passive diameter was used to assess the active tone (% of passive
diameter) generated by arterioles in response to intravascular pressure
and to normalize the changes in diameter in response to increases in
flow in each vessel. Wall shear stress was calculated by the equation
4
/
r3, where is the viscosity of
the perfusion solution (0.007 poise at 37°C), is the
perfusate flow, and r is the vessel radius. Data are
presented as means ± SE; n is the number of rats.
Statistical significance was calculated by repeated-measures two-way
ANOVA followed by Tukey-Kramer's multiple-comparison test. Student's t-test was also used, as appropriate. Significance level was
taken at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Table 1 summarizes the changes in
body weight, uterine weight, the uterine-to-body weight ratio, blood
pressure, and plasma concentrations of estradiol and
NO2/NO3 in two groups of rats. The uterus
weights of OVX rats were significantly lower than those of OVE rats. In
contrast, the body weights of OVX rats were significantly greater than
body weights of OVE rats. As a result, the ratio of uterus weight to
body weight was significantly less in OVX compared with that of OVE
rats. Plasma concentration of estradiol, which was negligible as a
result of ovariectomy, was normalized by estrogen replacement. Also, as
a function of L-NAME treatment, plasma concentration of
NO2/NO3 was reduced and was accompanied by a
significant elevation of blood pressure.
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Characteristics of arterioles of gracilis muscle from the two groups of
rats are summarized in Table 2. The
active diameter was significantly smaller in arterioles of OVX rats vs.
those of OVE rats, but their passive diameters were similar. Active diameters, as a percentage of the corresponding passive diameters, indicated a significantly greater basal tone in arterioles of OVX rats
compared with those of OVE rats.
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Figure 1 shows normalized diameter
(A) and wall shear stress (B), as a function of
perfusate flow, in arterioles of both groups of rats. The changes in
diameter of arterioles, in response to step increases in perfusate
flow, were not significantly different in the two groups of rats.
However, increases in flow elicited significantly greater increases in
shear stress, at each flow rate, in arterioles of OVX vs. OVE rats.
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The endothelial mediators responsible for flow-induced dilations of
arterioles of OVX rats are illustrated in Fig.
2, showing that Indo, which did not
affect the basal tone of arterioles from either group of rats,
abolished the dilator responses to flow (Fig. 2A). In a
separate group of experiments, the specific roles of COX-1 and COX-2 in
the mediation of Indo-sensitive flow-induced dilation were tested by
using VSA and NS-398, respectively. Each inhibitor alone significantly
inhibited flow-induced dilation by ~50%, and a combination of both
inhibitors essentially eliminated the responses (Fig. 2, B
and C).
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The endothelial mediators responsible for flow-induced dilations of
arterioles of OVE rats are shown in Figs. 3 and 4. Indo, although
eliminating flow-induced dilations in arterioles of OVX rats, had no
effect on the responses of OVE rat arterioles (Fig. 3A). However, the
Indo-resistant, flow-induced dilations were abolished by MCZ (Fig. 3),
indicating a CYP-dependent response. Furthermore, when the arterioles
were treated with ChTX, a blocker of Ca2+-dependent
K+ channels, a target of CYP metabolites/EDHF in
smooth muscle (13, 31), flow-induced dilation was
abolished (Fig. 4A). However, ChTX did not affect the responses in arterioles of OVX rats (Fig. 4B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study confirms our hypothesis that the gender difference in the adaptation to the lack of NO is estrogen dependent. In L-NAME-treated OVX rats, flow-induced dilation is solely mediated by prostaglandins, a response that mimics that observed in NO-deficient arterioles of male rats and mice (28, 31). An upregulation of COX-2, together with prostaglandins derived from COX-1, seems to be responsible for the mediation of the response. Estrogen replacement causes a switch of the prostaglandin mediation to an EDHF-mediated response, recovering entirely the profile of the response observed in NO-deficient arterioles of female rats and mice (13, 31).
To single out the specific role of estrogen in the gender differences
observed in the mediation of flow-induced dilation when NO is absent,
L-NAME-treated female rats were ovariectomized and then
received hormone replacement treatment with 17-estradiol or
injections of the vehicle. The significant reduction in uterine weight
and plasma concentration of estrogen and the reversal of this reduction
in animals receiving estrogen demonstrate the effectiveness of
ovariectomy and estrogen replacement therapy. The significant increases
in blood pressure and reduced plasma NO2/NO3
level are indicative of NO deficiency caused by chronic treatment with
L-NAME (Table 1).
