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.

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.

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 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.

Abstract P166: The Effects of V2 Receptor Antagonist Treatment on the Renal Medullary Circulation and Urinary Sodium Excretion in Rat

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Yusuke Ohsaki ◽  
Takefumi Mori ◽  
Kento Akao ◽  
Yoshimi Nakamichi ◽  
Chika Takahashi ◽  
...  
Keyword(s):  
Blood Flow ◽  
Urine Volume ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Sodium Reabsorption ◽  
No Production ◽  
Doppler Flowmetry ◽  
Medullary Blood Flow ◽  
V2 Receptor ◽  
Renal Medullary Blood Flow

Objective: V2 receptor (V2R) antagonist increases aquaresis, and was reported to have renoprotective and natriuretic effect, although the mechanism is not fully clarified. Renal medullary hemodynamics contributes sodium retention and renal injury. Therefore, the present study was designed to evaluate the effect of V2R antagonist on renal medullary blood flow. Methods: Catheter was inserted in femoral artery and vein of anesthetized SD rats to monitor blood pressure (BP), heart rate (HR) and to infuse drugs, respectively. Renal medullary blood flow (MBF) and renal medullary oxygen pressure (pO2) were measured with laser-Doppler flowmetry or oxygen microelectrode, respectively. V2R antagonist, OPC-31260 (OPC, 0.25mg/kg bw/h) or furosemide (Furo, 0.5mg/kg bw/h) was intravenously administrated for 90min. Urine was collected in 30 min interval and urinary sodium (UNaV), hydrogen peroxide (UH2O2V) and [nitrate + nitrite] (UNOxV) excretion were measured. Results: OPC and Furo treatment did not change BP and HR. Urine volume was significantly increased by OPC (1.1+0.2 to 6.1+0.5 g/30 min) and Furo (1.4+0.6 to 4.7+0.3 g/30 min) treatment but was not different between groups. MBF was significantly decreased in Furo (12+4% decrease from baseline), while OPC did not changed MBF (1+3% increase from baseline). pO2 was significantly increased by both OPC and Furo treatment (20+6 and 27+10% increase from baseline, respectively). UNaV was significantly increased in OPC (0.10+0.02 to 0.44+0.05 mEq/30 min) and Furo (0.14+0.08 to 0.69+0.06 mEq/30 min) treatment, the increase of UNaV was significantly higher in Furo than OPC group. UH2O2V was significantly increased by Furo treatment (16+4 to 28+6 nmol/30 min), while did not change in OPC treatment (10+2 to 19+4 nmol/30 min). UNOx was significantly increased in OPC treatment (211+30 to 376+45 nmol/30 min), while did not change in Furo treatment (142+27 to 237+75 nmol/30 min). Conclusion: OPC treatment increased NO production. Increased NO could contribute to decrease of sodium reabsorption, result in increase of renal medullary pO2. This scheme could be one on the mechanisms of renal protective effect by V2R antagonist treatment.

Importance of the renal medullary circulation in the control of sodium excretion and blood pressure

2003 ◽  
Vol 284 (1) ◽  
pp. R13-R27 ◽  
Author(s):  
David L. Mattson
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Medulla ◽  
Water Excretion ◽  
Vascular Architecture ◽  
Excretory Function ◽  
Medullary Blood Flow ◽  
Arterial Blood ◽  
Renal Medullary Blood Flow ◽  
The Impact

The control of renal medullary perfusion and the impact of alterations in medullary blood flow on renal function have been topics of research interest for almost four decades. Many studies have examined the vascular architecture of the renal medulla, the factors that regulate renal medullary blood flow, and the influence of medullary perfusion on sodium and water excretion and arterial pressure. Despite these studies, there are still a number of important unanswered questions in regard to the control of medullary perfusion and the influence of medullary blood flow on renal excretory function and blood pressure. This review will first address the vascular architecture of the renal medulla and the potential mechanisms whereby medullary perfusion may be regulated. The known extrarenal and local systems that influence the medullary vasculature will then be summarized. Finally, this review will present an overview of the evidence supporting the concept that selective changes in medullary perfusion can have a potent influence on sodium and water excretion with a long-term influence on arterial blood pressure regulation.

l-Arginine uptake affects nitric oxide production and blood flow in the renal medulla

2004 ◽  
Vol 287 (6) ◽  
pp. R1478-R1485 ◽  
Author(s):  
Masao Kakoki ◽  
Hyung-Suk Kim ◽  
William J. Arendshorst ◽  
David L. Mattson
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Amino Acid ◽  
Renal Medulla ◽  
Amino Acid Transporter ◽  
Cationic Amino Acid Transporter ◽  
Cationic Amino Acid ◽  
Arginine Transport ◽  
Medullary Blood Flow ◽  
Interstitial Infusion

