Abstract 625: Role Of Proximal Na+ Reabsorption In The Fructose-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Gabriella D Queiroz-Leite ◽  
Elida A Neri ◽  
Nancy A Rebouças ◽  
Gerhard Malnic
Keyword(s):  
Volume Expansion ◽  
Wistar Rats ◽  
Control Diet ◽  
Fractional Excretion ◽  
Urine Flow ◽  
Induced Hypertension ◽  
Pressure Natriuresis ◽  
Nhe3 Inhibitor

Methods/Results: Wistar rats were fed for 2 or 8 weeks with control diet (CTRL) or isocaloric 60% fructose diet (HF). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. There was no difference in the SBP (mmHg) after 2 weeks of HF intake (110 ± 1.7 CTRL x 121 ± 5.8 HF); however, there was an increase in SBP after 8 weeks (111.9 ± 1.3 CTRL x 143.3 ± 1.5 HF, P < 0.0001). Urine of 24h collected in metabolic cages showed a reduction in urine flow (mL/min) (2 weeks - 0.018 ± 0.002 CTRL x 0.009 ± 0.001 HF, P = 0.0007 and 8 weeks - 0.017 ± 0.002 CTRL x 0.007 ± 0.0004 HF, P = 0.001). Glomerular filtration rate (GFR) was not altered after 2 weeks (1.31 ± 0.3 CTRL x 1.22 ± 0.5 HF), but was decreased after 8 weeks (1.82 ± 0.4 CTRL x 0.37 ± 0.1 HF, P = 0.001). Na+ fractional excretion (Na-FE), in % of creatinine clearance, was decreased after 2 weeks (0.37 ± 0.05 CRTL x 0.13 ±0.03 HF), but was increased after 8 weeks (0.18 ± 0.06 CTRL x 0.54 ± 0.14 HF, P = 0.038). After 2 or 8 weeks, rats were subjected to in situ microperfusion experiments and had their proximal tubules (TP) perfused with an alkaline solution to investigate Na+ reabsorption by means of bicarbonate flux (JHCO3-, in nmol/cm2 x s). JHCO3- was increased after 2 weeks (1.78 ± 0.09 CTRL x 2.7 ± 0.14 HF), but was reduced after 8 weeks (2.00 ± 0.09 CRTL x 1.19 ± 0.04 HF). The perfusion of PT with S3226, a specific NHE3 inhibitor, showed that fructose acts stimulating NHE3 activity after 2 weeks (0.82 ± 0.09 CRTL + S3226 x 1.83 ± 0.14 HF + S3226, P < 0.0001) and inhibiting NHE3 activity after 8 weeks (0.85 ± 0.09 CRTL x 0.22 ± 0.04 HF, P < 0.0001). Conclusions: Reduced Na+-FE and urine flow, associated with increased NHE3 activity after 2 weeks of HF suggest that, initially, fructose leads to a state of Na+ overload, which may contribute to the development of hypertension observed after 8 weeks of HF intake. Kidney damage was increased after 8 weeks, since GFR was decreased, explaining the persistence of reduced urine flow, despite reduced NHE3 activity. These data, together with the increase in Na-FE and installation of hypertension, suggest that the mechanism of pressure-natriuresis was activated after 8 weeks, in order to compensate for volume expansion. Our data suggest a role of increased Na+ reabsorption in the development of fructose-induced hypertension.

Role of atrial natriuretic peptide in volume-expansion natriuresis

1986 ◽  
Vol 251 (2) ◽  
pp. R310-R313 ◽  
Author(s):  
T. R. Schwab ◽  
B. S. Edwards ◽  
D. M. Heublein ◽  
J. C. Burnett
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Fractional Excretion ◽  
Urinary Sodium Excretion ◽  
Urine Flow ◽  
Urinary Sodium ◽  
Right Atrial ◽  
Fractional Excretion Of Sodium

