scholarly journals Interaction of Angiotensin II and Nitric Oxide in Isolated Perfused Afferent Arterioles of Mice

2001 ◽  
Vol 12 (6) ◽  
pp. 1122-1127
Author(s):  
ANDREAS PATZAK ◽  
RALF MROWKA ◽  
EBERHARD STORCH ◽  
BERTHOLD HOCHER ◽  
PONTUS B. PERSSON
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Enos Gene ◽  
Acute Administration ◽  
Ang Ii ◽  
Wild Type ◽  
Afferent Arterioles ◽  
Dose Responses ◽  
Arteriolar Diameter

Abstract. The present study was performed to evaluate angiotensin II (Ang II)—nitric oxide (NO) interaction in afferent arterioles (Af) of wild-type mice and mice that are homozygous (-/-) for disruption of the endothelial NO synthase (eNOS) gene. Af were microperfused, and the dose responses were assessed for the NO precursor L-arginine (n= 4), NO inhibitor NG-nitro-L-arginine methyl ester (L-NAME,n= 5), L-NAME after pretreatment with L-arginine (n= 5), Ang II (n= 8), and Ang II after pretreatment with L-NAME (n= 7). Acute administration of L-arginine and L-NAME (both in doses from 10-6to 10-3mol/L) did not change arteriolar diameter. Moreover, pretreatment with L-arginine did not change the response to L-NAME. However, Ang II, applied in doses of 10-12, 10-10, 10-8, and 10-6mol/L, significantly reduced the lumen to 66.5 ± 7.0% and 62.2 ± 8.0% at 10-8and 10-6mol/L Ang II, respectively. The contraction was augmented after L-NAME pretreatment (19.5 ± 13.6% and 25.5 ± 10.2% at 10-8and 10-6mol/L Ang II, respectively). In eNOS (-/-) mice (n= 8), the response to Ang II also was enhanced (9.1 ± 6.0% and 11.2 ± 8.2% at 10-8and 10-6mol/L Ang II, respectively). Female mice did not differ from male mice in their reactivity to Ang II (n= 9) and Ang II + L-NAME pretreatment (n= 11). The study shows that (1) it is feasible to microperfuse mouse Af, (2) the basal production of endothelial NO is very low and not inducible by L-arginine in Af of mice, and (3) a counteracting effect of NO is initiated by Ang II. High Ang II sensitivity in eNOS (-/-) mice underscores the considerable role of endothelial-derived NO to balance Ang II vasoconstriction in Af.

Angiotensin II response in afferent arterioles of mice lacking either the endothelial or neuronal isoform of nitric oxide synthase

2008 ◽  
Vol 294 (2) ◽  
pp. R429-R437 ◽  
Author(s):  
Andreas Patzak ◽  
Andreas Steege ◽  
En Yin Lai ◽  
Jan Ole Brinkmann ◽  
Eckehardt Kupsch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Enos Gene ◽  
Angiotensin Ii Receptor ◽  
Afferent Arterioles ◽  
Dose Responses ◽  
Oxide Synthase ◽  
The Impact ◽  
Deficient Mice

The aim of the study is to evaluate the impact of nitric oxide (NO) produced by endothelial NO synthase (eNOS) and neuronal NOS (nNOS) on the angiotensin II response in afferent arterioles (Af). Dose responses were assessed for angiotensin II in microperfused Af of mice homozygous for disruption of the eNOS gene [eNOS(−/−)], or nNOS gene [nNOS(−/−)], and their wild-type controls, eNOS(+/+) and nNOS(+/+). Angiotensin II at 10−8 and 10−6 mol/l reduced the lumen to 69% and 68% in eNOS(+/+), and to 59% and 50% in nNOS(+/+). NG-nitro-l-arginine methyl ester (l-NAME) did not change basal arteriolar diameters, but augmented angiotensin II contraction, reducing diameters to 23% and 13% in eNOS(+/+), and 7% and 10% in nNOS(+/+) at 10−8 and 10−6 mol/l. The response to angiotensin II was enhanced in nNOS(−/−) mice (41% and 25% at 10−8 and 10−6 mol/l) and even more enhanced in eNOS(−/−) mice (12% and 9%) compared with nNOS(+/+) and eNOS(+/+). l-NAME led to complete constriction of Af in these groups. Media-to-lumen ratios of Af did not differ between controls and gene-deficient mice. mRNA expression of angiotensin II receptor types 1A and 1B and type 2 also did not differ. The results reveal that angiotensin II-induced release of NO from both eNOS and nNOS significantly contributes to the control of Af. Results also suggest that eNOS-derived NO is of greater importance than nNOS-derived NO in this isolated arteriolar preparation.