Experiments were performed to determine whether l-arginine transport regulates nitric oxide (NO) production and hemodynamics in the renal medulla. The effects of renal medullary interstitial infusion of cationic amino acids, which compete with l-arginine for cellular uptake, on NO levels and blood flow in the medulla were examined in anesthetized rats. NO concentration in the renal inner medulla, measured with a microdialysis-oxyhemoglobin trapping technique, was significantly decreased by 26–44% and renal medullary blood flow, measured by laser Doppler flowmetry, was significantly reduced by 20–24% during the acute renal medullary interstitial infusion of l-ornithine, l-lysine, and l-homoarginine (1 μmol·kg−1·min−1 each; n = 6–8/group). In contrast, intramedullary infusion of l-arginine increased NO concentration and medullary blood flow. Flow cytometry experiments with 4-amino-5-methylamino-2′,7′-difluorescein diacetate, a fluorophore reactive to intracellular NO, demonstrated that l-ornithine, l-lysine, and l-homoarginine decreased NO by 54–57% of control, whereas l-arginine increased NO by 21% in freshly isolated inner medullary cells (1 mmol/l each, n > 1,000 cells/experiment). The mRNA for the cationic amino acid transporter-1 was predominantly expressed in the inner medulla, and cationic amino acid transporter-1 protein was localized by immunohistochemistry to the collecting ducts and vasa recta in the inner medulla. These results suggest that l-arginine transport by cationic amino acid transport mechanisms is important in the production of NO and maintenance of blood flow in the renal medulla.

Control of renal medullary blood flow by vasopressin V1 and V2 receptors

1995 ◽  
Vol 269 (1) ◽  
pp. R193-R200 ◽  
Author(s):  
K. Nakanishi ◽  
D. L. Mattson ◽  
V. Gross ◽  
R. J. Roman ◽  
A. W. Cowley
Keyword(s):  
Blood Flow ◽  
Laser Doppler Flowmetry ◽  
Arginine Vasopressin ◽  
Laser Doppler ◽  
Receptor Stimulation ◽  
Doppler Flowmetry ◽  
Medullary Blood Flow ◽  
V2 Receptor ◽  
Renal Medullary Blood Flow ◽  
Interstitial Infusion

Experiments were performed in anesthetized renal-denervated rats to determine the contribution of renal medullary vasopressin V1 and V2 receptor stimulation in the regulation of renal medullary blood flow. Renal medullary interstitial infusion of the selective V1 agonist [Phe2,Ile3,Orn8]vasopressin (2 ng.kg-1.min-1) significantly decreased outer medullary blood flow by 15% and inner medullary blood flow by 35%, as measured with implanted optical fibers for laser-Doppler flowmetry. Medullary interstitial infusion of equimolar doses of arginine vasopressin (AVP) also decreased outer medullary blood flow by 15% but decreased inner medullary blood flow by only 17%, a decrease significantly less than that during the infusion of the V1 agonist. These results were confirmed in videomicroscopy experiments on the exposed papilla, which demonstrated that the V1 agonist and AVP decreased descending and ascending vasa recta capillary red blood cell velocity and calculated blood flow, with greater decreases during infusion of the V1 agonist. In further laser-Doppler flowmetry studies, stimulation of V2 receptors by medullary interstitial infusion of 1-desamino-8-D-arginine vasopressin (2 ng.kg-1.min-1) or AVP in rats pretreated with the vasopressin V1 receptor antagonist d(CH2)5[Tyr(Me)2,Ala-NH2]AVP increased renal medullary blood flow by 16 +/- 3 and 27 +/- 8%, respectively. The present experiments indicate that vasopressin V1 receptor stimulation serves to decrease renal medullary blood flow while V2 receptor stimulation appears to increase renal medullary blood flow; however, the net effect of AVP is to decrease renal medullary blood flow.