Studies were performed to investigate the role of circulating atrial natriuretic peptide (ANP) in acute volume-expansion natriuresis. Sham-operated (SHAM, n = 6) and right atrial appendectomized (ATRX, n = 12) anesthetized rats underwent acute volume expansion with isoncotic albumin. After equilibration and control periods, volume expansion increased urine flow rate, urinary sodium excretion, fractional excretion of sodium, and circulating ANP. Absolute increases in urine flow rate (delta 46 +/- 4 SHAM; delta 25 +/- 5 microliter/min ATRX), urinary sodium excretion (delta 9.48 +/- 1.01 SHAM; delta 4.77 +/- 1.03 mueq/min ATRX), fractional excretion of sodium (delta 3.16 +/- 0.53 SHAM; delta 1.65 +/- 0.32% ATRX), and ANP (delta 303.3 +/- 35.9 SHAM; delta 156.6 +/- 26.0 pg/ml ATRX) were significantly reduced by right atrial appendectomy. No significant differences in mean arterial pressure, central venous pressure, or glomerular filtration rate during volume expansion were observed between groups. These studies support the hypothesis that right atrial appendectomy in the rat attenuates acute volume expansion-induced increases in circulating ANP and urinary sodium excretion and that the natriuresis of acute volume expansion is mediated in part by an increase in circulating ANP.

Effect of renal decapsulation on renal interstitial hydrostatic pressure and natriuresis

1989 ◽  
Vol 257 (1) ◽  
pp. R44-R48 ◽  
Author(s):  
A. A. Khraibi ◽  
F. G. Knox
Keyword(s):  
Hydrostatic Pressure ◽  
Volume Expansion ◽  
Wistar Rats ◽  
Control Period ◽  
Fractional Excretion ◽  
Wistar Rat ◽  
Renal Perfusion ◽  
Fractional Excretion Of Sodium ◽  
Male Wistar Rats ◽  
Pressure Natriuresis

The objective of this study was to investigate the possible causal role of renal interstitial hydrostatic pressure (RIHP) in the natriuretic and diuretic responses of the Wistar rat. The relationship between renal perfusion pressure (RPP), RIHP, and fractional excretion of sodium (FENa) was established in the acutely decapsulated kidney and the contralateral control kidney of the same rat. The renal response to acute saline volume expansion was also studied in control and decapsulated kidney. When RPP was allowed to increase from 100 +/- 1.2 to 123 +/- 1.3 mmHg in male Wistar rats (n = 10), RIHP and FENa increased significantly from 3.3 +/- 0.4 mmHg and 0.57 +/- 0.15% to 4.3 +/- 0.4 mmHg and 1.77 +/- 0.41% in the decapsulated kidney and from 4.1 +/- 0.4 mmHg and 0.86 +/- 0.17% to 6.9 +/- 0.5 mmHg and 2.56 +/- 0.38% in control kidney. During saline volume expansion, RIHP and FENa increased significantly from 6.3 +/- 0.5 mmHg and 1.30 +/- 0.43% to 9.8 +/- 0.5 mmHg and 7.53 +/- 0.88% in the decapsulated kidney. In the control kidney, RIHP and FENa were 8.3 +/- 0.6 mmHg and 1.81 +/- 0.35% during control period and increased significantly to 12.7 +/- 0.4 mmHg and 9.31 +/- 0.50% during acute saline volume expansion. We conclude that the renal capsule is essential for the full increase in RIHP and for the full expression of the natriuretic and diuretic responses of pressure natriuresis and acute volume expansion of Wistar rats.

Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs

1993 ◽  
Vol 264 (1) ◽  
pp. F79-F87 ◽  
Author(s):  
D. S. Majid ◽  
A. Williams ◽  
L. G. Navar
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sodium Excretion ◽  
Renin Angiotensin System ◽  
Fractional Excretion ◽  
Urine Flow ◽  
Synthesis Inhibition ◽  
Fractional Excretion Of Sodium ◽  
Anesthetized Dogs ◽  
Pressure Natriuresis

Inhibition of nitric oxide (NO) synthesis by intrarenal administration of nitro-L-arginine (NLA) leads to decreases in urinary sodium excretion (UNaV) in association with the increases in renal vascular resistance (RVR). In the present study, we examined the ability of the kidney to alter its sodium excretion in response to acute changes in renal arterial pressure (RAP) in anesthetized dogs before and during intrarenal infusion of NLA (50 micrograms.kg-1.min-1). NO synthesis inhibition in 11 dogs increased RVR by 32 +/- 4% and decreased renal blood flow (RBF) by 25 +/- 3%, outer cortical blood flow by 25 +/- 6%, urine flow by 37 +/- 14%, UNaV by 71 +/- 5%, and fractional excretion of sodium (FENa) by 71 +/- 4%. Glomerular filtration rate was not significantly changed during NLA infusion. As previously reported, there was suppression of the RBF autoregulation plateau during NO synthesis inhibition. In addition, there was a marked attenuation of urine flow and UNaV responses to reductions in RAP (150 to 75 mmHg), with significant reductions in the slopes of the relationships between RAP vs. UNaV and RAP vs. FENa during NLA infusion. Similar responses were observed in nine other dogs treated with the angiotensin receptor antagonist losartan, indicating that an augmented activity of the renin-angiotensin system is not responsible for attenuation of the slope of the pressure-natriuresis relationship during NLA infusion. These data suggest that NO may participate in the mediation of the pressure-natriuresis response.

