Increase In Renal Sodium Excretion Research Articles

Fluid intake and blood pressure in children: the Salus per Aquam project.

Sodium intake is known to contribute to the development of hypertension, thus intake reduction is a cornerstone in the prevention and management of hypertension. The increase in renal sodium excretion might represent a further potential preventive and/or therapeutic opportunity. To explore the working hypothesis that an increased fluid intake can improve renal sodium handling towards a decrease in blood pressure. The SPA Project is a multicenter, observational, cross-sectional, cohort study investigating healthy children, aged 5-8 years as to sodium and fluid intake by means of urinary sodium and creatinine from multiple samples taken in different days in order to characterize them in lower/higher sodium and lower/higher fluid intake. Both SBP and DBP (by multiple office blood pressure measurements) were used as outcome measures. Three hundred and thirty-nine healthy, nonoverweight children (51.6% boys) with a median age of 5.7 years old (IQR: 5.3-6.2) participated in the study but only 223 could be analyzed. Among children with higher sodium intake, those introducing more fluids, showed a significantly lower blood pressure (both systolic and diastolic) compared with those with lower fluid intake: systolic 86.0 ± 8.5 vs. 90.0 ± 8.1 mmHg; P = 0.014 and diastolic: 53.8 ± 4.9 vs. 58.6 ± 6.6 mmHg; P < 0.0001. An increased fluid intake is associated with a reduced blood pressure possibly by increasing renal sodium excretion. We speculate that this simple, highly acceptable, inexpensive, and harmless measure might have a role in preventing and/or minimizing the epidemics of hypertension and of its related morbidities both in children and in adults.

Fluid Intake and Blood Pressure in Children. The Spa Project

Background: Sodium intake is known to contribute to the development of hypertension. The reduction of sodium intake is currently a cornerstone in the prevention and management of hypertension. Inducing an increase in renal sodium excretion might represent a further potential preventive and/or therapeutic opportunity .Methods: The SPA Project is a multicenter, observational, cohort study aimed at investigating blood pressure in relation to fluid and sodium intake with the working hypothesis that an increased fluid intake can improve renal sodium handling towards a decreased blood pressure. Children were investigated as to their sodium and fluid intake by means of urinary sodium and creatinine from 4 samples of urine taken in different days in order to characterize them in low/high sodium and low/high fluid intake groups. Both systolic and diastolic blood pressure (by multiple office blood pressure measurements) were used as outcome measures.Findings: Three hundred and thirty-nine healthy, non-overweight children (51.6% boys) with a median age of 5.7 years old (IQR: 5.3-6.2) participated in the study. Among children with higher sodium intake, those introducing more fluids, showed a significantly lower blood pressure (both systolic and diastolic) compared to those with lower fluid intake: systolic 86.0 + 8.5 vs 90.0 + 8.1 mmHg; p: 0.014 and diastolic: 53.8 + 4.9 vs 58.6 + 6.6 mmHg; p<0.0001. A difference in blood pressure was not observed among children with lower sodium intake. Interpretation: Our findings support the hypothesis that an increased fluid intake reduces blood pressure possibly by increasing renal sodium excretion. We speculate that this simple, highly acceptable, inexpensive and harmless measure might have a role in preventing and/or minimizing the epidemics of hypertension and of its related morbidities both in children and in adults. Funding: The SPA Project was financed by an unrestricted research grant from private source. The funder did not participate in the work. Declaration of Interest: None to declare. Ethical Approval: Ethical approval was granted by the local ethical committee., The study was performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments.

Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma.

Human studies have demonstrated that physiologically relevant changes in circulating glucagon‐like peptide‐1 (GLP‐1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut‐kidney axis, responsible for a rapid‐acting feed‐forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP‐1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12‐hr fasting period. Arterial blood samples were collected at 10–20‐min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty‐four‐hour baseline urinary sodium excretions were similar between study days. Arterial GLP‐1 levels increased during both oral glucose loads and were significantly higher at the 40–80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose‐dependent insulinotropic polypeptide as well as glucose, insulin, and C‐peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP‐1 was higher (60–80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP‐1 plasma concentration. Thus, GLP‐1 may be part of an acute feed‐forward mechanism for natriuresis.