Role of AT1 receptors in the renal papillary effects of acute and chronic nitric oxide inhibition

1998 ◽  
Vol 274 (3) ◽  
pp. R760-R766 ◽  
Author(s):  
M. Clara Ortíz ◽  
Lourdes A. Fortepiani ◽  
Francisco M. Ruiz-Marcos ◽  
Noemí M. Atucha ◽  
Joaquín García-Estañ
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Chronic Administration ◽  
Acute Administration ◽  
Synthesis Inhibitor ◽  
Renal Vasoconstriction ◽  
Oxide Inhibition ◽  
Stimulation Of

Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1 angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1 receptor blocker losartan did not modify the decreases in RBF or PBF secondary to l-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.

Abstract 1436: CYP2J2 Endothelial Overexpression Increases Nitric Oxide and Cyclooxygenase Independent Renal Dilation and Attenuates Endothelin-1 Vasoconstriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John D Imig ◽  
Craig R Lee ◽  
Alyce Bradbury ◽  
Joan P Graves ◽  
Laura M DeGraff ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Vasculature ◽  
Specific Expression ◽  
Endothelin 1 ◽  
Afferent Arterioles ◽  
Oxide Synthase ◽  
Renal Vascular ◽  
Arteriolar Diameter ◽  
Regulation Of Vascular Tone

Human CYP2J2 is expressed in endothelial cells and active in the biosynthesis of epoxyeico-satrienoic acids (EETs). However, the functional role of CYP2J2 and its products in the renal vasculature remain poorly characterized. To address this, we developed transgenic (Tr) mice with constitutive, endothelial cell-specific expression of human CYP2J2 ( Tie2 promoter and full enhancer) and enhanced EET biosynthesis. Experiments were conducted in the juxtamedullary nephron preparation to determine renal microvascular responses to acetylcholine (ACh) and endothelin-1 in Tie2 -CYP2J2 Tr mice and wild type (Wt) littermate controls. Administration of phenylephrine to kidney perfusate decreased the diameter of afferent arterioles from 20.1±0.5 to 13.9±0.6 μm (n=21) in Wt mice and 19.4±0.6 to 13.5±0.6 μm (n=23) in Tie2 -CYP2J2 Tr mice. Following phenylephrine, the afferent arteriole diameter response to ACh (0.01nM-10μM) was determined. There was a leftward shift in the logEC50 in Tie2 -CYP2J2 Tr mice (−6.5±0.2, n=13) compared to Wt mice (−6.1±0.2, n=11). However, the maximal afferent arteriolar relaxation to ACh was decreased in Tie2 -CYP2J2 Tr mice (59±6%) compared to Wt mice (70±7%, p=0.12). Endothelial expression of CYP2J2 increased the maximal renal vascular response to ACh in the presence of nitric oxide synthase (100μM L-NAME) and cyclooxygenase (10μM indomethacin) inhibition. Afferent arterioles relaxed by 27±4% (n=12) in Wt mice and 44±6% (n=10, p=0.018) in Tie2 -CYP2J2 Tr mice (10μM ACh). The afferent arteriolar dose response curve to endothelin-1 (0.001–10nM) was significantly attenuated in Tie2 -CYP2J2 Tr compared to Wt mice. Afferent arteriolar diameter decreased by 24±4% (n=6) in Wt mice and 13±2% (n=5, p=0.023) in Tie2 -CYP2J2 Tr mice (3nM endothelin-1). These results demonstrate that the nitric oxide- and cyclooxygenase-independent afferent arteriolar dilation to ACh is enhanced by endothelial overexpression of CYP2J2, and endothelin-1 mediated constriction is attenuated. In conclusion, endothelial overexpression of CYP2J2 can oppose renal vascular constrictor responses and enhance dilator responses in mice, implicating the important role of CYP2J2-derived eicosanoids in the regulation of vascular tone.

