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© 1998 American Heart Association, Inc.
Rapid Communication |
Superoxide Released to High Intra-arteriolar Pressure Reduces Nitric Oxide–Mediated Shear Stress– and Agonist-Induced Dilations
From the Department of Physiology, New York Medical College, Valhalla, NY.
Correspondence to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
Abstract
Abstract—It is thought that
elevated levels of reactive oxygen metabolites contribute to the
dysfunction of vascular endothelium in hypertension. We
hypothesized that high intravascular pressure itself elicits
production of superoxide, which then interferes with nitric
oxide (NO)–mediated responses of arterioles. Thus, isolated arterioles
(
80 µm in diameter) from gracilis muscle of normotensive
Wistar rats were cannulated and exposed to 140 mm Hg perfusion
pressure for 30 minutes (in the absence of perfusate flow).
After high intravascular pressure treatment, dilations to increases in
perfusate flow (0 to 30 µL/min) were significantly reduced
(from 39±2.2 to 19±2.1 µm at 30 µL/min), eliciting an
increase in wall shear stress from 20 to 60 dyne/cm2.
N
-nitro-L-arginine (10-4 mol/L)
did not affect, whereas indomethacin eliminated,
flow-induced dilations after pressure treatment. In control, substance
P (SP, 10-9 to 5x10-8 mol/L), sodium
nitroprusside (SNP, 10-8 to 10-6 mol/L), and
adenosine (ADO, 10-6 to 5x10-5
mol/L) elicited dilations (SP: 31.5±1.9 µm, SNP: 45.6±4
µm, and ADO: 37.2±4.1 µm, at maximum concentrations,
respectively). After pressure treatment, maximum dilations to SP and
SNP were significantly reduced (by 49% and 39%, respectively),
whereas responses to ADO were not affected. Presence of superoxide
dismutase (120 U/mL) and catalase (80 U/mL), but not catalase alone, in
the perfusate solution prevented the reduction in dilation of
arterioles to flow and agonists after pressure treatment by restoring
NO mediation. We conclude that high intravascular pressure per se
elicits the release of superoxide, which then interferes with NO, a
mechanism that contributes to the elevation of wall shear stress and
peripheral resistance in hypertension.
Key Words: intravascular pressure • hypertension • reactive oxygen metabolites • wall shear stress • microcirculation
In a variety of forms of human and experimental hypertension, a significant dysfunction of the vascular endothelium has been documented.1 2 3 4 5 6 7 8 9 It is therefore quite plausible that, independent of origin, the increased intravascular pressure itself has a deleterious effect on the vasomotor regulatory function of endothelium. This idea is congruent with studies that show that the functional and morphologic changes in arteries observed in hypertension could be prevented by normalizing intravascular pressure.10 In cat cerebral arteries, it was shown that pressure releases a transferable endothelial contractile factor11 and that elevated transmural pressure inhibits the release of endothelium-derived relaxing factor.12 Furthermore, in the dog coronary artery, acute increases in blood pressure selectively alter endothelium-dependent responses, resulting in enhanced constriction to serotonin.13 Because of the complexity of whole-organ experiments, the sole effect of an increase in pressure could not be ascertained, given that, in addition to pressure, several other factors may change concurrently to interfere with the interpretation of the results. Interestingly, endothelial cells in culture produce less NO when exposed to high ambient pressure,14 but the effect of such changes on endothelial regulation of vascular resistance is not known.
Recent studies demonstrated important changes in the function of microvessels in hypertension, ie, reduced dilations to acetylcholine, substance P (SP), and other endothelium-dependent vasoactive substances.7 In addition, a deficiency was shown to be present in the basal production of nitric oxide (NO) by the endothelium of arterioles of genetically hypertensive rats.6 One of the primary stimuli for the release of NO is an increase in wall shear stress (WSS).15 Previously, we found that in genetic hypertension, the flow/shear stress–induced dilation in skeletal muscle arterioles is significantly reduced, because of the absence of the NO-mediated portion of the response.16 17 Similar findings were reported by others in mesenteric arterioles as well.18 Collectively, these findings suggest that in different forms of hypertension, the endothelial synthesis or action of NO is impaired and that NO-mediated responses are adversely affected by high transmural pressure.