Basal tone of arterioles of NO-deficient OVX and OVE rats. Ovariectomy significantly enhanced the basal tone of arterioles of OVX rats, due to a decrease in their active diameter but without affecting their passive diameter. Estrogen replacement decreased the basal tone, suggesting that the chronic presence of circulating estrogen is necessary for the maintenance of a reduced basal tone of arterioles (Table 2). We previously demonstrated that, due to the presence of estrogen, arterioles from females have a lower basal tone than those from males, which is related to an enhanced release of endothelium-derived NO (14, 16). In the present study, the reduced basal tone of arterioles from estrogen-treated rats persists even in the absence of NO, indicating that non-NO-dependent mechanisms are also involved. Because neither Indo nor MCZ affected the basal diameter of arterioles in the present study, we suspect that the estrogen-related attenuation of arteriolar tone in NO deficiency may not be dependent on the presence of endothelium.
Flow- and shear stress-induced dilation in arterioles of NO-deficient OVX and OVE rats. We previously demonstrated a greatly enhanced NO-contribution to flow-induced dilation in arterioles of normal female and OVE rats, compared with that in arterioles of male and OVX rats (15, 17, 18). In the present study, conducted on vessels of L-NAME-treated OVX and OVE rats, however, increases in perfusate flow dilated the arterioles to an equal degree (Fig. 1A). On the other hand, the physiological relevance of estrogen replacement is indicated by a significantly reduced wall shear stress, at each flow step, (Fig. 1B) in arterioles of OVE rats, suggesting that in vessels of these rats a lower shear stress is required than in those from OVX rats to achieve a dilation of similar magnitude.
Mediation of dilation to flow in arterioles of NO-deficient OVX rats. In adapting to the lack of NO and estrogen, flow-induced dilation of arterioles from OVX rats is exclusively prostaglandin dependent, as indicated by the elimination of the responses with Indo (Fig. 2A). These results are identical to those observed in male mice and rats, in which eNOS is absent due to the genetic ablation of the eNOS gene (28) or chronic treatment with L-NAME (31). The upregulation of prostaglandin synthesis in response to the absence of NO activity has been well documented (11, 28). More specifically, however, we demonstrate here that the compensatory upregulation of prostaglandin synthesis involves inducible COX (COX-2), since NS-398 inhibits the portion of response that is otherwise mediated by NO in normal male rats and mice (28, 31). On the other hand, NS-398 has no effect on the Indo-sensitive portion of flow-induced dilation in normal males, but VSA does. In keeping with the present findings, expression of the COX-2 gene in response to shear stress has also been demonstrated (26) in human umbilical vein endothelial cells. In addition, it was reported that vanadate, an inhibitor of protein-tyrosine phosphatase, elicited the expression of COX-2 mRNA and consequently increased corresponding protein levels in human umbilical vein endothelial cells. This vanadate-induced enhancement of expression of COX-2 mRNA was abolished by tyrphostin-47, an inhibitor of protein-tyrosine kinases (12). In this context, we previously found that flow-induced dilation in skeletal muscle arterioles is tyrosine protein phosphorylation dependent (29). The question then arises as to why this compensatory activity, in response to NO deficiency, depends specifically on COX-2. The literature regarding the "cross-talk" between the NOS and COX pathways is divided with respect to whether NO activates or inhibits prostaglandin production (1, 10, 27). Recent evidence shows that NO exerts divergent effects on the constitutive and inducible COX isoforms, potentiating COX-1 but inhibiting COX-2 (6). This study reports that exposure of resting cells to NO enhances the production of PGE2, which was inhibited by Indo but not by NS-398. In contrast, exposure of lipopolysaccharide-stimulated cells to NO inhibited PGE2 production, which associated with a decrease in COX-2 expression and nitration of the enzyme, which interferes with its catalytic activity (9). Thus the divergent effects of NO on the COX isoforms may explain why COX-2 becomes functional when NO synthesis is absent. Similar findings in mesenteric arteries of L-NAME-treated rats indicated an overproduction of prostaglandins in response to shear stress, resulting in part from an increase in COX-2 expression (11).
Mediation of dilation to flow in arterioles of NO-deficient OVE
rats.
L-NAME-treated OVX rats that have received 17-estradiol
for 4 wk exhibited an EDHF-mediated dilation to flow, restoring a female pattern of mediation (13, 31). It was previously
reported that in cerebral arterioles metabolites of CYP cause
vasodilation via activation of COX (7). The present
finding that Indo did not but MCZ and ChTX did inhibit flow-induced
dilation (Figs. 3 and 4A) argues against the idea that the
COX pathway is a downstream effector of the responses, suggesting
rather that arteriolar hyperpolarization, consequent to the opening of
Ca2+-dependent K+ channels of smooth muscle, is
responsible for the full expression of the response.
