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.

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 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.

α2-Adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction

2000 ◽  
Vol 279 (3) ◽  
pp. R769-R777 ◽  
Author(s):  
Ai-Ping Zou ◽  
Allen W. Cowley
Keyword(s):  
Intravenous Infusion ◽  
Adrenergic Receptors ◽  
Collecting Duct ◽  
Renal Medulla ◽  
In Vivo Microdialysis ◽  
No Production ◽  
Thick Ascending Limb ◽  
Doppler Flowmetry ◽  
Interstitial Infusion

The present study was designed to investigate the role of nitric oxide (NO) in modulating the adrenergic vasoconstrictor response of the renal medullary circulation. In anesthetized rats, intravenous infusion of norepinephrine (NE) at a subpressor dose of 0.1 μg · kg−1 · min−1 did not alter renal cortical (CBF) and medullary (MBF) blood flows measured by laser-Doppler flowmetry nor medullary tissue Po 2(Pm o 2) as measured by a polarographic microelectrode. In the presence of the NO synthase inhibitor nitro-l-arginine methyl ester (l-NAME) in the renal medulla, intravenous infusion of NE significantly reduced MBF by 30% and Pm o 2 by 37%. With the use of an in vivo microdialysis-oxyhemoglobin NO-trapping technique, we found that intravenous infusion of NE increased interstitial NO concentrations by 43% in the renal medulla. NE-stimulated elevations of tissue NO were completely blocked either by renal medullary interstitial infusion ofl-NAME or the α2-antagonist rauwolscine (30 μg · kg−1 · min−1). Concurrently, intavenous infusion of NE resulted in a significant reduction of MBF in the presence of rauwolscine. The α1-antagonist prazosin (10 μg · kg−1 · min−1 renal medullary interstitial infusion) did not reduce the NE-induced increase in NO production, and NE increased MBF in the presence of prazosin. Microdissection and RT-PCR analyses demonstrated that the vasa recta expressed the mRNA of α2B-adrenergic receptors and that medullary thick ascending limb and collecting duct expressed the mRNA of both α2A- and α2B-adrenergic receptors. These subtypes of α2-adrenergic receptors may mediate NE-induced NO production in the renal medulla. We conclude that the increase in medullary NO production associated with the activation of α2-adrenergic receptors counteracts the vasoconstrictor effects of NE in the renal medulla and may play an important role in maintaining a constancy of MBF and medullary oxygenation.

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.

scholarly journals The Action of Pitressin on Solute Permeability of the Rabbit Nephron in Vivo

1966 ◽  
Vol 50 (1) ◽  
pp. 1-8 ◽  
Author(s):  
E. C. Foulkes
Keyword(s):  
Specific Activity ◽  
Specific Effect ◽  
Renal Medulla ◽  
Urine Flow ◽  
Intraarterial Infusion ◽  
Plasma Urea ◽  
Solute Permeability ◽  
Isotopic Equilibration ◽  
Constant Specific Activity

The isotopic equilibration of urea, thiourea, and inulin between urine and plasma was determined in rabbits in the presence or absence of antidiuretic hormone (ADH). Animals were anesthetized with ethanol and permitted to reach steady state after completion of surgery. Tracer was then administered by intraarterial infusion in such a manner that a high constant specific activity in plasma was rapidly attained. Urine flow was kept independent of ADH by addition of mannitol. Urea/creatinine clearance ratios and the accumulation of urea in renal medulla and papilla also remained unaffected by ADH. Under these conditions, thiourea and inulin at all times approached equilibrium, at similar rates. In the absence of ADH, urea also equilibrated at a rate similar to that of inulin. The addition of ADH, however, significantly prolonged the delay before urinary urea reached the high constant specific activity of plasma urea. These observations are interpreted in terms of a specific effect of the hormone on the solute permeability of the nephron.

Renal medullary interstitial infusion of norepinephrine in anesthetized rabbits: methodological considerations

1999 ◽  
Vol 277 (1) ◽  
pp. R112-R122 ◽  
Author(s):  
Anabela G. Correia ◽  
Göran Bergström ◽  
Andrew J. Lawrence ◽  
Roger G. Evans
Keyword(s):  
Intravenous Infusion ◽  
Renal Medulla ◽  
Systemic Circulation ◽  
Renal Hemodynamics ◽  
Autoradiographic Analysis ◽  
Methodological Considerations ◽  
Infusion Of Norepinephrine ◽  
Interstitial Infusion

We tested methods for delivery of drugs to the renal medulla of anesthetized rabbits. Outer medullary infusion (OMI) of norepinephrine (300 ng ⋅ kg−1 ⋅ min−1), using acutely or chronically positioned catheters, reduced both cortical (CBF; 15%) and medullary perfusion (MBF; 23–31%). Inner medullary infusion (IMI) did not affect renal hemodynamics, whereas intravenous infusion reduced CBF (15%) without changes in MBF. During OMI of [3H]norepinephrine, much of the radiolabel (∼40% with chronically positioned catheters) spilled over systemically. Nevertheless, autoradiographic analysis showed the concentration of radiolabel was about fourfold greater in the infused medulla than the cortex. In contrast, during IMI, only ∼5% of the infused radiolabel spilled over into the systemic circulation and ∼64% was excreted by the infused kidney. The resultant intrarenal levels of radiolabel were considerably less with IMI compared with OMI. In rabbits, OMI therefore provides a useful method for targeting agents to the renal medulla, but given the considerable systemic spillover with OMI, its utility is probably limited to substances that are rapidly degraded in vivo.

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.

Evidence for the presence of smooth muscle α-actin within pericytes of the renal medulla

1997 ◽  
Vol 273 (5) ◽  
pp. R1742-R1748 ◽  
Author(s):  
Frank Park ◽  
David L. Mattson ◽  
Lou A. Roberts ◽  
Allen W. Cowley
Keyword(s):  
Smooth Muscle ◽  
Pcr Amplification ◽  
Renal Medulla ◽  
Immunoblot Analysis ◽  
Rt Pcr ◽  
Medullary Blood Flow ◽  
Vasa Recta ◽  
Actin Mrna ◽  
Renal Medullary Blood Flow ◽  
Actin Protein

This study was designed to determine whether smooth muscle α-actin mRNA and smooth muscle α-actin contractile protein elements were present within the renal medullary pericytes. Extraction of total RNA from microdissected outer medullary descending vasa recta allowed for the detection of smooth muscle α-actin mRNA expression using reverse transcription-polymerase chain reaction (RT-PCR). Expression of smooth muscle α-actin was specific to the descending vasa recta and not a result of tubular contamination because RT-PCR amplification of the vasopressin V2 receptor, which is a specific tubular marker, did not occur. To determine the exact cell type(s) that translate the mRNA into protein, we performed immunohistochemistry on the renal outer and inner medulla using a monoclonal smooth muscle α-actin antibody, whose specificity was determined by immunoblot analysis. Smooth muscle α-actin protein was found selectively within the pericytes surrounding the descending vasa recta from the outer and inner medullary tissue sections. This study demonstrates that the pericytes alone that surround the descending vasa recta within the outer and inner medulla contain smooth muscle α-actin mRNA and protein and are therefore the site of the contractile elements that could play a vasomodulatory role in the control of renal medullary blood flow and its distribution within the renal medulla.

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