Differences In Urinary Sodium Excretion Research Articles

#3314 DIURETIC AND RENOPROTECTIVE EFFECTS OF GOREISAN IN A RAT MODEL OF NEPHROTIC SYNDROME

Abstract Background and Aims Goreisan, a traditional Chinese medicine composed of five herbs, is commonly used for the purpose of control of edema and gastrointestinal symptoms. However, the detailed mechanisms have not been fully elucidated. In clinical settings, nephrotic syndrome often causes edema, mainly due to hypoalbuminemia and sodium retention. Thus, we investigated the effects of Goreisan on the kidney using a rat model of nephrotic syndrome. Method A model of nephrotic syndrome was created by a right nephrectomy and subsequent administration of adriamycin using Sprague Dawley rats. Nephrotic rats were randomly divided into three groups at 10 weeks of age as follows; vehicle (control), Goreisan 0.5 g/kg (GL), and Goreisan 1.0 g/kg (GH) groups. Goreisan was administered once a day for 4 weeks. At 14 weeks of age, the rats were sacrificed for the evaluation of blood, urine, mRNA expressions, and kidney histopathology. Results Urine volume was significantly increased in the GL and GH groups than in the control group (Δurine volume: control; −1.25±2.48 mL, GL group; 9.83±4.16 mL, GH group; 10.00±2.62 mL). The GH group showed significantly lower urine osmotic pressure compared to the control group. There were no significant differences in urinary sodium excretion and serum arginine-vasopressin levels among the three groups. Subsequently, we assessed the expression of aquaporin (AQP) in kidney tissue using real-time PCR and immunohistochemical staining. The mRNA expression of AQP1, AQP2, AQP3, and AQP4 did not differ among the three groups. However, immunohistochemical staining showed that the localization of AQP2 at the apical plasma membrane of the collecting ducts was decreased by treatment with Goreisan. Furthermore, deterioration of kidney function was prevented by treatment with Goreisan. Histological analysis revealed that glomerular and tubulointerstitial damages were ameliorated in the GL and GH groups compared to the control group (glomerular damage score: control; 2.19±0.05, GL group; 1.71±0.05, GH group; 1.10±0.05, tubulointerstitial damage score: control; 2.55±0.09, GL group; 2.28±0.10, GH group; 2.12±0.10). In addition, urinary 8-OHdG, which is an oxidative stress marker, was significantly lower in the GL and GH groups than in the control group. Conclusion Our results suggested that Goreisan may have diuretic and renoprotective effects by suppressing the trafficking of AQP2 to the apical plasma membrane of the collecting ducts and possibly reducing systemic oxidative stress.

Characteristics of urinary sodium excretion in patients with chronic kidney disease in Jiangsu, China.

The current study aimed to assess the dietary salt intake in patients with CKD in Jiangsu province and investigate the relationship of urinary sodium excretion with blood pressure. A total of 800 patients with CKD stages 1–4 were recruited. All enrolled patients were asked to collect complete 24‐h urine specimen. At the same time, patient's demographic and laboratory data were recorded. The mean age was 47.45 ± 15.25 years old, including 423 men and 377 women. There was no significant difference in urinary sodium excretion among different stages of CKD (p = .748). This study revealed that the median urinary sodium excretion of all patients was 127.20 mmol/d (IQR 91.03–172.06), corresponding to a salt intake of 7.4 g/d. Among them, only 167 (20.9%) cases had salt intake <5 g/d. Moreover, urinary sodium excretion in overweight group and obese group was higher than that in normal weight group (p = .001, p ˂ .001). Likewise, urinary sodium excretion in men was higher than that in women (p ˂ .001). Spearman correlation analysis indicated that urinary sodium excretion positively correlated with urinary protein excretion (r = .178, p ˂ .001), SBP (r = .109, p = .002), and DBP (r = .086, p = .015). After adjusting for age, gender, BMI, eGFR, urinary protein excretion, and history of taking antihypertensive drug, multivariate linear regression demonstrated that higher level of urinary sodium excretion associated with increased level of SBP, DBP, and MAP (β = 0.020, p = .049; β = 0.015, p = .040; β = 0.016, p = .025, respectively). In conclusion, the dietary salt intake in CKD patients, especially in male, overweight and obese subjects, remains high in Jiangsu province. It is vital to decline salt intake to control blood pressure in Jiangsu patients with CKD.