1956-P: Increased Salt Intake Amplifies the Postprandial Glucagon-Like Peptide-1 Secretion

We have previously demonstrated that physiologically relevant changes in circulating glucagon-like peptide-1 (GLP-1) elicit a rapid increase in renal sodium excretion during intravenous sodium loading. The present study was designed to investigate the hypothesis that postprandial GLP-1 secretion is sensitive to dietary salt intake and is part of a feedforward natriuretic system. Under fixed sodium intake, 11 lean healthy males were examined twice in random order. Arterial blood samples were collected in 10-20 min intervals for 140 minutes after 75-g oral glucose load vs. 75-g oral glucose + 6-g oral salt load. Subjects remained supine during the experiments. Prior to each experiment, all subjects conducted a 4-day standardized diet with fixed salt intake and 24-h urine collections were completed successfully with urinary sodium excretions being similar between subjects (116±10 mmol). Arterial GLP-1 levels increased transiently in both studies and were higher around 80 min after the glucose+salt load compared to glucose alone (46 ± 4 pmol/L vs. 33 ± 3 pmol/L, p=0.011). The postprandial increase in arterial CCK levels was reduced by the glucose+salt load throughout the study (1.9 ± 0.1 pmol/L vs. 2.8 ± 0.2 pmol/L, p&amp;lt;0.001), whereas arterial GIP and gastrin levels increased transiently and similarly in both studies. The transient increase in arterial glucose, insulin and c-peptide levels were similar on both study days. Arterial renin and aldosterone levels did not change within subjects and between study days, whereas angiotensin II was significantly reduced around 80 min after the glucose+salt load (10.9 ± 1.5 pg/mL vs. 14.4 ± 1.5 pg/mL, p=0.004). Arterial proANP, ANP, and BNP levels remained unchanged on both days. This study demonstrates that an increased salt intake amplifies the postprandial GLP-1 secretion in healthy individuals, supporting a possible GLP-1-mediated feedforward natriuretic system, likely via a suppression of angiotensin II. Disclosure A. Asmar: None. P.K. Cramon: None. C.M. Sorensen: None. S. Madsbad: None. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. B.L. Jensen: None. M. Asmar: None.

Effect of Treatment on Body Fluid in Patients with Unilateral Aldosterone Producing Adenoma

Background: There is limited information about the effect of prolonged aldosterone excess and treatment on body fluid. Objective: To investigate the effects of adrenalectomy versus spironolactone treatment on body composition in primary aldosteronism (PA) patients with unilateral aldosterone producing adenoma (APA). Method: We determined body composition changes assessed by a bio-impedance spectroscopy device, the Body Composition Monitor (BCM). We examined pretreatment relative overhydration (%), relative fat (%) and relative lean tissue mass (%) in PA patients with APA and followed-up with patients after adrenalectomy or spironolactone treatment. We also assessed biomarkers related to fluid overload. Results: This prospective, multicenter study included 41 PA patients with APA. Twenty-one patients received adrenalectomy, whereas 20 patients were treated with spironolactone. Patients with APA receiving adrenalectomy, as compared with those treated with spironolactone, had significantly lower relative OH (p = 0.011) and urine albumin excretion (p = 0.003), and significantly higher urine sodium excretion (p < 0.001) and relative fat (p = 0.034) four weeks after treatment. These differences dissipated 12 weeks after the initial treatment. Patients who underwent adrenaelctomy had significantly decreased TNF-α and increased serum potassium level when compared to patients treated with spironolactone 4 and 12 weeks after treatment. Conclusions: In this pilot study, we found that adrenalectomy leads to the normalization of plasma aldosterone concentration followed by an earlier increase in renal sodium excretion and decreases in body fluid content, TNF-α, and urine albumin excretion. Adrenalectomy yields a therapeutic effect more rapidly, which has been shown to ameliorate overhydration in PA patients.

Abstract 516: Intestinal Cell Gastrin Secretion is Regulated by a Sodium-Induced Increase in PPAR-A that is Mediated by Dopaminergic Stimulation

