Nitric oxide synthase inhibition accelerates the pressor response to low-dose angiotensin II, exacerbates target organ damage, and induces renin escape

We investigated whether or not Relaxin ameliorates the hypertension induced damage to heart and kidney. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). These rats develop moderately severe Hypertension but die of end-organ cardiac and renal damage by week 7. Untreated dTGRs had an around 50% mortality rate at 7 weeks. The heart shows necrosis and fibrosis, whereas the kidneys esemble the hemolytic-uremic syndrome vasculopathy. We started Relaxin-treatment on four weeks old dTGR in low (26 μg/kg/d) and high dose (240 μg/kg/d) and age-matched SD rats. Blood-pressure- and albuminuria-measurements were monitored during the treatment period (three weeks). Seven weeks old animals were killed, hearts and kidneys were isolated and used for histochemical and quantitative TaqMan RT-PCR analysis. Systolic blood pressure increased progressively in untreated dTGRs from 161.6 ± 3.02 mmHg in week 5 to 225.3 ± 4.48 mmHg in week 7. Relaxin treatment had no significant influence on blood pressure (low dose 208.0 ± 5.51 mmHg and high dose 222.2 ± 5.60 mmHg at week 7 ) whereas SD rats were normotensive (106.3 ± 1.15 mmHg). Untreated (5.38 ± 0.13 mg/g) and Relaxin treated dTGRs (low dose 5.20 ± 0.18 mg/g and high dose 5.33 ± 0.29 mg/g) had similar cardiac hypertrophy indices (heart-to-body weight ratio), which were significantly higher compared with nontransgenic SD rats (2.90 ± 0.08 mg/g). BNP and CTFG mRNA expression in the hearts was significant higher in untreated dTGRs compared to SD rats. There were no differences in BNP and CTFG expression between untreated and Relaxin treated dTGRs. Relaxin treatment (low dose 78502 ± 16848 μg/day and high dose 43642 ± 10852 μg/day at week 7) did not ameliorate albuminuria compared with untreated dTGRs (57937 ± 6122 μg/day at week 7). Furthermore the treatment with Relaxin did not prevent matrix deposition in the heart and kidney of d TGRs. Finally, Relaxin treatment did not reduce mortality. Although survival was 52 %, in untreated dTGRs 36 % in low dose and 54 % high dose Relaxin treated dTGRs at week 7. These data demonstrate that Relaxin did not improve angiotensin II-induced target organ damage.

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AUGMENTATION OF THE PRESSOR RESPONSE TO ANGIOTENSIN II AFTER NITRIC OXIDE SYNTHASE INHIBITION IN MAN

Journal of Hypertension ◽

10.1097/00004872-200406002-00665 ◽

2004 ◽

Vol 22 (Suppl. 2) ◽

pp. S192

Author(s):

N. A.J. van der Linde ◽

F. Boomsma ◽

A. H. van den Meiracker

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Pressor Response ◽

Oxide Synthase

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Angiopoietin-1 Gene Therapy Attenuates Hypertension and Target Organ Damage in Nitric Oxide Synthase Inhibited Spontaneously Hypertensive Rats

Korean Circulation Journal ◽

10.4070/kcj.2011.41.10.590 ◽

2011 ◽

Vol 41 (10) ◽

pp. 590 ◽

Cited By ~ 4

Author(s):

Wonhee Suh ◽

Jung-Sun Lee ◽

Koung Li Kim ◽

Sun-Hwa Song ◽

Gou Young Koh ◽

...

Keyword(s):

Nitric Oxide ◽

Gene Therapy ◽

Spontaneously Hypertensive Rats ◽

Target Organ Damage ◽

Organ Damage ◽

Target Organ ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Oxide Synthase ◽

Angiopoietin 1

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Angiotensin II is involved in nitric oxide synthase and cyclo-oxygenase inhibition-induced leukocyte-endothelialcell interactions in vivo

British Journal of Pharmacology ◽

10.1038/sj.bjp.0703867 ◽

2001 ◽

Vol 132 (3) ◽

pp. 677-684 ◽

Cited By ~ 14

Author(s):

Angeles Alvarez ◽

Laura Piqueras ◽

Regina Bello ◽

Amparo Canet ◽

Lucrecia Moreno ◽

...