scholarly journals Myoglobin facilitates angiotensin II-induced constriction of renal afferent arterioles

2017 ◽  
Vol 312 (5) ◽  
pp. F908-F916 ◽  
Author(s):  
Z. Z. Liu ◽  
S. Mathia ◽  
T. Pahlitzsch ◽  
I. C. Wennysia ◽  
P. B. Persson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Vessel Wall ◽  
Kidney Injury ◽  
Cytosolic Calcium ◽  
Calcium Transients ◽  
Ang Ii ◽  
Combined Application ◽  
Afferent Arterioles ◽  
No Bioavailability ◽  
Arteriolar Diameter

Vasoconstriction plays an important role in the development of acute kidney injury in rhabdomyolysis. We hypothesized that myoglobin enhances the angiotensin II (ANG II) response in afferent arterioles by increasing superoxide and reducing nitric oxide (NO) bioavailability. Afferent arterioles of C57Bl6 mice were isolated perfused, and vasoreactivity was analyzed using video microscopy. NO bioavailability, superoxide concentration in the vessel wall, and changes in cytosolic calcium were measured using fluorescence techniques. Myoglobin treatment (10−5 M) did not change the basal arteriolar diameter during a 20-min period compared with control conditions. NG-nitro-l-arginine methyl ester (l-NAME, 10−4 M) and l-NAME + myoglobin reduced diameters to 94.7 and 97.9% of the initial diameter, respectively. Myoglobin or l-NAME enhanced the ANG II-induced constriction of arterioles compared with control (36.6 and 34.2%, respectively, vs. 65.9%). Norepinephrine responses were not influenced by myoglobin. Combined application of myoglobin and l-NAME further facilitated the ANG II response (7.0%). Myoglobin or l-NAME decreased the NO-related fluorescence in arterioles similarly. Myoglobin enhanced the superoxide-related fluorescence, and tempol prevented this enhancement. Tempol also partly prevented the myoglobin effect on the ANG II response. Myoglobin increased the fura 2 fluorescence ratio (cytosolic calcium) during ANG II application (10−12 to 10−6 M). The results suggest that the enhanced afferent arteriolar reactivity to ANG II is mainly due to a myoglobin-induced increase in superoxide and associated reduction in the NO bioavailability. Signaling pathways for the augmented ANG II response include enhanced cytosolic calcium transients. In conclusion, myoglobin may contribute to the afferent arteriolar vasoconstriction in this rhabdomyolysis model.

Role of NOX2 in the regulation of afferent arteriole responsiveness

2009 ◽  
Vol 296 (1) ◽  
pp. R72-R79 ◽  
Author(s):  
Mattias Carlström ◽  
En Yin Lai ◽  
Zufu Ma ◽  
Andreas Patzak ◽  
Russell D. Brown ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Perfusion ◽  
Afferent Arteriole ◽  
Ang Ii ◽  
Wild Type ◽  
Simultaneous Application ◽  
Nitric Oxide Deficiency ◽  
Sensitizing Effect