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ACKNOWLEDGEMENTS |
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This study was supported by American Heart Association Grant 9930244N and National Heart, Lung, and Blood Institute Grants HL-43023 and HL-46813.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Huang, Dept. of Physiology, New York Medical College, Valhalla, NY, 10595 (E-mail: An_Huang{at}nymc.edu).
Original submission in response to a special call for papers on "Genome and Hormones: Gender Differences in Physiology."
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. Section 1734 solely to indicate this fact.
Received 12 June 2001; accepted in final form 31 July 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 R. D. Shipley, S. J. Kim, and J. M. Muller-Delp Time course of flow-induced vasodilation in skeletal muscle: contributions of dilator and constrictor mechanisms Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1499 - H1507. [Abstract] [Full Text] [PDF]
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J. G. R. De Mey, P. M. Schiffers, R. H. P. Hilgers, and M. M. W. Sanders Toward functional genomics of flow-induced outward remodeling of resistance arteries Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1022 - H1027. [Abstract] [Full Text] [PDF]
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 A. Huang, D. Sun, A. Jacobson, M. A. Carroll, J. R. Falck, and G. Kaley Epoxyeicosatrienoic Acids Are Released to Mediate Shear Stress-Dependent Hyperpolarization of Arteriolar Smooth Muscle Circ. Res., February 18, 2005; 96(3): 376 - 383. [Abstract] [Full Text] [PDF]
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 R. S. Scotland, M. Madhani, S. Chauhan, S. Moncada, J. Andresen, H. Nilsson, A. J. Hobbs, and A. Ahluwalia Investigation of Vascular Responses in Endothelial Nitric Oxide Synthase/Cyclooxygenase-1 Double-Knockout Mice: Key Role for Endothelium-Derived Hyperpolarizing Factor in the Regulation of Blood Pressure in Vivo Circulation, February 15, 2005; 111(6): 796 - 803. [Abstract] [Full Text] [PDF]
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 J. Rogers and D. D. Sheriff Role of estrogen in nitric oxide- and prostaglandin-dependent modulation of vascular conductance during treadmill locomotion in rats J Appl Physiol, August 1, 2004; 97(2): 756 - 763. [Abstract] [Full Text] [PDF]
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X. Li, G. G. Geary, R. J. Gonzales, D. N. Krause, and S. P. Duckles Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H588 - H594. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, Z. Wu, C. Yan, M. A. Carroll, H. Jiang, J. R. Falck, and G. Kaley Estrogen Elicits Cytochrome P450--Mediated Flow-Induced Dilation of Arterioles in NO Deficiency: Role of PI3K-Akt Phosphorylation in Genomic Regulation Circ. Res., February 6, 2004; 94(2): 245 - 252. [Abstract] [Full Text] [PDF]
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J. M. Muller-Delp, D. B. Lubahn, K. E. Nichol, B. J. Philips, E. M. Price, E. M. Curran, and M. H. Laughlin Regulation of nitric oxide-dependent vasodilation in coronary arteries of estrogen receptor-{alpha}-deficient mice Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2150 - H2157. [Abstract] [Full Text] [PDF]
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R. H.P. Hilgers, S. Bergaya, P. M.H. Schiffers, P. Meneton, C. M. Boulanger, D. Henrion, B. I. Levy, and J. G.R. De Mey Uterine Artery Structural and Functional Changes During Pregnancy in Tissue Kallikrein-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1826 - 1832. [Abstract] [Full Text] [PDF]
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Z. F. Ba, J. F. Kuebler, L. W. Rue III, K. I. Bland, P. Wang, and I. H. Chaudry Gender dimorphic tissue perfusion response after acute hemorrhage and resuscitation: role of vascular endothelial cell function Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2162 - H2169. [Abstract] [Full Text] [PDF]
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C. T. Fulton and J. N. Stallone Sexual dimorphism in prostanoid-potentiated vascular contraction: roles of endothelium and ovarian steroids Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2062 - H2073. [Abstract] [Full Text] [PDF]
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D. A. Rosenbaum, M. Pretorius, J. V. Gainer, D. Byrne, L. J. Murphey, C. A. Painter, D. E. Vaughan, and N. J. Brown Ethnicity Affects Vasodilation, but Not Endothelial Tissue Plasminogen Activator Release, in Response to Bradykinin Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1023 - 1028. [Abstract] [Full Text] [PDF]
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