Role of renal medullary blood flow in the development of L-NAME hypertension in rats

1995 ◽  
Vol 268 (2) ◽  
pp. R317-R323 ◽  
Author(s):  
K. Nakanishi ◽  
D. L. Mattson ◽  
A. W. Cowley
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Flow Distribution ◽  
Renal Medulla ◽  
Sodium Balance ◽  
Cortical Blood Flow ◽  
Medullary Blood Flow ◽  
Intrarenal Blood Flow ◽  
Renal Medullary Blood Flow ◽  
Renal Cortical Blood Flow

The effect of chronic intravenous infusion of the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 8.6 mg.kg-1.day-1) on blood pressure, intrarenal blood flow distribution, and sodium and water balance was studied in conscious rats. On the 1st day of intravenous L-NAME infusion, renal medullary blood flow was reduced by 22%, renal cortical blood flow was unaltered, approximately 1 meq of sodium and 12 ml of water were retained, and blood pressure increased from 96 +/- 2 to 118 +/- 2 mmHg. Medullary blood flow was maintained at this decreased level, sodium continued to be retained, body weight continued to increase, and blood pressure remained elevated for the 5 days of L-NAME infusion. During the postcontrol period, blood flow in the renal medulla returned to levels not significantly different from control; the animals went into negative sodium balance and stopped gaining weight, and blood pressure returned to control. The present experiments indicate that decreased renal medullary blood flow and retention of sodium and water play an important role in the development of hypertension during chronic systemic L-NAME administration despite no measurable changes in renal cortical blood flow.

Role of renal NO production in the regulation of medullary blood flow

2003 ◽  
Vol 284 (6) ◽  
pp. R1355-R1369 ◽  
Author(s):  
Allen W. Cowley ◽  
Takefumi Mori ◽  
David Mattson ◽  
Ai-Ping Zou
Keyword(s):  
Blood Flow ◽  
Renal Medulla ◽  
No Synthase ◽  
No Production ◽  
Unique Role ◽  
Medullary Blood Flow ◽  
The Impact ◽  
Renal Medullary Function

The unique role of nitric oxide (NO) in the regulation of renal medullary function is supported by the evidence summarized in this review. The impact of reduced production of NO within the renal medulla on the delivery of blood to the medulla and on the long-term regulation of sodium excretion and blood pressure is described. It is evident that medullary NO production serves as an important counterregulatory factor to buffer vasoconstrictor hormone-induced reduction of medullary blood flow and tissue oxygen levels. When NO synthase (NOS) activity is reduced within the renal medulla, either pharmacologically or genetically [Dahl salt-sensitive (S) rats], a super sensitivity to vasoconstrictors develops with ensuing hypertension. Reduced NO production may also result from reduced cellular uptake of l-arginine in the medullary tissue, resulting in hypertension. It is concluded that NO production in the renal medulla plays a very important role in sodium and water homeostasis and the long-term control of arterial pressure.

Increased H2O2 counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla

2003 ◽  
Vol 285 (4) ◽  
pp. R827-R833 ◽  
Author(s):  
Ya-Fei Chen ◽  
Allen W. Cowley ◽  
Ai-Ping Zou
Keyword(s):  
Renal Medulla ◽  
In Vivo Microdialysis ◽  
Urine Flow ◽  
Amplex Red ◽  
Medullary Blood Flow ◽  
Diethyldithiocarbamic Acid ◽  
Renal Medullary Blood Flow ◽  
Direct Delivery ◽  
Interstitial Infusion

A membrane-permeable SOD mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (tempol), has been used as an antioxidant to prevent hypertension. We recently found that this SOD mimetic could not prevent development of hypertension induced by inhibition of renal medullary SOD with diethyldithiocarbamic acid. The present study tested a hypothesis that increased H2O2 counteracts the effects of tempol on renal medullary blood flow (MBF) and Na+ excretion (UNaV), thereby restraining the antihypertensive effect of this SOD mimetic. By in vivo microdialysis and Amplex red H2O2 microassay, it was found that interstitial H2O2 levels in the renal cortex and medulla in anesthetized rats averaged 55.91 ± 3.66 and 102.18 ± 5.16 nM, respectively. Renal medullary interstitial infusion of tempol (30 μmol·min-1·kg-1) significantly increased medullary H2O2 levels by 46%, and coinfusion of catalase (10 mg·min-1·kg-1) completely abolished this increase. Functionally, removal of H2O2 by catalase enhanced the tempol-induced increase in MBF, urine flow, and UNaV by 28, 41, and 30%, respectively. Direct delivery of H2O2 by renal medullary interstitial infusion (7.5-30 nmol·min-1· kg-1) significantly decreased renal MBF, urine flow, and UNaV, and catalase reversed the effects of H2O2. We conclude that tempol produces a renal medullary vasodilator effect and results in diuresis and natriuresis. However, this SOD mimetic increases the formation of H2O2, which constricts medullary vessels and, thereby, counteracts its vasodilator actions. This counteracting effect of H2O2 may limit the use of tempol as an antihypertensive agent under exaggerated oxidative stress in the kidney.

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