Elevated blood pressure may induce an oxidative stress in the endothelium.19 Moreover, reactive oxygen species are known to interfere directly with NO, as indicated by the finding that superoxide causes reduction in the arteriolar dilation to acetylcholine that can be reversed by superoxide dismutase (SOD).20 21 Recently, it has also been shown that in hypertension, there is an enhanced oxidative stress in microvessels22 23 and that superoxide may interfere with NO in hypertension.24
Thus, we hypothesized that in hypertension, the increase in intravascular pressure itself elicits an enhanced production of superoxide, which then interferes with the NO-mediated portion of flow/shear stress–induced dilation of arterioles. This mechanism has not yet been investigated in skeletal muscle arterioles, which are responsible for a large portion of peripheral resistance. To test our hypothesis, we aimed to characterize the effects of an acute elevation of intravascular pressure on flow/shear stress– and agonist-induced responses of isolated skeletal muscle arterioles of normotensive rats. In addition, the possible role of oxygen free radicals in the modulation of NO-mediated dilations was assessed by the use of agents affecting the metabolism of reactive oxygen metabolites.
Materials and Methods
Experiments were conducted on isolated arterioles (80
µm) of gracilis muscle of 7-week-old male normotensive Wistar rats
(Charles River Laboratories, Wilmington, Mass). Rats were
anesthetized with intraperitoneal
injections of sodium pentobarbital (50 mg/kg). The isolation procedure
of gracilis muscle arterioles has been described
previously.17 Briefly, the gracilis muscle of
rats was cut out and placed on a Petri dish containing cold (0°C to
4°C) salt solution (pH 7.4) that was composed of (in mmol/L)
NaCl 145, KCl 5.0, CaCl2 2.0,
MgSO4 1.0,
NaH2PO4 1.0, dextrose 5.0,
pyruvate 2.0, EDTA 0.02, and MOPS 3.0. An arteriole (1 mm in
length) supplying gracilis muscle was isolated and transferred to the
vessel chamber; the rats were then euthanized by an overdose of sodium
pentobarbital. The chamber contained a pair of glass micropipettes
filled with a physiological salt solution (PSS)
containing (in mmol/L) NaCl 110.0, KCl 5.0,
CaCl2 2.5, MgSO4 1.0,
dextrose 10.0, NaHCO3 24.0, and EDTA 0.02, which
was then equilibrated with a gas mixture of 21%
O2+5% CO2 and balanced
with N2, at pH 7.4 (37°C). From a reservoir
(syringe and connecting tube; 85 mL), the vessel chamber (15 mL) was
continuously supplied with PSS at a rate of 40 mL/min.
After cannulation of the vessel, the perfusion pressure was raised to 20 mm Hg to clear the clotted blood from the lumen, then the other end of the vessel was mounted on the distal pipette. Both proximal (inflow) and distal (outflow) micropipettes were connected with silicone tubing to a pressure-servo syringe system (Living Systems Inc) in which pressure and flow could be controlled independently.16 17
In all protocols, only those vessels that developed spontaneous tone to
pressure were used, because there was no vasoactive agent added to the
PSS. After the equilibration period (1 hour), flow-diameter
relationships were obtained in control conditions. Perfusate
flow was established at a constant intravascular pressure (80
mm Hg) by changing proximal and distal pressures to an equal degree
but in opposite directions, to keep midpoint luminal pressure constant.
The flow was measured by a ball flowmeter (Omega). Each flow step was
maintained for 5 minutes, and the diameter was measured. Responses
of arterioles to vasoactive agents, SP (10-9 to
5x10-8 mol/L), sodium nitroprusside (SNP,
10-8 to 10-6 mol/L), and
adenosine (ADO, 10-6 to
5x10-5 mol/L) were tested. All procedures were
in accordance with guidelines set by the Institutional Animal Care and
Use Committee of New York Medical College.
Experimental Procedures
At 80 mm Hg perfusion pressure, changes in diameter
of arterioles in response to increases in perfusate flow (from
0 to 30 µL/min, in 5-µL/min steps) and agonists were measured with
an image shearing monitor (IPM, model 907) and recorded with an X-Y
recorder (Multicorder, MC6625). After obtaining control responses,
perfusion pressure was increased to 140 mm Hg for 30 minutes in
the absence of perfusate flow. Perfusion pressure was returned
to 80 mm Hg, and responses to increases in perfusate flow
and agonists were obtained again.