SALT-SENSITIVE BLOOD PRESSURE RISE IN TYPE 1 DIABETES IS ACCOMPANIED BY INCAPACITY FOR VASODILATION – A RANDOMIZED EXPERIMENTAL CROSS-OVER STUDY

Objective: Diabetes mellitus type 1 (DM1) is suggested to be associated with salt sensitivity. However, strong evidence to support this is scarce, and the pathophysiology is not known. For a long time, the volume-regulating function of the kidney was thought to be the only important factor in salt-sensitive hypertension. Due to insufficient sodium excretion by the kidney, sodium excess was considered to increase extracellular fluid volume (ECFV) and cardiac output (CO), resulting in a blood pressure (BP) rise. However, recent publications put forward that systemic vascular resistance (SVR) might be central in BP regulation. We hypothesized that in salt-sensitive hypertension in DM1, vasodysfunction rather than increases in ECFV and CO plays a role.Design and method: We included 8 DM1 patients and 12 age-matched healthy controls (HC), with normal BP, body mass index, and kidney function. All subjects adhered to an 8-day low salt diet (LSD) and an 8-day high salt diet (HSD), in randomized order. After each diet, hemodynamic measurements included BP (Omron) and CO (Nexfin™), and SVR was calculated accordingly. To assess volume-dependent changes, ECFV, interstitial fluid volume (IFV) and plasma volume (PV) were calculated by the use of iohexol and 125I-albumin distribution. HC were divided in two subgroups: those with versus those without a BP increase after HSD. Results: After HSD, patients with DM1 showed a BP increase (mean arterial pressure HSD vs LSD (85 (5) mmHg vs. 80 (3) mmHg; P = 0.03) while BP in HC did not rise (78 (5) mmHg vs. 78 (5) mmHg; P = 0.85). The difference in BP response was not accompanied by differences in urinary sodium excretion between the DM1 patients and HC (Figure 1) nor by differences in CO, ECFV or ICF (Table 1). HC without a BP increase after HSD (n = 5) showed a SVR reduction after HSD, while this reduction was not present in the HC with a BP increase after HSD (n = 7) or in the DM1 patients (Figure 2, Table 1). Conclusions: DM1 is associated with increased salt sensitivity compared to HC, coinciding with incapacity for vasodilation.

Protein kinase Cα deletion causes hypotension and decreased vascular contractility

Protein kinase Cα (PKCα) is a critical regulator of multiple cell signaling pathways including gene transcription, posttranslation modifications and activation/inhibition of many signaling kinases. In regards to the control of blood pressure, PKCα causes increased vascular smooth muscle contractility, while reducing cardiac contractility. In addition, PKCα has been shown to modulate nephron ion transport. However, the role of PKCα in modulating mean arterial pressure (MAP) has not been investigated. In this study, we used a whole animal PKCα knock out (PKC KO) to test the hypothesis that global PKCα deficiency would reduce MAP, by a reduction in vascular contractility. Radiotelemetry measurements of ambulatory blood pressure (day/night) were obtained for 18 h/day during both normal chow and high-salt (4%) diet feedings. PKCα mice had a reduced MAP, as compared with control, which was not normalized with high-salt diet (14 days). Metabolic cage studies were performed to determine urinary sodium excretion. PKC KO mice had a significantly lower diastolic, systolic and MAP as compared with control. No significant differences in urinary sodium excretion were observed between the PKC KO and control mice, whether fed normal chow or high-salt diet. Western blot analysis showed a compensatory increase in renal sodium chloride cotransporter expression. Both aorta and mesenteric vessels were removed for vascular reactivity studies. Aorta and mesenteric arteries from PKC KO mice had a reduced receptor-independent relaxation response, as compared with vessels from control. Vessels from PKC KO mice exhibited a decrease in maximal contraction, compared with controls. Together, these data suggest that global deletion of PKCα results in reduced MAP due to decreased vascular contractility.

110-POS

Objectives Preeclampsia is a hypertensive disorder of pregnancy known to increase the risk of cardiovascular disease in both mothers and offspring later in life. Offspring exposed to a suboptimal intrauterine environment during critical periods of growth may experience altered fetal programming and subsequent long term cardiovascular changes. The aim of this study was to investigate changes in vascular response in offspring from experimental preeclamptic (EPE) compared to normotensive baboon pregnancies (controls), following a high salt diet challenge. Methods After one week of baseline measurements on a standard diet, animals were fed a high salt diet for two weeks. Systolic and diastolic blood pressure (SBP, DBP) were measured and urinary sodium assessed in offspring from EPE (n = 6) and controls (n = 6). A generalized linear model was performed to compare BP between the two groups at both baseline and day 14, adjusted for current age. Data is reported as the mean ± standard error. Significance was set at P Results At baseline there were no differences between the groups for SBP (P = 0.89) and DBP (P = 0.38). After salt loading the EPE group had significantly higher SBP (92 ± 5 mmHg) compared to the control group (83 ± 4 mmHg, P = 0.03). There was no significant difference in DBP between the two groups (P = 0.10). There was no difference in urinary sodium excretion between groups (average for both groups 30 mmol/day). Conclusions Offspring from EPE pregnancies had significantly higher blood pressure after a two week salt challenge, compared with controls. Salt sensitivity may differ in offspring from hypertensive pregnancies due to fetal programming. This could have long term consequences for cardiovascular health of EPE offspring. Further research is required to determine exact mechanisms. Disclosures K.R. Yeung: None. S.M. Lim: None. S. Heffernan: None. S. Pears: None. J.M. Lind: None. A. Hennessy: None. A. Makris: None.

