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

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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.269.1.r193 ◽

1995 ◽

Vol 269 (1) ◽

pp. R193-R200 ◽

Cited By ~ 13

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.

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Influence of the renal medullary circulation on the control of sodium excretion

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.5.r963 ◽

1993 ◽

Vol 265 (5) ◽

pp. R963-R973 ◽

Cited By ~ 16

Author(s):

R. J. Roman ◽

A. P. Zou

Keyword(s):

Blood Flow ◽

Renal Perfusion ◽

Sodium Reabsorption ◽

Doppler Flowmetry ◽

Medullary Blood Flow ◽

Tubular Sodium Reabsorption ◽

Vasa Recta ◽

Urinary Concentrating Ability ◽

Reliable Methods

Although the role of the renal medullary circulation in the control of urinary concentrating ability is well established, its potential influence on tubular sodium reabsorption is not generally recognized. Nearly 30 years ago, changes in the intrarenal distribution of blood flow were first proposed to contribute to the natriuretic response to volume expansion. However, the lack of reliable methods for studying medullary blood flow limited progress in this area. The recent development of laser-Doppler flowmetry and videomicroscopic techniques for the study of the vasa recta circulation has renewed interest in the role of medullary hemodynamics in the control of sodium reabsorption. Results of these studies indicate that changes in renal medullary hemodynamics alter renal interstitial pressure and the medullary solute gradient and play an important role in the natriuretic response to elevations in renal perfusion pressure, intravenous infusion of saline, and changes in tubular sodium reabsorption produced by vasoactive compounds. What is emerging from these studies is the view that changes in renal medullary hemodynamics represent an important but misunderstood and long-ignored factor in the control of tubular sodium reabsorption.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.5.r1667 ◽

1998 ◽

Vol 275 (5) ◽

pp. R1667-R1673 ◽

Cited By ~ 19

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.

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Autoregulation of renal medullary blood flow in rabbits

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00061.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. R233-R244 ◽

Cited By ~ 28

Author(s):

Gabriela A. Eppel ◽

Göran Bergström ◽

Warwick P. Anderson ◽

Roger G. Evans

Keyword(s):

Blood Flow ◽

Arterial Pressure ◽

Laser Doppler Flowmetry ◽

Systemic Arterial Pressure ◽

Laser Doppler ◽

Kidney Volume ◽

Doppler Flowmetry ◽

Medullary Blood Flow ◽

Vasa Recta ◽

Renal Medullary Blood Flow

We examined the extent of renal medullary blood flow (MBF) autoregulation in pentobarbital-anesthetized rabbits. Two methods for altering renal arterial pressure (RAP) were compared: the conventional method of graded suprarenal aortic occlusion and an extracorporeal circuit that allows RAP to be increased above systemic arterial pressure. Changes in MBF were estimated by laser-Doppler flowmetry, which appears to predominantly reflect erythrocyte velocity, rather than flow, in the kidney. We compared responses using a dual-fiber needle probe held in place by a micromanipulator, with responses from a single-fiber probe anchored to the renal capsule, to test whether RAP-induced changes in kidney volume confound medullary laser-Doppler flux (MLDF) measurements. MLDF responses were similar for both probe types and both methods for altering RAP. MLDF changed little as RAP was altered from 50 to ≥170 mmHg (24 ± 22% change). Within the same RAP range, RBF increased by 296 ± 48%. Urine flow and sodium excretion also increased with increasing RAP. Thus pressure diuresis/natriuresis proceeds in the absence of measurable increases in medullary erythrocyte velocity estimated by laser-Doppler flowmetry. These data do not, however, exclude the possibility that MBF is increased with increasing RAP in this model, because vasa recta recruitment may occur.

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Renal Vasodilatation: Studies on the Site of Action in the Nephron

Clinical Science ◽

10.1042/cs0420535 ◽

1972 ◽

Vol 42 (5) ◽

pp. 535-543 ◽

Cited By ~ 5

Author(s):

S. G. Massry ◽

J. J. Ahumada

Keyword(s):

Urine Volume ◽

Free Water ◽

Urinary Sodium Excretion ◽

Sodium Reabsorption ◽

Water Reabsorption ◽

Diluting Segment ◽

Free Water Clearance ◽

Medullary Blood Flow ◽

Site Of Action ◽

Additional Role

1. The effect of unilateral renal vasodilatation produced by acetylcholine or bradykinin on free water clearance (CH2O) and free water reabsorption (TcH2O) was investigated in dogs in an effort to localize the site(s) in the nephron where renal vasodilatation inhibits tubular sodium reabsorption. 2. Renal vasodilatation in dogs undergoing water diuresis produced an increase in urinary sodium excretion, urine volume and CH2O. However, for any given level of sodium delivery to the diluting segment of the nephron, CH2O was less during the intrarenal infusion of the vasodilator drugs than during the infusion of hypo-osmotic saline. 3. During renal vasodilatation in hydropenic dogs receiving vasopressin and hyperosmotic saline, TcH2O at a given rate of osmolal clearance was depressed. The effect of bradykinin on TcH2O was greater than that of acetylcholine. 4. The results indicate that renal vasodilatation inhibits sodium reabsorption in the proximal tubule and the diluting segment of the nephron as well. Increased medullary blood flow may play an additional role in the effect of acetylcholine and bradykinin on TcH2O.