The role of NO in the mediation of arteriolar responses was assessed by
the use of N-nitro-L-arginine
(L-NNA, 10-4 mol/L), an inhibitor of
NO synthesis. Vessels were incubated with L-NNA for 15 minutes, and
then flow-induced responses were reassessed. The role of
prostaglandins was assessed similarly by use of
indomethacin (INDO, 10-5 mol/L),
an inhibitor of prostaglandin synthesis.
In another series of experiments, after obtaining control responses, SOD (120 U/mL), to metabolize superoxide, and catalase (CAT, 80 U/mL), to eliminate hydrogen peroxide,20 21 were administered to the perfusion solution, and vessels were perfused at a rate of 5 µL/min for 10 minutes. After the pressure treatment, flow- and agonist-induced responses were obtained in the presence of SOD+CAT. The effects of L-NNA and L-NNA+INDO were tested in sequence in these conditions as well. The effect of CAT alone in the perfusate solution on these responses was also tested.
All salts and chemicals were obtained from Sigma Chemical Co or Aldrich Chemical Co and were prepared on the day of the experiment. All drugs were added to the reservoir connected to the vessel chamber, and final concentrations are reported. To assess the maximum passive diameter of arterioles (at 80 mm Hg pressure), at the conclusion of each experiment, the suffusion solution was changed to a Ca2+-free PSS that contained SNP (10-4 mol/L) and EGTA (1.0 mmol/L).
WSS was calculated by the formula 4 
Q/r3,
where is the viscosity of the perfusate (0.007 poise at
37°C), Q is the perfusate flow, and r is the vessel radius.
Data are presented as mean±SEM; n refers to the number of
vessels. Only one vessel per rat was used. Statistical analyses
were done by ANOVA, followed by Tukey post hoc test, regression
analysis, and paired and grouped Student t tests, as
appropriate. A P value of <0.05 was considered
significant.
Results
The active diameters of arterioles in control and after high intravascular pressure treatment were significantly different (85.6±6.9 and 74.1±6.6 µm, respectively; P<0.01). In the same conditions but in Ca2+-free solution, the mean passive diameter of arterioles was 153.7±9.4 µm. The arteriolar tone, expressed as a percent of passive diameter, was also significantly different in the two conditions (55.1±2.2% in control and 47.2±2.1% after pressure treatment; P<0.001).
Figure 1
(top) demonstrates the changes
in diameter of rat gracilis arterioles in response to step increases in
perfusate flow in control conditions and after exposure to high
intravascular pressure. In control conditions, increases in flow (0 to
30 µL/min, in 5-µL/min steps) elicited substantial increases in the
diameter of arterioles, from 85.6±5 to 124.6±6 µm. After
pressure treatment, however, dilations to flow were significantly
reduced; the diameter of arterioles increased from 74.1±5 to
93.1±6 µm. Also, the significant difference in the slope of the
flow-diameter curves indicates that after pressure treatment,
arterioles dilated significantly less to step increases in
perfusate flow compared with control conditions. Calculation of
WSS (Figure 1, bottom) indicates that in control conditions, WSS was
maintained at 20 dyne/cm2, whereas after
pressure treatment, WSS increased to 60
dyne/cm2.
|
We investigated whether endothelial mechanisms were
responsible for the impaired flow-induced dilation observed after
pressure treatment. Our previous studies showed that in gracilis muscle
arterioles, both NO and prostaglandins are involved in
mediation of flow-dependent dilation.16 To
examine the contribution of NO in the flow-induced response, we used
L-NNA, which, however, did not affect flow-induced arteriolar dilation
obtained after pressure treatment (Figure 2, top). In contrast, in the presence of
L-NNA, further administration of INDO practically eliminated
flow-induced arteriolar responses after exposure to high intravascular
pressure (Figure 2, top).