Ouabain- and central sodium-induced hypertension depend on the ventral anteroventral third ventricle region

1999 ◽  
Vol 276 (1) ◽  
pp. H63-H70 ◽  
Author(s):  
Shereeni J. Veerasingham ◽  
Frans H. H. Leenen
Keyword(s):  
Hypertonic Saline ◽  
Wistar Rats ◽  
Third Ventricle ◽  
Cardiovascular Responses ◽  
Ibotenic Acid ◽  
Air Jet ◽  
Artificial Cerebrospinal Fluid ◽  
Induced Hypertension ◽  
Chronic Infusion

To examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension induced by chronic subcutaneous ouabain and intracerebroventricular hypertonic saline, neurons in this area were destroyed by microinjection of an excitotoxin, ibotenic acid. Sham-operated or lesioned Wistar rats were administered ouabain (50 μg/day) or placebo for 3 wk from subcutaneously implanted controlled release pellets or artificial cerebrospinal fluid (CSF) or CSF containing 0.8 mol/l NaCl (5 μl/h) infused intracerebroventricularly for 2 wk. At the end of the experiment, mean arterial pressure (MAP) and heart rate at rest and in response to ganglionic blockade by intravenous hexamethonium (30 mg/kg) were assessed. In rats infused with hypertonic saline, responses to air jet stress were also assessed. Baseline MAP in sham-operated rats receiving intracerebroventricular hypertonic saline or subcutaneous ouabain was significantly higher than in control rats (115 ± 1 vs. 97 ± 3 and 121 ± 3 vs. 103 ± 3 mmHg, respectively). vAV3V lesions abolished the increase in MAP elicited by chronic infusion of hypertonic saline or administration of ouabain. Sham-operated rats treated with hypertonic saline or ouabain exhibited significantly enhanced decreases in MAP to hexamethonium, but lesioned rats did not. Rats infused with hypertonic saline demonstrated enhanced responses to air jet stress that were similar in sham-operated and lesioned rats. These results demonstrate that neurons in the vAV3V are essential for the hypertension induced by intracerebroventricular hypertonic saline and subcutaneous ouabain, possibly by increasing sympathetic tone. Cardiovascular responses to air jet stress appear not to be mediated by the vAV3V.

Effect of Adrenalectomy on the Development of Isolation-Induced Hypertension in Rats

1981 ◽  
Vol 61 (5) ◽  
pp. 511-519 ◽  
Author(s):  
S. M. Gardiner ◽  
K. E. Milmer ◽  
T. Bennett
Keyword(s):  
Volume Expansion ◽  
Chloride Solution ◽  
Wistar Rats ◽  
Sodium Chloride Solution ◽  
Adrenal Glands ◽  
Tap Water ◽  
Fluid Retention ◽  
Induced Hypertension ◽  
Male Wistar Rats ◽  
Adrenalectomized Rats

1. Male Wistar rats develop systolic arterial hypertension when housed in glass metabolism cages. The present experiments were designed to investigate the involvement of the adrenal glands in this form of hypertension. 2. Rats were bilaterally adrenalectomized and maintained by either salt supplementation (1% sodium chloride solution instead of tap water to drink) or steroid replacement (corticosterone solution in the drinking water). 3. Adrenalectomized rats treated as above did not develop hypertension in response to isolation, whereas sham-operated rats (drinking either 1% saline or tap water) did. 4. Hypertension in the sham-operated rats was not accompanied by a renal retention of sodium and water. 5. It is concluded that increased adrenal activity is involved in the development of isolation-induced hypertension, but not by causing a fluid retention and hence volume expansion. The relative contributions of adrenal medullary and cortical activity remain to be determined.

