Renal medullary nitric oxide deficit of Dahl S rats enhances hypertensive actions of angiotensin II

2002 ◽  
Vol 283 (1) ◽  
pp. R266-R272 ◽  
Author(s):  
Mátyás Szentiványi ◽  
Ai-Ping Zou ◽  
David L. Mattson ◽  
Paulo Soares ◽  
Carol Moreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Intravenous Infusion ◽  
Renal Medulla ◽  
Brown Norway ◽  
Ang Ii ◽  
Outer Medulla ◽  
Doppler Flowmetry ◽  
Medullary Blood Flow ◽  
Induced Hypertension ◽  
Renal Medullary Blood Flow

Studies were designed to examine the hypothesis that the renal medulla of Dahl salt-sensitive (Dahl S) rats has a reduced capacity to generate nitric oxide (NO), which diminishes the ability to buffer against the chronic hypertensive effects of small elevations of circulating ANG II. NO synthase (NOS) activity in the outer medulla of Dahl S rats (arginine-citrulline conversion assay) was significantly reduced. This decrease in NOS activity was associated with the downregulation of protein expression of NOS I, NOS II, and NOS III isoforms in this region as determined by Western blot analysis. In anesthetized Dahl S rats, we observed that a low subpressor intravenous infusion of ANG II (5 ng · kg−1 · min−1) did not increase the concentration of NO in the renal medulla as measured by a microdialysis with oxyhemoglobin trapping technique. In contrast, ANG II produced a 38% increase in the concentration of NO (87 ± 8 to 117 ± 8 nmol/l) in the outer medulla of Brown-Norway (BN) rats. The same intravenous dose of ANG II reduced renal medullary blood flow as determined by laser-Doppler flowmetry in Dahl S, but not in BN rats. A 7-day intravenous ANG II infusion at a dose of 3 ng · kg−1 · min−1 did not change mean arterial pressure (MAP) in the BN rats but increased MAP in Dahl S rats from 120 ± 2 to 138 ± 2 mmHg ( P< 0.05). ANG II failed to increase MAP after NO substrate was provided by infusion of l-arginine (300 μg · kg−1 · min−1) into the renal medulla of Dahl S rats. Intravenous infusion ofl-arginine at the same dose had no effect on the ANG II-induced hypertension. These results indicate that an impaired NO counterregulatory system in the outer medulla of Dahl S rats makes them more susceptible to the hypertensive actions of small elevations of ANG II.

Renal medullary interstitial infusion ofl-arginine prevents hypertension in Dahl salt-sensitive rats

1998 ◽  
Vol 275 (5) ◽  
pp. R1667-R1673 ◽  
Author(s):  
Noriyuki Miyata ◽  
Ai Ping Zou ◽  
David L. Mattson ◽  
Allen W. Cowley
Keyword(s):  
Blood Flow ◽  
Control Period ◽  
Renal Medulla ◽  
High Salt ◽  
No Production ◽  
Medullary Blood Flow ◽  
Induced Hypertension ◽  
Renal Medullary Blood Flow ◽  
Wistar Kyoto ◽  
Interstitial Infusion