|
In the next experimental series, after obtaining control responses,
vessels were treated with SOD (120 U/mL) and CAT (60 U/mL) administered
in the perfusate solution. Prior administration of SOD+CAT
prevented the reduction of flow-induced dilation of arterioles after
high-pressure treatment (Figure 2
, bottom) by preventing the impairment
of the NO-mediated portion of flow-induced dilation. Use of CAT alone,
unlike the combined use of SOD+CAT in the perfusate solution,
did not prevent this impairment (Figure 3).
|
To ascertain further that high intravascular pressure treatment affects
NO-dependent dilation of arterioles, responses to SP, SNP, and ADO were
investigated. Responses to SP and SNP were significantly reduced
(Figures 4 and 5, top), whereas dilations to ADO
remained unchanged (Figure 6, top) after
high-pressure treatment. Administration of SOD+CAT in the
perfusate solution, before pressure treatment, prevented the
reduction of NO-mediated responses and left responses to ADO unaffected
(Figures 4 through 6, bottom).
|
|
|
Discussion
The salient findings of the present study are that in isolated arterioles, a brief period of high intravascular pressure eliminates the NO-mediated portion of flow/shear stress–induced dilations, resulting in a substantial increase in the level of WSS, and significantly reduces NO-mediated dilation to agonists. This impairment of NO-mediated responses is primarily due to superoxide released to high intra-arteriolar pressure.
Previous investigation of arteries of hypertensive animals revealed morphologic changes in the wall of arteries,25 as well as reduction in the number of the arterioles.26 These changes were used to explain the enhanced peripheral resistance that accompanies hypertension. Recent studies, however, support the idea that an altered function of the endothelium of arterioles is intimately involved in the early development of vascular changes in hypertension and may also contribute to the increase in peripheral resistance. Several studies have suggested that in hypertension, changes in the function of endothelium might be linked to a reduced synthesis or action of NO1 2 3 4 5 6 7 8 9 17 18 19 and that this may be due to an enhanced production of superoxide anions.20 21 22 23 24
One of the primary functions of microvascular endothelium is to sense and regulate WSS, thereby preventing an unnecessary power loss in the circulation.27 Previously, we have found, however, that flow/shear stress–dependent dilation of arterioles is impaired in hypertension, and that this is due to a lack of NO mediation of the response.17 A reduction in flow-induced dilation was also reported in coronary arteries of patients with essential hypertension.28 In accordance with these findings, a reduced plasma level of nitrite and nitrate was found in hypertensive patients.29 The reasons for the impairment of NO-related responses have not yet been clearly elucidated, but the finding that endothelial function is impaired in hypertensive conditions of different origin suggests that there may be a common cause for all these changes. We hypothesized that the high transmural pressure itself elicits substantial changes in the function of arteriolar endothelium and that the impaired vasomotor function of arterioles is due to the interaction of NO and superoxide, which is produced in response to high intravascular pressure. In this context, previous studies in large cerebral vessels showed that an increase in pressure causes the release of a transferable endothelial constrictor factor11 and that high ambient pressure itself can reduce NO synthesis in cultured endothelial cells.14 In contrast, cyclic strain was shown to elicit an upregulation of NO synthesis,30 indicating the dynamic response of NO-mediated mechanisms to hemodynamic forces.