Abstract 011: An Orally Absorbable Potent NHE3 Inhibitor Attenuates Angiotensin II-induced Hypertension Primarily by Inhibiting NHE3 in the Proximal Tubule of the Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Hoang Nguyen ◽  
Jia L Zhuo
Keyword(s):  
Proximal Tubule ◽  
The Body ◽  
High Salt ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Small Intestines ◽  
Orally Active ◽  
Nhe3 Inhibitor

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global ( Nhe3 -/- ) and Nhe3 -/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg Nhe3 -/- ), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg ( p <0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg ( p <0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice ( p <0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl ( p <0.01), respectively. Further treatment with AVE0657 and losartan, an AT 1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg, p <0.01). In the kidney, AVE0657 significantly increased 24h urinary Na + excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h ( p <0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na + excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h, n.s. ) or global Nhe3 -/- mice (50.8 ± 0.8 μmol/24h, p <0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.

Effect of direct increases in renal interstitial hydrostatic pressure on sodium excretion

1988 ◽  
Vol 254 (4) ◽  
pp. F527-F532 ◽  
Author(s):  
J. P. Granger ◽  
J. A. Haas ◽  
D. Pawlowska ◽  
F. G. Knox
Keyword(s):  
Hydrostatic Pressure ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Saline Solution ◽  
Fractional Excretion ◽  
Urine Flow ◽  
Renal Interstitium ◽  
Interstitial Volume ◽  
Sustained Effect ◽  
Direct Technique

This study examined the effect of increases in renal interstitial hydrostatic pressure (PI) on sodium excretion (UNaV) utilizing a direct technique for increasing renal interstitial volume. PI was increased by renal interstitial volume expansion (RIVE) via injection of 50 microliters of a 2% albumin in saline solution into the renal interstitium through a chronically implanted interstitial catheter. RIVE resulted in a stable increase in PI (4.6 +/- 0.4 to 9.4 +/- 0.8 mmHg) that was sustained over a 30- to 40-min period without significant changes in renal blood flow or glomerular filtration rate. Increases in PI were associated with significant increases in urine flow (13.8 +/- 3.4 to 31.7 +/- 5.0 microliters/min) and UNaV (2.3 +/- 0.6 to 6.2 +/- 1.1 micro eq/min) and fractional excretion of Na (2.6 +/- 0.8 to 6.9 +/- 1.5%). To determine the importance of albumin in maintaining an elevated PI, the effects of renal interstitial injections of saline were compared with albumin in saline solution. Injection of 50 microliters of saline into the renal interstitium had no sustained effect on PI. Injection of 2% albumin in saline solution in the same group of rats resulted in significant elevations in PI and UNaV. These data indicate that direct increases in PI via renal interstitial volume expansion result in significant increases in UNaV, thus supporting a role for PI in controlling UNaV.

Role of atrial natriuretic factor in the natriuresis of acute volume expansion

1987 ◽  
Vol 252 (5) ◽  
pp. R921-R924 ◽  
Author(s):  
A. A. Khraibi ◽  
J. P. Granger ◽  
J. C. Burnett ◽  
K. R. Walker ◽  
F. G. Knox
Keyword(s):  
Atrial Natriuretic Factor ◽  
Volume Expansion ◽  
Fractional Excretion ◽  
Sprague Dawley ◽  
Volume Loading ◽  
Fourfold Increase ◽  
Natriuretic Factor ◽  
Fractional Excretion Of Sodium ◽  
Atrial Natriuretic

The quantitative role of atrial natriuretic factor (ANF) in mediating the natriuresis induced by acute volume loading was determined in these studies. Plasma level of ANF (PANF), glomerular filtration rate (GFR), and renal excretory responses were measured in three groups of anesthetized Sprague-Dawley rats. In one group of rats (n = 8), acute volume expansion was established by intravenous infusion of saline (5% body wt) over a period of 30 min. A second group of rats (n = 13) was infused with synthetic ANF (2 micrograms X kg-1 X h-1 iv) to mimic the high PANF observed during acute volume loading. A third group (n = 13) served as control. PANF was similar and significantly elevated (P less than 0.05) in volume-expanded and ANF-infused groups compared with control. In control rats, PANF measured 122.0 +/- 12.1 pg/ml, whereas it averaged 389.4 +/- 30.3 pg/ml for volume-expanded and 368.1 +/- 22.3 pg/ml for ANF-infused rats. GFR was also comparable and significantly increased (P less than 0.05) in volume-expanded and ANF-infused groups compared with control rats. Infusion of ANF at a dose to mimic PANF obtained during acute volume expansion resulted in a fourfold increase in the fractional excretion of sodium. The results of these studies suggest that ANF may play an important quantitative role in promoting natriuresis during acute volume expansion.