Studies were designed to examine the effects of renal medullary interstitial infusion of l-arginine (l-Arg) on the development of high-salt-induced hypertension in Dahl salt-sensitive/Rapp (DS) rats. The threshold dose of l-Arg (300 μg ⋅ kg−1 ⋅ min−1) that increased the renal medullary blood flow without altering the cortical blood flow was first determined in anesthetized DS rats. Studies were then carried out to determine the effects of this dose ofl-Arg on salt-induced hypertension in DS rats. In the absence of chronic medullaryl-Arg infusion, mean arterial pressure (MAP) increased in DS rats from 125 ± 2 to 167 ± 5 mmHg by day 5 of a high-salt diet (4.0%), with no change observed in Wistar-Kyoto (WKY) or Dahl salt-resistant/Rapp (DR) rats. MAP did not change significantly with medullary infusion ofl-Arg alone in DR rats (control = 104 ± 1 mmHg) or in WKY rats (control = 120 ± 3 mmHg) and was not significantly changed from these levels during the 7 days ofl-Arg infusion combined with high-NaCl diet. The same amount of l-Arg that prevented salt-induced hypertension in DS rats when infused into the renal medulla (300 μg ⋅ kg−1 ⋅ min−1) failed to blunt salt-induced hypertension when administered intravenously to DS rats. DS rats receiving l-Arg (300 μg ⋅ kg−1 ⋅ min−1iv) exhibited an increase in plasma l-Arg from control concentrations of 138 ± 11 to 218 ± 4 μmol/l, while MAP, which averaged 124 ± 3 mmHg during the 3-day control period, rose to 165 ± 5 mmHg by day 5of high salt (4%) intake. These results indicate that the prevention of salt sensitivity in DS rats was due specifically to the action of l-Arg on renal medullary function and that DS rats may have a deficit of medullary substrate availability and NO production.

Abnormal renal medullary response to angiotensin II in SHR is corrected by long-term enalapril treatment

2001 ◽  
Vol 280 (4) ◽  
pp. R1076-R1084 ◽  
Author(s):  
Stephen A. W. Dukacz ◽  
Ming-Guo Feng ◽  
Lu-Fang Yang ◽  
Robert M. K. W. Lee ◽  
Robert L. Kline
Keyword(s):  
Renal Medulla ◽  
Term Treatment ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Long Term Treatment ◽  
Renal Medullary Blood Flow ◽  
Wistar Kyoto

This study tested the hypotheses that renal medullary blood flow (MBF) in spontaneously hypertensive rats (SHR) has enhanced responsiveness to angiotensin (ANG) II and that long-term treatment with enalapril can correct this. MBF, measured by laser Doppler flowmetry in anesthetized rats, was not altered significantly by ANG II in Wistar-Kyoto (WKY) rats, but was reduced dose dependently (25% at 50 ng · kg−1 · min−1) in SHR. Infusion of N G-nitro-l-arginine methyl ester (l-NAME) into the renal medulla unmasked ANG II sensitivity in WKY rats while l-arginine given into the renal medulla abolished the responses to ANG II in SHR. In 18- to 19-wk-old SHR treated with enalapril (25 mg · kg−1 · day−1 when 4 to 14 wk old), ANG II did not alter MBF significantly, but sensitivity to ANG II was unmasked after l-NAME was infused into the renal medulla. Endothelium-dependent vasodilation (assessed with aortic rings) was significantly greater in treated SHR when compared with that in control SHR. These results indicate that MBF in SHR is sensitive to low-dose ANG II and suggest that this effect may be due to an impaired counterregulatory effect of nitric oxide. Long-term treatment with enalapril improves endothelium-dependent vascular relaxation and decreases the sensitivity of MBF to ANG II. These effects may be causally related to the persistent antihypertensive action of enalapril in SHR.

Gene expression reveals vulnerability to oxidative stress and interstitial fibrosis of renal outer medulla to nonhypertensive elevations of ANG II

2003 ◽  
Vol 284 (5) ◽  
pp. R1219-R1230 ◽  
Author(s):  
Baozhi Yuan ◽  
Mingyu Liang ◽  
Zhizhang Yang ◽  
Elizabeth Rute ◽  
Norman Taylor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Control Period ◽  
Renal Medulla ◽  
Differentially Expressed ◽  
Ang Ii ◽  
Outer Medulla ◽  
Renal Outer Medulla

