Pressure Natriuresis in AT2 Receptor–Deficient Mice with L-NAME Hypertension

Obst, Michael; Groß, Volkmar; Janke, Jürgen; Wellner, Maren; Schneider, Wolfgang; Luft, Friedrich C.

doi:10.1097/01.asn.0000043904.26730.11

Cited by 27 publications

(18 citation statements)

References 42 publications

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“…Consistent with our present findings, Chatziantoniou et al (7) found that in mice, chronic L-NAME treatment produced a gradual increase in arterial pressure (measured by tail cuff) over a period of 14 wk. Other studies have also demonstrated pressor responses to L-NAME, administered via the drinking water, of comparable magnitude to that which we observed in the present study (2,29,30,32). The fact that MAP was lower in mice treated chronically with L-NAME than in eNOS Ϫ/Ϫ mice may reflect incomplete blockade of NOS by this oral L-NAME treatment.…”

Section: Discussionsupporting

confidence: 87%

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Fitzgerald

Kemp-Harper²,

Parkington³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Fitzgerald SM, Kemp-Harper BK, Parkington HC, Head GA, Evans RG. Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endotheliumderived hyperpolarizing factor. Am J Physiol Regul Integr Comp Physiol 293: R707-R713, 2007. First published May 23, 2007; doi:10.1152/ajpregu.00807.2006.-We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of N -nitro-L-arginine methyl ester (L-NAME; 100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water; 97 Ϯ 3 mmHg) than after vehicle treatment (88 Ϯ 3 mmHg). MAP was also elevated in eNOS null mice (113 Ϯ 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in L-NAME-treated mice (108 Ϯ 5 mmHg) but not in vehicle-treated mice (88 Ϯ 3 mmHg) nor eNOS null mice (104 Ϯ 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic L-NAME or induction of diabetes but was reduced by 42 Ϯ 6% in L-NAMEtreated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholineinduced vasorelaxation were altered; the EDHF component was enhanced by L-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during earlystage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production. diabetes; endothelial function; endothelial nitric oxide synthase; mice IT IS CLEAR THAT DYSFUNCTION of endothelium-dependent vasodilation contributes to the pathogenesis of vascular diabetic complications (36). Endothelium-dependent vasodilation is mediated by multiple factors, including nitric oxide (NO), vasodilator prostanoids such as prostacyclin, and the so called endothelium-derived hyperpolarizing factor (EDHF) (36). To complicate matters further, EDHF appears to be not a unique substance but a range of factors whose contribution to endothelium-dependent vasodilation differs between various organs and species (5,12,13,16,21). Importantly, the relative contributions of dysfunction of these various endotheliumdependent relaxing factors to vascular diabetic complications remain a matter of intense debate (8,16,37).While in established diabetes reduced NO synthesis and enhanced NO breakdown likely make an important contribution to endothelium-dependent vasodilator dysfunction (36), there is also evidence t...

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Section: Discussionsupporting

confidence: 87%

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Fitzgerald

Kemp-Harper²,

Parkington³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Baseline values of GFR in KO mice were not significantly different from those in WT mice as reported previously (13). The inhibition of NOS was also reported to have none or minimal effect on GFR in many studies (6,19,23,24,29,36). These findings are consistent with the concept that NO exerts a proportionate influence on both preglomerular and postglomerular resistance segments (28).…”

Section: Discussionsupporting

confidence: 71%

Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91^phoxsubunit of NAD(P)H oxidase

Haque¹,

Majid²

2008

American Journal of Physiology-Renal Physiology

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Ϫ activity in the kidney, responses to administration of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 200 g ⅐ min Ϫ1 ⅐ kg body wt Ϫ1 ) were assessed in knockout mice the lacking NAD(P)H oxidase subunit gp91 phox (KO; n ϭ 10) and in wild-type (WT; n ϭ 10) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances, respectively. Baseline RBF was higher in KO compared with WT mice (5.8 Ϯ 0.5 vs. 4.5 Ϯ 0.3 ml ⅐ min Ϫ1 ⅐ g Ϫ1 ; P Ͻ 0.04) without significant differences in GFR (0.62 Ϯ 0.04 vs. 0.73 Ϯ 0.05 ml ⅐ min Ϫ1 ⅐ g Ϫ1 ) and in mean arterial pressure (MAP; 91 Ϯ 6 vs. 88 Ϯ 4 mmHg). L-NAME infusion for 60 min caused similar increases in MAP (114 Ϯ 6 vs. 113 Ϯ 3 mmHg) in both groups but resulted in a lesser degree of reduction in RBF in KO compared with WT mice (Ϫ7 Ϯ 3 vs. Ϫ17 Ϯ 3%; P Ͻ 0.02), although GFR remained unchanged in both groups. The natriuretic response to systemic L-NAME infusion was attenuated in KO compared with WT mice (⌬: 3.1 Ϯ 0.7 vs. 5.2 Ϯ 0.6 mol ⅐ min Ϫ1 ⅐ g Ϫ1 ). L-NAME increased urinary 8-isoprostane excretion rate in WT (5.9 Ϯ 1 to 7.7 Ϯ 1 pg ⅐ min Ϫ1 ⅐ g Ϫ1 ; P Ͻ 0.02) but not in KO mice (5.6 Ϯ 1 to 4.9 Ϯ 0.3 pg ⅐ min Ϫ1 ⅐ g Ϫ1 ). In contrast, responses to another vasoconstrictor, norepinephrine, were similar in both strains of mice. These data indicate that activation of NAD(P)H oxidase results in the enhancement of O 2 Ϫ activity that influences renal hemodynamics and excretory function in the condition of NO deficiency. superoxide; oxidative stress; renal blood flow; sodium excretion; 8-isoprostane excretion CURRENT LITERATURE REVEALS an increasing recognition that the interaction between nitric oxide (NO) and superoxide (O 2 Ϫ ) plays an important role in the physiology as well as in the pathophysiology of kidney function and in hypertension (8,19,(23)(24)(25)42). Most of the evidence suggests that there is a balance between the production of NO and O 2 Ϫ that regulates the body function by opposing each other's action. It was demonstrated in vitro that O 2 Ϫ production was increased during NO inhibition in an isolated aortic strip (11). Enhancement of O 2 Ϫ activity by inhibiting SOD enzymes has been shown to decrease renal blood flow (RBF) and sodium excretion (U Na V; Refs. 8,19,20,24,26), and these responses to SOD inhibition were markedly enhanced during inhibition of the NO synthase (NOS) enzyme (20,24,25