Segmental chloride reabsorption during volume expansion and recovery

1981 ◽  
Vol 240 (5) ◽  
pp. F395-F399
Author(s):  
A. U. Sheth ◽  
T. F. Knight ◽  
E. Pace ◽  
H. O. Senekjian ◽  
E. J. Weinman
Keyword(s):  
Volume Expansion ◽  
Wistar Rats ◽  
Isotonic Saline ◽  
Extracellular Fluid ◽  
Distal Tubule ◽  
Fractional Excretion ◽  
Fluid Volume ◽  
Extracellular Fluid Volume ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

Clearance and micropuncture studies were performed in Sprague-Dawley and Munich-Wistar rats to examine the nephron sites of chloride reabsorption in animals undergoing sustained volume expansion (SVE) (10% of body wt) with isotonic saline and in animals in which the extracellular fluid volume was expanded to 10% of body wt over 60 min, after which the sustaining saline volume was abruptly discontinued (recovery) (R). Net sodium and chloride balances were not significantly different in R compared with SVE. The fractional excretion of chloride, however, was significantly lower (2.62 +/- 0.25 vs. 4.18 +/- 0.62%, P less than 0.05). In the Sprague-Dawley rats, chloride delivery to the early distal tubule average 18% in both groups. Chloride delivery to the late distal tubule was significantly lower in R (4.39 +/- 0.79%) than in SVE (8.55 +/- 0.76%, P less than 0.005). In the Munich-Wistar rats, samples were obtained from the late distal tubule and base and tip of the papilla. Chloride delivery to the base did not differ from that to the late distal tubule in either group, but was significantly lower in R compared with SVE. These results indicate that the so-called “post-volume expansion” antinatriuresis is the result, at least in part, of enhanced reabsorption in the distal tubule.

Effects of renal artery pressure on interstitial pressure and Na excretion during renal vasodilation

1988 ◽  
Vol 255 (5) ◽  
pp. F828-F833 ◽  
Author(s):  
J. P. Granger ◽  
J. W. Scott
Keyword(s):  
Perfusion Pressure ◽  
Marked Effect ◽  
Excretion Rate ◽  
Fractional Excretion ◽  
Urinary Sodium Excretion ◽  
Renal Perfusion ◽  
Interstitial Pressure ◽  
Pressure Natriuresis ◽  
The Relationship

Renal vasodilation has a marked effect on the pressure-natriuresis relationship. The purpose of this study was to determine the role of renal interstitial hydrostatic pressure (RIHP) in mediating the effect of renal perfusion pressure (RPP) on urinary sodium excretion rate (UNaV) in control and vasodilated kidneys. The effects of RPP on UNaV and RIHP were determined in dogs under control conditions and during renal vasodilation with acetylcholine (Ach, 2.0 micrograms.kg-1.min-1) or secretin (SEC, 0.025 micrograms.kg-1.min-1). Decreases in RPP in control kidneys from 130 to 60 mmHg decreased UNaV from 2.9 +/- 0.1 to 0.6 +/- 0.3 microeq/min and fractional excretion of Na (FENa) from 0.15 +/- 0.08 to 0.06 +/- 0.04%. These changes were associated with significant reductions in RIHP (8.9 +/- 0.6 to 5.6 +/- 1.2 mmHg). In Ach-vasodilated kidneys, reductions in RPP from 130 to 60 mmHg decreased UNaV from 149.8 +/- 52.4 to 0.2 +/- 0.1 microeq/min and FENa from 3.42 +/- 1.18 to 0.012 +/- 0.01%. RIHP decreased from 17.8 +/- 3.4 to 8.4 +/- 1.3 mmHg, despite autoregulation of RBF. Renal vasodilation with SEC, which did not affect RIHP, had only a small effect on the relationship between RPP and UNaV. These data suggest that RIHP may be playing an important role in mediating the effect of RPP on UNaV.

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