The present study was designed to determine whether nonhypertensive elevations of plasma ANG II would modify the expression of genes involved in renal injury that could influence oxidative stress and extracellular matrix formation in the renal medulla using microarray, Northern, and Western blot techniques. Sprague-Dawley rats were infused intravenously with either ANG II (5 ng · kg−1 · min−1) or vehicle for 7 days ( n = 6/group). Mean arterial pressure averaged 110 ± 0.6 mmHg during the control period and 113 ± 0.4 mmHg after ANG II. The mRNA of 1,751 genes (∼80% of all currently known rat genes) that was differentially expressed (ANG II vs. saline) in renal outer and inner medulla was determined. The results of 12 hybridizations indicated that in response to ANG II, 11 genes were upregulated and 25 were downregulated in the outer medulla, while 11 were upregulated and 13 were downregulated in the inner medulla. These differentially expressed genes, most of which were not known previously to be affected by ANG II in the renal medulla, were found to group into eight physiological pathways known to influence renal injury and kidney function. Particularly, expression of several genes would be expected to increase oxidative stress and interstitial fibrosis in the outer medulla. Western blot analyses confirmed increased expression of transforming growth factor-β1 and collagen type IV proteins in the outer medulla. Results demonstrate that nonhypertensive elevations of plasma ANG II can significantly alter the expression of a variety of genes in the renal outer medulla and suggested the vulnerability of the renal outer medulla to the injurious effect of ANG II.

Role of renal medullary adenosine in the control of blood flow and sodium excretion

1999 ◽  
Vol 276 (3) ◽  
pp. R790-R798 ◽  
Author(s):  
Ai-Ping Zou ◽  
Kasem Nithipatikom ◽  
Pin-Lan Li ◽  
Allen W. Cowley
Keyword(s):  
Blood Flow ◽  
Sodium Excretion ◽  
Renal Medulla ◽  
Urine Flow ◽  
Doppler Flowmetry ◽  
Blood Flows ◽  
Medullary Blood Flow ◽  
Adenosine Concentration ◽  
Interstitial Infusion

This study determined the levels of adenosine in the renal medullary interstitium using microdialysis and fluorescence HPLC techniques and examined the role of endogenous adenosine in the control of medullary blood flow and sodium excretion by infusing the specific adenosine receptor antagonists or agonists into the renal medulla of anesthetized Sprague-Dawley rats. Renal cortical and medullary blood flows were measured using laser-Doppler flowmetry. Analysis of microdialyzed samples showed that the adenosine concentration in the renal medullary interstitial dialysate averaged 212 ± 5.2 nM, which was significantly higher than 55.6 ± 5.3 nM in the renal cortex ( n = 9). Renal medullary interstitial infusion of a selective A1antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 300 pmol ⋅ kg−1 ⋅ min−1, n = 8), did not alter renal blood flows, but increased urine flow by 37% and sodium excretion by 42%. In contrast, renal medullary infusion of the selective A2 receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX; 150 pmol ⋅ kg−1 ⋅ min−1, n = 9) decreased outer medullary blood flow (OMBF) by 28%, inner medullary blood flows (IMBF) by 21%, and sodium excretion by 35%. Renal medullary interstitial infusion of adenosine produced a dose-dependent increase in OMBF, IMBF, urine flow, and sodium excretion at doses from 3 to 300 pmol ⋅ kg−1 ⋅ min−1( n = 7). These effects of adenosine were markedly attenuated by the pretreatment of DMPX, but unaltered by DPCPX. Infusion of a selective A3receptor agonist, N 6-benzyl-5′-( N-ethylcarbonxamido)adenosine (300 pmol ⋅ kg−1 ⋅ min−1, n = 6) into the renal medulla had no effect on medullary blood flows or renal function. Glomerular filtration rate and arterial pressure were not changed by medullary infusion of any drugs. Our results indicate that endogenous medullary adenosine at physiological concentrations serves to dilate medullary vessels via A2 receptors, resulting in a natriuretic response that overrides the tubular A1 receptor-mediated antinatriuretic effects.