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“…It may be that overexpression of AT 2 -R protects against the hypertensive effect of L-NAME as a previous study demonstrated that AT 2 -R null mice demonstrated significantly greater blood pressure response to L-NAME than WT controls. 26 …”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling

et al. 2004

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Abstract-We hypothesized that nitric oxide (NO) mediates the benefits of cardiac angiotensin II type 2 (AT 2 -R) overexpression during postmyocardial infarction (post-MI) remodeling. Eleven wild-type (WT) C57BL/6 mice and 28 transgenic (TG) mice with AT 2 -R overexpression were studied by cardiac magnetic resonance imaging (CMR) at baseline and days 1 and 28 post-MI induced by left anterior descending artery occlusion and reperfusion. Sixteen TG mice were treated from day 1 through 28 post-MI with the NO synthase inhibitor N G -nitro-L-arginine methyl ester in drinking water at 1 mg/mL (TG-Rx). Left ventricular mass index (LVMI), end-diastolic volume index (EDVI) and end-systolic volume index (ESVI), wall thickness, percent thickening, and ejection fraction (EF) were measured. Infarct size on day 1 was assessed by post-contrast CMR. Interstitial collagen was quantified in noninfarcted regions. At baseline, heart rate (HR), blood pressure (BP), LVMI, EDVI, and ESVI were similar between groups, as were infarct size and weekly post-MI HR and systolic BP. By day 28 post-MI, EDVI and ESVI were similar in WT and TG-Rx, but significantly lower in TG (ESVI: 1.41Ϯ0.18 L/g versus 2.53Ϯ0.14 L/g in WT; 2.17Ϯ0.14 L/g in TG-Rx; PϽ0.008 for both). At day 28, EF was higher in TG (46.3%Ϯ2.9%) compared with WT and TG-Rx (32.7Ϯ2.3% and 33.7Ϯ2.3, respectively; PϽ0.003 for both). Wall thickening at day 28 post-MI was greater in the base and mid-LV in TG than WT and TG-Rx. Noninfarcted region interstitial collagen was similar between groups. Thus, the NO pathway may mediate much of the benefits of cardiac AT 2 -R overexpression during post-MI remodeling. . 1 However, the role of the angiotensin II type 2 receptor (AT 2 -R) in left ventricular (LV) remodeling in disease states is an area of active investigation. [2][3][4][5][6] In fact, many of the beneficial effects of AT 1 -R blockade postmyocardial infarction (post-MI) or of angiotensin-converting enzyme (ACE) inhibitors may be mediated by Ang II stimulation of the AT 2 -R. 7,8 We have previously demonstrated that AT 2 -R overexpression in the mouse heart preserves LV size and function during post-MI remodeling. 9 The transgenic mice (TG) demonstrated preserved LV cavity size, wall thickness within the infarct zone, and regional and global LV function during post-MI remodeling compared with wild-type controls (WT). Others have shown that deletion of the AT 2 -R is detrimental post-MI, leading to myocardial rupture, 10 heart failure, and increased mortality. 10,11 Studies in vascular smooth muscle and the kidney suggest that the benefits of AT 2 -R stimulation may be through signaling pathways involving the kinin and nitric oxide (NO) system 12 AT 2 -R-mediated increases in cGMP caused by bradykinin and NO have been demonstrated in studies of the aorta and kidney, 13,14 and blood pressure-lowering effects of AT 1 -R blockade involve AT 2 -R-mediated release of renal bradykinin and NO production. 15 Recently, Ang II stimulation of the AT 2 -R in the TG model of cardiac overexpression...

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Pressure Natriuresis in AT2 Receptor–Deficient Mice with L-NAME Hypertension

Cited by 27 publications

References 42 publications

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91^phoxsubunit of NAD(P)H oxidase

Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling

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Pressure Natriuresis in AT2 Receptor–Deficient Mice with L-NAME Hypertension

Cited by 27 publications

References 42 publications

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91phoxsubunit of NAD(P)H oxidase

Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling

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Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91^phoxsubunit of NAD(P)H oxidase