Effects of Etoricoxib and Comparator Nonsteroidal Anti‐Inflammatory Drugs on Urinary Sodium Excretion, Blood Pressure, and Other Renal Function Indicators in Elderly Subjects Consuming a Controlled Sodium Diet

This multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessed renal function during dosing with etoricoxib 90 mg daily, celecoxib 200 mg twice daily, and naproxen 500 mg twice daily. Male and female subjects 60 to 81 years old (n = 85), in sodium balance on a controlled, normal sodium diet, were treated for 15 days. There were no clinically meaningful between-treatment differences in urinary sodium excretion, creatinine clearance, body weight, or serum electrolytes during the 2 weeks of treatment. Etoricoxib and celecoxib had no effect on the urinary thromboxane metabolite, 11-dehydrothromboxane B(2), while significantly decreasing the urinary prostacyclin metabolite, 2,3-dinor-6-keto PGF(1alpha). Decreases were greater for both metabolites following naproxen. Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with moderately greater increases for etoricoxib relative to other active treatments on day 14. Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen but not for celecoxib.

Enhanced Superoxide Activity Modulates Renal Function in NO-Deficient Hypertensive Rats

An enhancement of superoxide (O2-) activity was shown to contribute to the development of hypertension induced by NO deficiency. To better understand the mechanistic role of O2- in this NO-deficient hypertension, we evaluated the renal responses to acute intraarterial administration of an O2- scavenger, tempol (50 microg/min per 100 g of body weight) in anesthetized male Sprague-Dawley rats treated with NO synthase inhibitor nitro-L-arginine methyl ester (15 mg/kg per day in drinking water, n=7) for 4 weeks, which caused increases in mean arterial pressure (146+/-3 versus 124+/-2 mm Hg) compared with normotensive control rats (n=6). Hypertensive rats had higher renal vascular resistance (29+/-2 versus 20+/-1 mm Hg/mL per minute per gram), as well as lower renal blood flow (5.2+/-0.3 versus 6.3+/-0.2 mL/min per gram; cortical blood flow, 153+/-13 versus 191+/-8 perfusion units; medullary blood flow, 43+/-2 versus 51+/-3 perfusion units) and glomerular filtration rate (0.69+/-0.04 versus 0.90+/-0.05 mL/min per gram) without a significant difference in urinary sodium excretion (0.81+/-0.07 versus 0.86+/-0.12 micromol/min per gram) compared with normotensive rats. Urinary 8-isoprostane excretion rate (6.8+/-0.7 versus 4.5+/-0.3 pg/min per gram) was higher in hypertensive than normotensive rats. Intraarterial infusion of tempol did not alter renal function in normotensive rats. However, tempol significantly decreased renal vascular resistance by 12+/-2% and urinary 8-isoprostane excretion rate by 24+/-4% and increased renal blood flow by 10+/-2%, cortical blood flow by 9+/-2%, medullary blood flow by 15+/-6%, glomerular filtration rate by 11+/-3%, and urinary sodium excretion by 19+/-5% in hypertensive rats. These data indicate that enhanced O2- activity modulates renal hemodynamics and excretory function during reduced NO production and, thus, contributes to the pathophysiology of the NO-deficient form of hypertension.

Temporal influence of the renal nerves on renal excretory function during chronic inhibition of nitric oxide synthesis.