Evidence That Reduced Renal Medullary NOS Activity of Dahl S Rats Enables Small Elevations of Avp to Produce Sustained Hypertension

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 682-682
Author(s):  
Baozhi Yuan ◽  
Allen W Cowley
Keyword(s):  
Nitric Oxide ◽  
Control Level ◽  
Renal Medulla ◽  
Renal Tissue ◽  
Brown Norway ◽  
Experimental Hypertension ◽  
Chronic Hypertension ◽  
No Production ◽  
Potent Vasoconstrictor ◽  
Plasma Arginine

27 It remains unclear why sustained elevations of plasma arginine vasopressin (AVP), a potent vasoconstrictor and fluid retaining hormone, do not generally result in hypertension. Related to this, there have been 4 general observations: 1) AVP is elevated in many forms of human and experimental hypertension, including Dahl S rats; 2) AVP can stimulate nitric oxide synthases (NOS) and nitric oxide (NO) production in the renal medulla of normal rats; 3) AVP stimulated NO production can buffer AVP induced reductions of medullary blood flow; 4) partial reduction of medullary NOS activity (via medullary L-NAME infusion) unmasks chronic hypertensive effects of small elevations of plasma AVP (Hypertension. 2000; 35:740-745). In the present study, we hypothesize that Dahl salt-sensitive rats (DS) have reduced capacity to synthesize medullary NO which sensitizes them to the hypertensive effects of small elevations of circulating AVP. DS and Brown Norway (BN) rats with implanted arterial and venous catheters were fed a 0.4% salt diet and infused continuously for 14 days with a chronic “subpressor” dose of AVP (2 ng/kg/min). Conscious mean arterial pressure (MAP) was measured 2 hours daily with rats maintained in their home cages. MAP in DS rats increased during day1 of AVP infusion from a control level of 127 ± 0.9 mmHg to an average of 147 ± 1.6 mmHg after 14 days. MAP did not return to control values even within three days following the end of AVP infusion. BN rats showed no changes of MAP during 14 days of AVP infusion (90.4 ± 0.6 mmHg and 92.3 ± 0.4 mmHg). Northern blot analysis of renal tissue from vehicle (saline) infused rats demonstrated that NOS I and NOS III mRNA expression was significantly less in DS rats in the renal outer medulla compared to BN rats. We conclude that small, normally subpressor elevations of plasma AVP can produce chronic hypertension in DS rats, a phenomenon probably related to reduced renal medullary NO synthesis.

Medullary blood flow responses to changes in arterial pressure in canine kidney

1996 ◽  
Vol 270 (5) ◽  
pp. F833-F838 ◽  
Author(s):  
D. S. Majid ◽  
L. G. Navar
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Renal Medulla ◽  
Doppler Flowmetry ◽  
Cortical Blood Flow ◽  
Surface Probe ◽  
Medullary Blood Flow ◽  
Needle Probe ◽  
Anesthetized Dogs ◽  
Electromagnetic Flow Probe

Although it is well recognized that whole kidney and cortical blood flow exhibit efficient autoregulation in response to alterations in renal arterial pressure (RAP), the autoregulatory behavior of medullary blood flow (MBF) has remained uncertain. We have evaluated MBF responses to stepwise reductions in RAP for both short-term (2 min, n = 6) and longer periods (15 min, n = 7) using single-fiber laser-Doppler flowmetry with needle probes inserted into the mid-medullary region in denervated kidneys of 13 anesthetized dogs. The changes in cortical blood flow (CBF) were assessed with either a surface probe or a needle probe inserted into the cortex. Control total renal blood flow (RBF), assessed by electromagnetic flow probe in these dogs, was 5.2 +/- 0.3 ml.min-1.g-1, and glomerular filtration rate was 0.97 +/- 0.05 ml.min-1.g-1 (n = 7). RBF, MBF, and CBF all exhibited efficient autoregulatory behavior during changes in RAP from 150 to 75 mmHg. The slopes of RAP vs. RBF, CBF, as well as MBF, were not significantly different from zero within this range of RAP. Below RAP of 75 mmHg, all indexes of blood flow showed linear decreases with reductions in pressure. The data indicate that blood flow in the renal medulla of dogs exhibits efficient autoregulatory behavior, similar to that in the cortex.

scholarly journals Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

2015 ◽  
Vol 308 (3) ◽  
pp. F179-F197 ◽  
Author(s):  
Allen W. Cowley ◽  
Michiaki Abe ◽  
Takefumi Mori ◽  
Paul M. O'Connor ◽  
Yusuke Ohsaki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Blood Flow ◽  
Reactive Oxygen ◽  
Selective Reduction ◽  
Renal Medulla ◽  
Thick Ascending Limb ◽  
Oxygen Species ◽  
Medullary Blood Flow

The physiological evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na+ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.