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Vasopressin modulation of medullary blood flow and pressure-natriuresis-diuresis in the decerebrated rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.5.r1472 ◽

1997 ◽

Vol 272 (5) ◽

pp. R1472-R1479 ◽

Cited By ~ 9

Author(s):

K. G. Franchini ◽

D. L. Mattson ◽

A. W. Cowley

Keyword(s):

Blood Flow ◽

Arterial Pressure ◽

Fluid Pressure ◽

Renal Medulla ◽

Urinary Sodium Excretion ◽

Water Restriction ◽

Vascular Effects ◽

Doppler Flowmetry ◽

Physiological Importance ◽

Medullary Blood Flow

Studies in our laboratory and others have demonstrated that arginine vasopressin (AVP) exerts potent vasoconstrictor actions on the vessels supplying the renal medulla. The physiological importance of these vascular effects of AVP has been difficult to assess because of high endogenous levels of AVP in anesthetized, surgically prepared animals. We have developed a decerebrated, hypophysectomized, renal-denervated rat model that enables us to study the effects of low levels of AVP on the pressure-diuresis, relationship under acute conditions. These rats maintain normal mean arterial pressure (MAP) and plasma AVP (2.5 pg/ml). Cortical and medullary blood flow (CBF and MBF, respectively) were measured by laser-Doppler flowmetry and total renal blood flow (RBF) by transit time flowmetry. Renal interstitial fluid pressure (RIFP) and urinary sodium excretion (UNaV) responses were determined during controlled increases of MAP produced by aortic occlusion below the renal arteries. From a baseline of 97 +/- 2 mmHg, 30% increases in MAP resulted in a 63% increase in MBF, 35% increase in RIFP, and sixfold increase in UNaV, whereas CBF and RBF remained unchanged. Infusion of AVP (0.50 ng.kg-1.min-1, which increased plasma AVP from normal control levels of 3 pg/ml to 11 pg/ml) produced no change in baseline MAP, RBF, or CBF but lowered MBF by 24%, RIFP by 26%, and UNaV by 71%. The slope of the relationship of AP and UNaV, MBF, and RIP was reduced to nearly zero by these small increases of plasma AVP. We conclude that an increase of plasma AVP in the range that occurs with water restriction decreases MBF selectively and greatly attenuates the arterial pressure-MBF and pressure-natriuretic relationship.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.3.r790 ◽

1999 ◽

Vol 276 (3) ◽

pp. R790-R798 ◽

Cited By ~ 40

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.

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Direct measurement of renal medullary blood flow in the dog

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.1.r253 ◽

1994 ◽

Vol 267 (1) ◽

pp. R253-R259 ◽

Cited By ~ 5

Author(s):

D. M. Strick ◽

M. J. Fiksen-Olsen ◽

J. C. Lockhart ◽

R. J. Roman ◽

J. C. Romero

Keyword(s):

Blood Flow ◽

Pressure Range ◽

Perfusion Pressure ◽

Renal Perfusion ◽

Flow Probe ◽

Renal Autoregulation ◽

Renal Perfusion Pressure ◽

Medullary Blood Flow ◽

Renal Medullary Blood Flow ◽

Doppler Flowmeter

We studied the responses of total renal blood flow (RBF) and renal medullary blood flow (RMBF) to changes in renal perfusion pressure (RPP) within and below the range of renal autoregulation in the anesthetized dog (n = 7). To measure RMBF, we developed a technique in which the medulla is exposed by excising a section of infarcted cortex and a multiple optical fiber flow probe, connected to a laser-Doppler flowmeter, is placed on the medulla. At the baseline RPP of 120 +/- 1 mmHg, RBF was 2.58 +/- 0.33 ml.min-1.g perfused kidney wt-1, and RMBF was 222 +/- 45 perfusion units. RPP was then decreased in consecutive 20-mmHg steps to 39 +/- 1 mmHg. At 80 +/- 1 mmHg, RBF remained at 89 +/- 4% of the baseline value; however, RMBF had decreased significantly (P < 0.05) to 73 +/- 4% of its baseline value. The efficiency of autoregulation of RBF and of RMBF within the RPP range of 120 to 80 mmHg was determined by calculating an autoregulatory index (AI) for each parameter using the formula AI = (%delta blood flow)/(%delta RPP). An AI of 0 indicates perfect autoregulation, and an index of 1 indicates a system with a fixed resistance. The AI for RBF averaged 0.33 +/- 0.12 over this pressure range and showed a significantly greater (P < 0.05) autoregulatory ability than did the RMBF (0.82 +/- 0.13). Decreasing perfusion pressure < 80 mmHg produced significant decreases in both RBF and RMBF.(ABSTRACT TRUNCATED AT 250 WORDS)

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