NADPH oxidases (NOX) are the major source of reactive oxygen species (ROS) in the vasculature and contribute to the control of renal perfusion. The role of NOX2 in the regulation of blood pressure and afferent arteriole responsiveness was investigated in NOX2−/− and wild-type mice. Arteriole constrictions to ANG II (10−14–10−6 mol/l) were weaker in NOX2−/− compared with wild types. Nω-nitro-l-arginine methyl ester (l-NAME; 10−4 mol/l) treatment reduced basal diameters significantly more in NOX2−/− (−18%) than in wild types (−6%) and augmented ANG II responses. Adenosine (10−11–10−4 mol/l) constricted arterioles of wild types but not of NOX2−/−. However, simultaneous inhibition of adenosine type-2 receptors induced vasoconstriction, which was stronger in NOX2−/−. Adenosine (10−8 mol/l) enhanced the ANG II response in wild type, but not in NOX2−/−. This sensitizing effect by adenosine was abolished by apocynin. Chronic ANG II pretreatment (14 days) did not change the ANG II responses in NOX2−/−, but strengthened the response in wild types. ANG II pretreatment augmented the l-NAME response in NOX2−/− (−33%), but not in wild types. Simultaneous application of l-NAME and ANG II caused a stronger constriction in the NOX2−/− (−64%) than in wild types (−46%). Basal blood pressures were similar in both genotypes, however, chronic ANG II infusion elevated blood pressure to a greater extent in wild-type (15 ± 1%) than in NOX2−/− (8 ± 1%) mice. In conclusion, NOX2 plays an important role in the control of afferent arteriole tone and is involved in the contractile responses to ANG II and/or adenosine. NOX2 can be activated by elevated ANG II and may play an important role in ANG II-induced hypertension. NOX2-derived ROS scavenges nitric oxide, causing subsequent nitric oxide-deficiency.

scholarly journals Nitric oxide and angiotensin II regulate cardiovascular homeostasis and the arterial baroreflex control of heart rate in conscious lambs

2011 ◽  
Vol 13 (1) ◽  
pp. 99-106 ◽  
Author(s):  
Stephanie J Wehlage ◽  
Francine G Smith
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Arterial Baroreflex ◽  
Baroreflex Control ◽  
Before And After ◽  
Cardiovascular Homeostasis ◽  
New Evidence

To investigate the potential role of angiotensin II (Ang II) type 1 receptors (AT1Rs) as well as endogenously produced nitric oxide (NO) in regulating cardiovascular homeostasis during ontogeny, experiments were carried out in conscious lambs aged approximately 1 week ( N = 9) and 6 weeks ( N = 11). The arterial baroreflex control of heart rate (HR) was assessed before and after intravenous (IV) infusion of the selective AT1R antagonist, ZD 7155, before and after IV administration of the L-arginine analogue, NG-nitro-L-arginine methyl ester (L-NAME). In both groups, after ZD 7155 alone, mean arterial pressure decreased then increased after L-NAME. At 1 but not 6 weeks, HR decreased after ZD 7155 as well as after L-NAME. At 1 but not 6 weeks, there was a decrease in the HR range after ZD 7155 and after ZD 7155 + L-NAME, as compared to control. There was also a decrease in minimum HR after ZD 7155 + L-NAME at 1 week. These data provide new evidence that, together, Ang II and NO regulate cardiovascular homeostasis as well as the arterial baroreflex of HR early in life which may help to explain the activation of these two systems early in life.

Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide

2007 ◽  
Vol 292 (1) ◽  
pp. H83-H92 ◽  
Author(s):  
Armin Just ◽  
Andrea J. M. Olson ◽  
Christina L. Whitten ◽  
William J. Arendshorst
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Vascular Remodeling ◽  
Oxygen Species ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Adrenergic Agonist ◽  
Renal Vasoconstriction ◽  
Sprague Dawley Rats

NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved in vasoconstriction and vascular remodeling during hypertension produced by chronic angiotensin II (ANG II) infusion. These effects are thought to be mediated largely through superoxide anion (O2−) scavenging of nitric oxide (NO). Little is known about the role of ROS in acute vasoconstrictor responses to agonists. We investigated renal blood flow (RBF) reactivity to ANG II (4 ng), norepinephrine (NE, 20 ng), and α1-adrenergic agonist phenylephrine (PE, 200 ng) injected into the renal artery (ira) of anesthetized Sprague-Dawley rats. The NOX inhibitor apocynin (1–4 mg·kg−1·min−1 ira, 2 min) or the superoxide dismutase mimetic Tempol (1.5–5 mg·kg−1·min−1 ira, 2 min) rapidly increased resting RBF by 8 ± 1% ( P < 0.001) or 3 ± 1% ( P < 0.05), respectively. During NO synthase (NOS) inhibition ( Nω-nitro-l-arginine methyl ester, 25 mg/kg iv), the vasodilation tended to increase (apocynin 13 ± 4%, Tempol 10 ± 1%). During control conditions, both ANG II and NE reduced RBF by 24 ± 4%. Apocynin dose dependently reduced the constriction by up to 44% ( P < 0.05). Similarly, Tempol blocked the acute actions of ANG II and NE by up to 48–49% ( P < 0.05). In other animals, apocynin (4 mg·kg−1·min−1 ira) attenuated vasoconstriction to ANG II, NE, and PE by 46–62% ( P < 0.01). During NOS inhibition, apocynin reduced the reactivity to ANG II and NE by 60–72% ( P < 0.01), and Tempol reduced it by 58–66% ( P < 0.001). We conclude that NOX-derived ROS substantially contribute to basal RBF as well as to signaling of acute renal vasoconstrictor responses to ANG II, NE, and PE in normal rats. These effects are due to O2− rather than H2O2, occur rapidly, and are independent of scavenging of NO.

gp91phox-containing NAD(P)H oxidase mediates attenuation of nitric oxide-dependent control of myocardial oxygen consumption by ANG II

2005 ◽  
Vol 289 (2) ◽  
pp. H862-H867 ◽  
Author(s):  
Shintaro Kinugawa ◽  
Juhua Zhang ◽  
Eric Messina ◽  
Erin Walsh ◽  
Harer Huang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Myocardial Oxygen Consumption ◽  
Inflammatory Cells ◽  
Oxygen Electrode ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Stimulation Of

We have previously reported that ANG II stimulation increased superoxide anion (O2−) through the activation of NAD(P)H oxidase and inhibited nitric oxide (NO)-dependent control of myocardial oxygen consumption (MV̇o2) by scavenging NO. Our objective was to investigate the role of NAD(P)H oxidase, especially the gp91phox subunit, in the NO-dependent control of MV̇o2. MV̇o2 in mice with defects in the expression of gp91phox [gp91phox(−/−)] was measured with a Clark-type oxygen electrode. Baseline MV̇o2 was not significantly different between wild-type (WT) and gp91phox(−/−) mice. Stimulation of NO production by bradykinin (BK) induced significant decreases in MV̇o2 in WT mice. BK-induced reduction in MV̇o2 was enhanced in gp91phox(−/−) mice. BK-induced reduction in MV̇o2 in WT mice was attenuated by 10−8 mol/l ANG II, which was restored by coincubation with Tiron or apocynin. In contrast to WT mice, BK-induced reduction in MV̇o2 in gp91phox(−/−) mice was not altered by ANG II. There was a decrease in lucigenin (5 × 10−6 mol/l)-detectable O2− in gp91phox(−/−) mice compared with WT mice. ANG II resulted in significant increases in O2− production in WT mice, which was inhibited by coincubation with Tiron or apocynin. However, ANG II had no effect on O2− production in gp91phox(−/−) mice. Histological examination showed that the development of abscesses and/or the invasion of inflammatory cells occurred in lungs and livers but not in hearts and kidneys from gp91phox(−/−) mice. These results indicate that the gp91phox subunit of NAD(P)H oxidase mediates O2− production through the activation of NAD(P)H oxidase and attenuation of NO-dependent control of MV̇o2 by ANG II.

scholarly journals Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles

2006 ◽  
Vol 290 (4) ◽  
pp. F873-F879 ◽  
Author(s):  
Ming-Guo Feng ◽  
L. Gabriel Navar
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Concomitant Treatment ◽  
Ang Ii ◽  
No Donor ◽  
Afferent Arterioles ◽  
Nos Inhibitor ◽  
The Difference ◽  
Oxide Synthase