Impairment of Flow-Induced Dilation After High Intravascular
Pressure Treatment
The diameter of gracilis muscle arterioles in control conditions
and after high-pressure treatment were different, which is also
indicated by the significant difference in the tone of arterioles
(diameter expressed as percent of passive diameter). Having been
exposed to high pressure, arterioles of rat gracilis muscle exhibited a
reduced dilation in response to increases in perfusate flow
compared with responses obtained before pressure treatment (control
conditions), as shown by the significant shift in the slope of the
flow-diameter curves (Figure 1, top). The
pathophysiological relevance of these findings is
indicated further by the calculated WSS-diameter curves, demonstrating
that there is a significant elevation in WSS after arterioles are
exposed to high intravascular pressure. These findings accord with the
idea that in hypertension, the high WSS is associated with an enhanced
power dissipation providing for the maintenance of normal
capillary pressure.27
Lack of NO-Mediated Dilation to Flow After Pressure
Treatment
Because flow-dependent dilation of skeletal muscle arterioles is
mediated by endothelial
factors,16 we hypothesized that changes in the
function of the endothelium due to high intravascular
pressure are responsible for the observed reduction in flow-induced
dilation. Previously, we found that at 80 mm Hg perfusion
pressure, inhibition of either NO or prostaglandin
synthesis alone significantly reduced arteriolar dilation to increases
in perfusate flow. Inhibition of the synthesis of both of these
mediators nearly eliminated flow-induced
dilation.16 17
After high-pressure treatment of arterioles—a condition in which flow-induced dilations were already reduced compared with control—inhibition of NO synthesis did not affect, whereas INDO nearly completely eliminated, the reduced flow-dependent response. These findings suggest that high intravascular pressure interferes with the NO-mediated portion of flow-induced dilation but not with the synthesis of vasodilator prostaglandins, which are responsible for the remaining dilation. The findings that after pressure treatment, dilations to SP and SNP but not ADO were reduced suggest that high intravascular pressure interferes with NO directly, regardless of whether it is produced in endothelium in response to SP or released by the NO donor SNP. Furthermore, the effect of high intravascular pressure seems to be specific to endothelial NO-mediated responses, given that dilations to ADO, which elicits relaxation of arteriolar smooth muscle by a mechanism unrelated to NO, were not affected. On the basis of our findings, we speculate that the impairment of NO-related responses in hypertension is not necessarily determined genetically nor is it due to a reduced function of endothelial NO synthase. Rather, the lack of a NO-mediated vasoregulation in hypertension is, most likely, due to the presence of high intra-arteriolar pressure per se. Therefore, it is likely that the endothelium is a target of high pressure rather than an initiator of increased resistance in hypertension, although its malfunction can further aggravate the increase in peripheral resistance.
The finding that SOD administered with CAT in the perfusate prevented the impairment of the NO-mediated portion of both flow- and agonist-induced dilations after exposure to high intravascular pressure suggests that during exposure to high intravascular pressure, reactive oxygen metabolites are produced that interfere with the NO released from endothelium or by the NO donor SNP. It is most likely superoxide, and not hydrogen peroxide, that is released to high intraluminal pressure, because hydrogen peroxide by activation of guanylate cyclase and the production of cGMP would not reduce, but enhance, dilation to SNP.31 A role for hydrogen peroxide released to high pressure was finally excluded by the present experiments, showing that CAT alone in the perfusate solution did not affect the impairment of flow-induced responses by high-pressure treatment. This finding underscores the subtle differences that exist in responses of vascular tissues to variation in hemodynamic forces, because cyclic, but not static, strain was previously shown to elicit the release of hydrogen peroxide.32
Superoxide production to high pressure may originate in the endothelium or vascular smooth muscle, primarily as a response to enhanced physical stretch. It is known that superoxide is produced in the course of the metabolism of arachidonic acid33 and that cytoplasmic microsomal NADH oxidoreductase is a major source for superoxide in bovine coronary endothelium.34 Alternatively, angiotensin II produced locally in the endothelium35 may elicit the production of superoxide, as suggested by previous studies.36 Therefore, it is tempting to speculate that perhaps one or more of these mechanisms become activated when intravascular pressure is high. The characterization of these mechanisms is a subject for future studies.
In conclusion, the present study is the first to demonstrate that high intravascular pressure per se, by eliciting increased production of superoxide, impairs the NO-mediated flow/shear stress– and agonist-induced dilation of skeletal muscle arterioles. The resultant elevation of arteriolar WSS is likely to contribute to the increased peripheral resistance in hypertension.
Acknowledgments
This study was supported by grants from the National Institutes of Health (HL-46813 and P01 HL43023) and the American Heart Association New York State Affiliate (970137). We appreciate the excellent secretarial assistance of Miriam Nunez and Mary Browne.
Received July 10, 1998; accepted September 9, 1998.