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Oxide Synthase

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Inflammatory Monocytes Determine Endothelial Nitric-oxide Synthase Uncoupling and Nitro-oxidative Stress Induced by Angiotensin II

Journal of Biological Chemistry ◽

10.1074/jbc.m114.604231 ◽

2014 ◽

Vol 289 (40) ◽

pp. 27540-27550 ◽

Cited By ~ 70

Author(s):

Sabine Kossmann ◽

Hanhan Hu ◽

Sebastian Steven ◽

Tanja Schönfelder ◽

Daniela Fraccarollo ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Inflammatory Monocytes ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

Infection and Immunity ◽

10.1128/iai.68.12.6879-6882.2000 ◽

2000 ◽

Vol 68 (12) ◽

pp. 6879-6882 ◽

Cited By ~ 105

Author(s):

Andrea M. Cooper ◽

John E. Pearl ◽

Jason V. Brooks ◽

Stefan Ehlers ◽

Ian M. Orme

Keyword(s):

Nitric Oxide ◽

Mycobacterium Tuberculosis ◽

Nitric Oxide Synthase ◽

Low Dose ◽

Interleukin 12 ◽

Infection Model ◽

Rapid Progression ◽

Ifn Γ ◽

Nitric Oxide Synthase 2 ◽

Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

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Angiotensin II causes nitric oxide synthase 3 uncoupling in the thick ascending limb

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.lb807 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Katherine Massey ◽

Jagannath J. Saikumar ◽

Mark D. Faber ◽

Jerry J. Yee ◽

Jeffrey L. Garvin

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Thick Ascending Limb ◽

Nitric Oxide Synthase 3 ◽

Oxide Synthase

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Angiotensin II and nitric oxide in neural control of intrarenal blood flow

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00477.2004 ◽

2005 ◽

Vol 289 (3) ◽

pp. R745-R754 ◽

Cited By ~ 16

Author(s):

Niwanthi W. Rajapakse ◽

Amanda K. Sampson ◽

Gabriela A. Eppel ◽

Roger G. Evans

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Angiotensin Ii ◽

Nitric Oxide Synthase ◽

Neural Control ◽

Renin Angiotensin System ◽

Renal Medulla ◽

Renal Nerve ◽

Intrarenal Blood Flow ◽

Oxide Synthase

We investigated the roles of the renin-angiotensin system and the significance of interactions between angiotensin II and nitric oxide, in responses of regional kidney perfusion to electrical renal nerve stimulation (RNS) in pentobarbital sodium-anesthetized rabbits. Under control conditions, RNS (0.5–8 Hz) reduced total renal blood flow (RBF; −89 ± 3% at 8 Hz) and cortical perfusion (CBF; −90 ± 2% at 8 Hz) more than medullary perfusion (MBF; −55 ± 5% at 8 Hz). Angiotensin II type 1 (AT1)-receptor antagonism (candesartan) blunted RNS-induced reductions in RBF ( P = 0.03), CBF ( P = 0.007), and MBF ( P = 0.04), particularly at 4 and 8 Hz. Nitric oxide synthase inhibition with NG-nitro-l-arginine (l-NNA) enhanced RBF ( P = 0.003), CBF ( P = 0.001), and MBF ( P = 0.03) responses to RNS, particularly at frequencies of 2 Hz and less. After candesartan pretreatment, l-NNA significantly enhanced RNS-induced reductions in RBF ( P = 0.04) and CBF ( P = 0.007) but not MBF ( P = 0.66). Renal arterial infusion of angiotensin II (5 ng·kg−1·min−1) selectively enhanced responses of MBF to RNS in l-NNA-pretreated but not in vehicle-pretreated rabbits. In contrast, greater doses of angiotensin II (5–15 ng·kg−1·min−1) blunted responses of MBF to RNS in rabbits with intact nitric oxide synthase. These results suggest that endogenous angiotensin II enhances, whereas nitric oxide blunts, neurally mediated vasoconstriction in the renal cortical and medullary circulations. In the renal medulla, but not the cortex, angiotensin II also appears to be able to blunt neurally mediated vasoconstriction.

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