Renal medullary blood flow: its measurement and physiology

1986 ◽  
Vol 64 (7) ◽  
pp. 873-880 ◽  
Author(s):  
W. A. Cupples
Keyword(s):  
Blood Flow ◽  
Renal Medulla ◽  
Vascular Bundles ◽  
Medullary Blood Flow ◽  
Vasa Recta ◽  
Countercurrent Exchange ◽  
Renal Medullary Blood Flow ◽  
Urinary Concentrating Ability ◽  
Velocity Tracking ◽  
Uptake Method

The vasculature of the mammalian renal medulla is complex, having neither discrete input nor output. There is also efficient countercurrent exchange between ascending and descending vasa recta in the vascular bundles. These considerations have hampered measurement of medullary blood flow since they impose pronounced constraints on methods used to assess flow. Three main strategies have been used: (i) indicator extraction; (ii) erythrocyte velocity tracking; and (iii) indicator dilution. These are discussed with respect to their assumptions, requirements, and limitations. There is a consensus that medullary blood flow is autoregulated, albeit over a narrower pressure range than is total renal blood flow. When normalized to gram tissue weight, medullary blood flow in the dog is similar to that in the rat, on the order of 1 to 1.5 mL∙min−1∙g−1. This is considerably greater than estimated by the radioiodinated albumin uptake method which has severe conceptual and practical problems. From both theoretical and experimental evidence it ssems that urinary concentrating ability is considerably less sensitive to changes in medullary blood flow than is often assumed.

scholarly journals Asymmetric dimethylarginine in angiotensin II-induced hypertension

2010 ◽  
Vol 298 (3) ◽  
pp. R740-R746 ◽  
Author(s):  
Jennifer M. Sasser ◽  
Natasha C. Moningka ◽  
Mark W. Cunningham ◽  
Byron Croker ◽  
Chris Baylis
Keyword(s):  
Nitric Oxide ◽  
Renal Injury ◽  
Asymmetric Dimethylarginine ◽  
Renal Cortex ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Plasma Adma ◽  
Induced Hypertension

Recent studies have shown that asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in hypertension and chronic kidney disease. However, little is known about the effects of hypertension per se on ADMA metabolism. The purpose of this study was to test the hypothesis that ANG II-induced hypertension, in the absence of renal injury, is associated with increased oxidative stress and plasma and renal cortex ADMA levels in rats. Male Sprague-Dawley rats were treated with ANG II at 200 ng·kg−1·min−1 sc (by minipump) for 1 or 3 wk or at 400 ng·kg−1·min−1 for 6 wk. Mean arterial pressure was increased after 3 and 6 wk of ANG II; however, renal injury (proteinuria, glomerular sclerosis, and interstitial fibrosis) was only evident after 6 wk of treatment. Plasma thiobarbituric acid reactive substances concentration and renal cortex p22phox protein abundance were increased early (1 and 3 wk), but urinary excretion of isoprostane and H2O2 was only increased after 6 wk of ANG II. An increased in plasma ADMA after 6 wk of ANG II was associated with increased lung protein arginine methyltransferase-1 abundance and decreased renal cortex dimethylarginine dimethylaminohydrolase activity. No changes in renal cortex ADMA were observed. ANG II hypertension in the absence of renal injury is not associated with increased ADMA; however, when the severity and duration of the treatment were increased, plasma ADMA increased. These data suggest that elevated blood pressure alone, for up to 3 wk, in the absence of renal injury does not play an important role in the regulation of ADMA. However, the presence of renal injury and sustained hypertension for 6 wk increases ADMA levels and contributes to nitric oxide deficiency and cardiovascular disease.

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