To determine whether the sympathetic nervous system contributes to the hypertension induced by long-term suppression of nitric oxide synthesis, we determined the neurally induced changes in renal excretory function during chronic administration of NG-nitro-L-arginine methyl ester (L-NAME). Studies were carried out in six conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into two hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. Animals were studied during acute (100 minutes) and chronic (5 days) intravenous infusion of L-NAME at 37.1 nmol/kg per minute (10 micrograms/kg per minute). During the first 100 minutes of L-NAME, there were no significant changes in mean arterial pressure (control: 96 +/- 3 mm Hg), but heart rate fell from 66 +/- 6 to 55 +/- 7 beats per minute. Changes in glomerular filtration rate were not significant, but renal plasma flow and urinary sodium excretion decreased to approximately 75% and 50% of control values, respectively; however, these changes were comparable in both kidneys. In association with these responses, plasma concentrations of norepinephrine (control: 887 +/- 130 pmol/L or 150 +/- 22 pg/mL) and epinephrine (control: 691 +/- 192 pmol/L or 108 +/- 30 pg/mL) tended to decrease. In contrast to the acute responses, mean arterial pressure increased from 92 +/- 3 to 106 +/- 3 mm Hg and heart rate decreased from 72 +/- 4 to 57 +/- 5 beats per minute by day 5 of L-NAME infusion, while renal plasma flow and glomerular filtration rate were not significantly different from control values. Most importantly, there were no significant differences in urinary sodium excretion between innervated (control: 31 +/- 2 mmol/d) and denervated (control 33 +/- 2 mmol/d) kidneys during chronic L-NAME infusion or during the recovery period. These results indicate that the renal sympathetic nerves do not play an important role in promoting sodium retention during either acute or chronic inhibition of nitric oxide synthesis in conscious dogs. Thus, increased renal sympathetic nerve activity does not contribute significantly to L-NAME-induced hypertension.

Enhanced slow pressor effect of angiotensin II in two-kidney, one clip rats.

Phase II of two-kidney, one clip (2K1C) Goldblatt hypertension in the rat is characterized by elevated blood pressure and near-normal plasma concentrations of angiotensin II (Ang II) but is reversed by inhibition of the renin-angiotensin system. We hypothesized that this angiotensin dependence is due to enhanced responsiveness to the slow pressor effect of Ang II caused by renal artery stenosis. To test this idea, we submitted rats to either renal artery clipping or sham operation. These groups were immediately subdivided; some animals received enalapril in their drinking water (508 mumol/L), and the rest drank distilled water only. After 10 to 14 days, catheters were inserted into the aorta and vena cava, and the rats were housed in metabolism cages. After 3 control days of measurement of mean arterial pressure and other variables, the enalapril-treated groups received an intravenous infusion of Ang II at a dose of 3.8 pmol/min (4 ng/min) for 14 days. Rats not drinking enalapril received only saline vehicle (2 mmol Na+ per day). After 3 days of Ang II infusion, the enalapril-treated 2K1C rats had attained a significantly higher level of mean arterial pressure than the enalapril-treated sham rats. At the end of the Ang II infusion, mean arterial pressure in enalapril-treated 2K1C rats was 151 +/- 6 mm Hg versus 107 +/- 7 mm Hg in enalapril-treated sham rats. Mean arterial pressure in the enalapril-treated sham rats after Ang II infusion was not significantly different from that of untreated sham rats (109 +/- 2 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting and 24-h Urinary Sodium/Creatinine Values in Young and Elderly Women on Low-Salt and Salt-Supplemented Regimens

A high sodium intake is a risk factor for both hypertension and osteoporosis. High-salt diets cause calciuresis and may influence blood pressure (BP) by stimulating calcium-regulating hormones and augmenting intracellular calcium concentrations. Urinary calcium rises in parallel with urinary sodium. However, aging may influence the rate of excretion of a dietary sodium load. This study compares sodium/creatinine (Na/Cr) values in 2-h urines collected after an overnight fast (12 h) with values obtained in 24-h urines from normotensive women aged (a) 19-23 years (n = 6) and (b) 65-70 years (n = 9) who were consuming either 70 mmol of Na/day [low-sodium regimen (LSR)] or 170 mmol of Na/day [supplemental sodium regimen (SSR)]. Young and elderly women excreted similar amounts of sodium per 24-h period. The 24-h urinary sodium excretion matched dietary sodium input appropriately on LSR and SSR, and SSR raised calcium excretion by 30%. However, whereas in the young women Na/Cr values were similar in fasting and 24-h collections on both LSR and SSR, these values were higher in 24-h than in fasting urines on SSR in the elderly women. We attribute this response to temporal differences in urinary sodium excretion associated with aging. We conclude that assessing sodium excretion from fasting urinary sodium measurements may underestimate total sodium loss (and hence calcium loss) in subjects on a stable sodium intake, particularly in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting and 24-h Urinary Sodium/Creatinine Values in Young and Elderly Women on Low-Salt and Salt-Supplemented Regimens