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 D. D. Gutterman, H. Miura, and Y. Liu Redox Modulation of Vascular Tone: Focus of Potassium Channel Mechanisms of Dilation Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 671 - 678. [Abstract] [Full Text] [PDF]
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F. A. DeLano, R. Balete, and G. W. Schmid-Schonbein Control of oxidative stress in microcirculation of spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H805 - H812. [Abstract] [Full Text] [PDF]
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J. Herrmann, S. T. Higano, R. J. Lenon, C. S. Rihal, and A. Lerman Myocardial bridging is associated with alteration in coronary vasoreactivity Eur. Heart J., December 1, 2004; 25(23): 2134 - 2142. [Abstract] [Full Text] [PDF]
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C. Cseko, Z. Bagi, and A. Koller Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways J Appl Physiol, September 1, 2004; 97(3): 1130 - 1137. [Abstract] [Full Text] [PDF]
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Z. Bagi, E. Toth, A. Koller, and G. Kaley Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH4 Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H626 - H633. [Abstract] [Full Text] [PDF]
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 Z. Ungvari, A. Csiszar, P. M. Kaminski, M. S. Wolin, and A. Koller Chronic High Pressure-Induced Arterial Oxidative Stress: Involvement of Protein Kinase C-Dependent NAD(P)H Oxidase and Local Renin-Angiotensin System Am. J. Pathol., July 1, 2004; 165(1): 219 - 226. [Abstract] [Full Text] [PDF]
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S. Veerareddy, C.-L. M. Cooke, P. N. Baker, and S. T. Davidge Gender differences in myogenic tone in superoxide dismutase knockout mouse: animal model of oxidative stress Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H40 - H45. [Abstract] [Full Text] [PDF]
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E. N. T. P. Bakker, O. Sorop, J. A. E. Spaan, and E. VanBavel Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2052 - H2056. [Abstract] [Full Text] [PDF]
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D. Sun, A. Huang, E. H. Yan, Z. Wu, C. Yan, P. M. Kaminski, T. D. Oury, M. S. Wolin, and G. Kaley Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2249 - H2256. [Abstract] [Full Text] [PDF]
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A. P. V Dantas, M. d. C. P Franco, M. M Silva-Antonialli, R. C.A Tostes, Z. B Fortes, D. Nigro, and M. H. C Carvalho Gender differences in superoxide generation in microvessels of hypertensive rats: role of NAD(P)H-oxidase Cardiovasc Res, January 1, 2004; 61(1): 22 - 29. [Abstract] [Full Text] [PDF]
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 Z. Ungvari, A. Csiszar, A. Huang, P. M. Kaminski, M. S. Wolin, and A. Koller High Pressure Induces Superoxide Production in Isolated Arteries Via Protein Kinase C-Dependent Activation of NAD(P)H Oxidase Circulation, September 9, 2003; 108(10): 1253 - 1258. [Abstract] [Full Text] [PDF]
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S. Meng, G. W. Cason, A. W. Gannon, L. C. Racusen, and R. D. Manning Jr Oxidative Stress in Dahl Salt-Sensitive Hypertension Hypertension, June 1, 2003; 41(6): 1346 - 1352. [Abstract] [Full Text] [PDF]
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J. C. Frisbee, K. G. Maier, and D. W. Stepp Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2160 - H2168. [Abstract] [Full Text] [PDF]
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Z. Ungvari, A. Csiszar, Z. Bagi, and A. Koller Impaired Nitric Oxide-Mediated Flow-Induced Coronary Dilation in Hyperhomocysteinemia : Morphological and Functional Evidence for Increased Peroxynitrite Formation Am. J. Pathol., July 1, 2002; 161(1): 145 - 153. [Abstract] [Full Text] [PDF]
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F. A. Sylvester, D. W. Stepp, J. C. Frisbee, and J. H. Lombard High-salt diet depresses acetylcholine reactivity proximal to NOS activation in cerebral arteries Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H353 - H363. [Abstract] [Full Text] [PDF]
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 A. Csiszar, Z. Ungvari, J. G. Edwards, P. Kaminski, M. S. Wolin, A. Koller, and G. Kaley Aging-Induced Phenotypic Changes and Oxidative Stress Impair Coronary Arteriolar Function Circ. Res., June 14, 2002; 90(11): 1159 - 1166. [Abstract] [Full Text] [PDF]
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A. P. V. Dantas, R. C.A. Tostes, Z. B. Fortes, S. G. Costa, D. Nigro, and M. H. C. Carvalho In Vivo Evidence for Antioxidant Potential of Estrogen in Microvessels of Female Spontaneously Hypertensive Rats Hypertension, February 1, 2002; 39(2): 405 - 411. [Abstract] [Full Text] [PDF]