Previous studies have shown that L-type Ca2+ channel (LCC) blockers primarily dilate resting and ANG II-constricted afferent arterioles (AA), but do not influence either resting or ANG II-constricted efferent arterioles (EA). In contrast, blockade of T-type Ca2+ channels (TCC) dilate EA and prevent ANG II-mediated efferent constriction. The present study determined the role of LCC and TCC in mediating the AA and EA constriction following inhibition of nitric oxide synthase (NOS) and tested the hypothesis that inhibition of NOS increases the influence of LCC on EA. With the use of an isolated blood-perfused rat juxtamedullary nephron preparation, single AA or EA were visualized and superfused with a NOS inhibitor, N-nitro-l-arginine (l-NNA), with or without concomitant treatment with an LCC blocker, diltiazem, or a TCC blocker, pimozide. In response to l-NNA (1, 10, and 100 μmol/l), AA and EA diameters decreased significantly by 6.0 ± 0.3, 13.7 ± 1.7, and 19.9 ± 1.4%, and by 6.2 ± 0.5, 13.3 ± 1.1, and 19.0 ± 1.9%, respectively. During TCC blockade with pimozide (10 μmol/l), l-NNA did not significantly constrict afferent (0.9 ± 0.6, 1.5 ± 0.5, and 1.7 ± 0.5%) or efferent (0.4 ± 0.1, 2.1 ± 0.7, and 2.5 ± 1.0%) arterioles. In contrast to the responses with other vasoconstictors, the l-NNA-induced constriction of EA, as well as AA, was reversed by diltiazem (10 μmol/l). The effects were overlapping as pimozide superimposed on diltiazem did not elicit further dilation. When the effects of l-NNA were reversed by superfusion with an NO donor, SNAP (10 μmol/l), diltiazem did not cause significant efferent dilation. As a further test of LCC activity, 55 mmol/l KCl, which depolarizes and constricts AA, caused only a modest constriction in resting EA (8.7 ± 1.3%), but a stronger EA constriction during concurrent treatment with l-NNA (23.8 ± 4.8%). In contrast, norepinephrine caused similar constrictions in both l-NNA-treated and nontreated arterioles. These results provide evidence that NO inhibits LCC and TCC activity and that NOS inhibition-mediated arteriolar constriction involves activation of LCC and TCC in both AA and EA. The difference in responses to high KCl between resting and l-NNA-constricted EA and the ability of diltiazem to block EA constriction caused by l-NNA contrasts with the lack of efferent effects in resting and SNAP-treated l-NNA-preconstricted arterioles and during ANG II-mediated vasoconstriction, suggesting a recruitment of LCC in EA when NOS is inhibited. These data help explain how endothelial dysfunction associated with hypertension may lead to enhanced activity of LCC in postglomerular arterioles and increased postglomerular resistance.

scholarly journals Protective role of the endothelial isoform of nitric oxide synthase in ANG II-induced inflammatory responses in the kidney

2013 ◽  
Vol 305 (7) ◽  
pp. F1031-F1041 ◽  
Author(s):  
Curtis Whiting ◽  
Alexander Castillo ◽  
Mohammed Z. Haque ◽  
Dewan S. A. Majid
Keyword(s):  
Nitric Oxide ◽  
High Mortality ◽  
Renal Injury ◽  
Inflammatory Responses ◽  
Protective Role ◽  
Ang Ii ◽  
Wild Type ◽  
Tnf Α ◽  
Oxide Synthase

In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-α. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O2−) scavenger, tempol (400 mg/l in the drinking water), or a TNF-α receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Δ36 ± 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Δ24 ± 3 mmHg; n = 6). In KO mice ( n = 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (Δ17 ± 7 mmHg; n = 6) but exaggeratedly in KO (Δ48 ± 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol ( n = 6) or etanercept ( n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II.

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