A high sodium intake is a risk factor for both hypertension and osteoporosis. High-salt diets cause calciuresis and may influence blood pressure (BP) by stimulating calcium-regulating hormones and augmenting intracellular calcium concentrations. Urinary calcium rises in parallel with urinary sodium. However, aging may influence the rate of excretion of a dietary sodium load. This study compares sodium/creatinine (Na/Cr) values in 2-h urines collected after an overnight fast (12 h) with values obtained in 24-h urines from normotensive women aged (a) 19-23 years (n = 6) and (b) 65-70 years (n = 9) who were consuming either 70 mmol of Na/day [low-sodium regimen (LSR)] or 170 mmol of Na/day [supplemental sodium regimen (SSR)]. Young and elderly women excreted similar amounts of sodium per 24-h period. The 24-h urinary sodium excretion matched dietary sodium input appropriately on LSR and SSR, and SSR raised calcium excretion by 30%. However, whereas in the young women Na/Cr values were similar in fasting and 24-h collections on both LSR and SSR, these values were higher in 24-h than in fasting urines on SSR in the elderly women. We attribute this response to temporal differences in urinary sodium excretion associated with aging. We conclude that assessing sodium excretion from fasting urinary sodium measurements may underestimate total sodium loss (and hence calcium loss) in subjects on a stable sodium intake, particularly in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

Water and sodium excretion in unilaterally denervated normal and sodium depleted anesthetized rats before and after plasma volume repletion

The possible role of a reduction in plasma volume (PV) by surgery as well as the importance of dietary Na supply in denervation natriuresis have been investigated on Inactin-anesthetized male rats subjected to acute unilateral renal sympathectomy. Four groups were studied: I. Normal Na diet (n = 14); II. Low Na diet (boiled rice for 2 weeks) -- isotonic glucose infusion (n = 10); III. Low Na diet -- isotonic saline infusion (n = 5); IV. Normal and low Na diet rats served as conscious control (n = 10). Surgery caused a 9-11% increase in hematocrit and a 15-18% decrease in PV in groups I-III. Plasma volume repletion (PVR) reverted these changes. In group I sodium excretion from both kidneys was only a fraction of that in conscious animals kept on the same diet (group IV) and marked denervation natriuresis was observed. After PVR sodium output of innervated (I) kidneys was not different from that of conscious rats but denervated (D) kidneys excreted twice that amount. In group II Na excretion was increased compared to conscious Na depleted controls, and PVR augmented further this difference. Surprisingly, the difference in urinary sodium excretion (UNaV) between I and D kidneys was absent after surgery and was minimal after PVR in this group. In group III physiological saline infusion reverted the effect of Na depletion and denervation natriuresis was present both before and after PVR. It is concluded that PV reduction does not play a major role in denervation phenomenon. In Na depleted anesthetized rats denervation natriuresis is absent or minimal.

A comparison of the segmental analysis of sodium reabsorption during Ringer's and hyperoncotic albumin infusion in the rat.

Studies were designed to compare the segmental analysis of sodium reabsorption along the nephron during volume expansion with either 10% body weight Ringer's or 0.6% body weight hyperoncotic albumin. Total kidney and nephron glomerular filtration rate increased similarly with both, but urinary sodium excretion (12.7 vs. 4.0 mueq/min, P < 0.001) and fractional sodium excretion (5.0 vs. 1.6%, P < 0.001) increased to a greater extent with Ringer's. Fractional reabsorption of sodium in the proximal tubule was diminished in both groups but to a significantly greater extent during Ringer's (P < 0.005). Absolute reabsorption was inhibited only in the Ringer's group. Delivery of filtrate out of the proximal tubule was greater in the Ringer's studies, 45 vs. 37 nl/min (P < 0.001). However, both fractional and absolute sodium delivery to the early and late distal tubule were not significantly different in the two groups. Fractional reabsorption in the collecting duct decreased from 96% in hydropenia to 31% during Ringer's but fell only slightly to 80% in the albumin studies. Absolute collecting duct reabsorption was also greater in the albumin studies, 0.55 vs. 0.21 neq/min (P < 0.001), which could totally account for the difference in urinary sodium excretion between the two groups. (22)Na recovery in the final urine after end distal microinjections was 71% during Ringer's infusion and 34% during albumin (P < 0.001). From these data we conclude that: (a) Ringer's solution has a greater inhibitory effect on proximal tubular sodium reabsorption, and (b) in spite of this effect, differences in mucosal to serosal collecting duct sodium transport are primarily responsible for the greater natriuresis during Ringer's infusion.