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D. Nyhan, S. Kim, S. Dunbar, D. Li, A. Shoukas, and D. E. Berkowitz Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide J Appl Physiol, January 1, 2002; 92(1): 33 - 40. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
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 S. Wedgwood, R. W. Dettman, and S. M. Black ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1058 - L1067. [Abstract] [Full Text] [PDF]
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J. C. Frisbee Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1568 - H1574. [Abstract] [Full Text] [PDF]
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 R. H. STEINHORN, G. ALBERT, D. D. SWARTZ, J. A. RUSSELL, C. R. LEVINE, and J. M. DAVIS Recombinant Human Superoxide Dismutase Enhances the Effect of Inhaled Nitric Oxide in Persistent Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 834 - 839. [Abstract] [Full Text] [PDF]
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J. C. Frisbee and D. W. Stepp Impaired NO-dependent dilation of skeletal muscle arterioles in hypertensive diabetic obese Zucker rats Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1304 - H1311. [Abstract] [Full Text] [PDF]
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Z. Ungvari and A. Koller Signal Transduction in Smooth Muscle: Selected Contribution: NO released to flow reduces myogenic tone of skeletal muscle arterioles by decreasing smooth muscle Ca2+ sensitivity J Appl Physiol, July 1, 2001; 91(1): 522 - 527. [Abstract] [Full Text] [PDF]
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Z. Bagi, Z. Ungvari, L. Szollar, and A. Koller Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A2 Mediation Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 233 - 237. [Abstract] [Full Text] [PDF]
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A.-P. Zou, N. Li, and A. W. Cowley Jr. Production and Actions of Superoxide in the Renal Medulla Hypertension, February 1, 2001; 37(2): 547 - 553. [Abstract] [Full Text] [PDF]
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O. A. Paniagua, M. B. Bryant, and J. A. Panza Transient Hypertension Directly Impairs Endothelium-Dependent Vasodilation of the Human Microvasculature Hypertension, December 1, 2000; 36(6): 941 - 944. [Abstract] [Full Text] [PDF]
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D. M. Lenda, B. A. Sauls, and M. A. Boegehold Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H7 - H14. [Abstract] [Full Text] [PDF]
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M. S. Wolin Interactions of Oxidants With Vascular Signaling Systems Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1430 - 1442. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, and A. Koller Shear Stress-Induced Release of Prostaglandin H2 in Arterioles of Hypertensive Rats Hypertension, April 1, 2000; 35(4): 925 - 930. [Abstract] [Full Text] [PDF]
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 T. Stefanec Endothelial Apoptosis: Could It Have a Role in the Pathogenesis and Treatment of Disease? Chest, March 1, 2000; 117(3): 841 - 854. [Abstract] [Full Text] [PDF]
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 K. G. Franchini Influence of hemodilution on the renal blood flow autoregulation during acute expansion in rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 1999; 277(6): R1662 - R1674. [Abstract] [Full Text] [PDF]
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J. A. Madden and N. J. T. Christman Integrin signaling, free radicals, and tyrosine kinase mediate flow constriction in isolated cerebral arteries Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2264 - H2271. [Abstract] [Full Text] [PDF]
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A. Koller and A. Huang Development of Nitric Oxide and Prostaglandin Mediation of Shear Stress-Induced Arteriolar Dilation With Aging and Hypertension Hypertension, November 1, 1999; 34(5): 1073 - 1079. [Abstract] [Full Text] [PDF]
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Z. Ungvari, P. Pacher, K. Rischak, L. Szollar, and A. Koller Dysfunction of Nitric Oxide Mediation in Isolated Rat Arterioles With Methionine Diet–Induced Hyperhomocysteinemia Arterioscler. Thromb. Vasc. Biol., August 1, 1999; 19(8): 1899 - 1904. [Abstract] [Full Text] [PDF]
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 H.-Y. Sohn, M. Keller, T. Gloe, H. Morawietz, U. Rueckschloss, and U. Pohl The Small G-protein Rac Mediates Depolarization-induced Superoxide Formation in Human Endothelial Cells J. Biol. Chem., June 16, 2000; 275(25): 18745 - 18750. [Abstract] [Full Text] [PDF]
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