Recently a novel gastro-renal axis has been discovered for the regulation of renal sodium excretion at the moment of sodium ingestion. Cells in the digestive track secrete gastrin in response to sodium ingestion which stimulates an increase in renal sodium excretion. Dopamine is largely responsible for the regulation of sodium excretion in the kidney, and has also been shown to decrease sodium transport in intestines. We hypothesized that dopamine might also be involved with the regulation of gastrin secretion in a human intestinal gastrin secreting cell line (SW626, ATCC, Manassas VA) that also contains dopaminergic receptors. We used the ionophore monensin (MON) to increase intracellular sodium in SW626 cells in order to simulate an oral sodium load. We also stimulated the cells with the dopaminergic agonist SKF38393 (SKF, D 1 -like receptor agonist). These two manipulations (compared to vehicle VEH) caused increased relative gene expression of gastrin (ΔΔCt gastrin to actin, VEH 0.00638±0.00283; MON 0.3913372±0.0985926; SKF 0.2139286±0.0253672; P&lt;0.01 VEH vs MON or SKF, N=6 per group). Peroxisome proliferator-activated receptor-alpha (PPAR-α) associates with the gastrin transcriptional promoter by CHIP-SEQ (ENCODE database) and PPAR-α activation by fenofibrate (FENO) has been shown to reduce blood pressure and increase sodium excretion. We hypothesized that PPAR alpha would increase gastrin expression. FENO increased the immunoreactive gastrin and this effect was blocked by a PPAR alpha antagonist GW6471 (VEH 16,440±2,438 RFU; FENO 42,639±4,891; FENO+GW 19,367±1,865; P&lt;0.001 VEH vs FENO and FENO vs FENO+GW). Stimulation with MON or SKF also significantly stimulated the production of immunoreactive gastrin (VEH 16,440±2,438 RFU; MON 22,345±935; SKF 24,386±1,124; GW alone 10,235±1,214; P&lt;0.05 VEH vs MON, SKF, or GW, N=6). SW626 appear to secrete gastrin, therefore we tested the ability of secreted gastrin obtained from the media bathing SW626 cells to bind to i22 human renal proximal tubule cells (RPTC). After incubation of i22 RPTC in SW626 media for 24 hours, we detected surface gastrin staining on the i22 RPTC. We conclude that gastrin is produced by SW626 cells, is secreted into the growth media, and can bind to cell surface receptors on RPTC.

Saline loading does not change renal medullary blood flow in essential hypertension

In essential hypertension (EH), the natriuresis during saline loading is exaggerated. It was hypothesized that this phenomenon is associated with an increase in renal medullary blood flow. Patients (n=6) with mild, monosymptomatic EH were investigated after an 18‐d drug washout period including 4 d on standardized diet. Regional, renal blood flows were determined before and after saline loading (0.72 mmol/kg/h for 4 h) by Positron Emission Tomography and Computer Tomography (PET/CT) using H215O tracer (Am J Physiol Regul Integr Comp Physiol 299:R1449, 2010). Renal medullary blood flows (ml/(g tissue)/min) were 2.0 ±0.4 and 1.7 ±0.3* before and after saline loading, respectively. During saline loading BP (mmHg) changed from 147.6/86.1 ±6.5/3.1 to 157.1*/92.1† ±4.4/3.3. Renal sodium excretion (μmol/min) increased from 39.2 ±7.0 to 145.6 ±38.5†. It is concluded that the increase in renal sodium excretion during saline loading is not associated with an increase in renal medullary blood flow. *(P = ns) †(P &lt; 0.05)Funded by The Danish Heart Foundation and The University of Southern Denmark.

Retrograde signaling does not mediate sodium excretion during dorsal column stimulation

Prior work found an increase in renal sodium excretion in male spontaneously hypertensive rats (SHR) following dorsal spinal column stimulation (DCS) at the spinal segment of the left renal sensory nerves (T12–T13). General sympathetic tone, and renal blood flow were unaltered by DCS. The effects of dorsal rhizotomy on the DCS‐induced renal sodium excretion was investigated in male SHR. SHR were randomly assigned to one of the following groups: no‐stimulation (NS), stimulation (S), no stimulation + Rhizotomy (NS+R), and Stimulation + Rhizotomy (S+R). Stimulated rats received DCS during the 2nd of five 15‐min. collection periods. Blood pressure was measured via a carotid artery cannula, and urine was collected via a bladder cannula. A standard stimulation parameter of 66% of the motor threshold (0.2 msec duration and 50 Hz) was used. Urine sodium was analyzed using flame photometry. Sodium excretion was significantly elevated in periods 3 and 4 in the S group when compared with corresponding periods in the NS group. Sodium excretion was significantly elevated in period 5 in the S+R group when compared with the NS+R. There were no differences between the S+R and the S groups. The DSC‐induced increase in sodium excretion is independent of retrograde signaling in the renal nerves. This research was funded by a departmental grant, in the Department of the Biological Sciences, Minnesota State University, Mankato, MN

Management of Refractory Ascites

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, high-dose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction (<90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (<78 mmol/d). Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated paracentesis and improves the quality of life. Several treatments that act at different steps in the pathogenesis of ascites are investigational, and some show promising results. Splanchnic and peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial volume and decrease activation of the renin-angiotensin system with resultant increase in renal sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid mobilization of ascites by significantly decreasing the sympathetic activity and renin-aldosterone levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign, liver transplantation should be considered and incorporated early in the treatment plan.

Impairment of Na/K-ATPase Signaling in Renal Proximal Tubule Contributes to Dahl Salt-sensitive Hypertension

We have observed that, in renal proximal tubular cells, cardiotonic steroids such as ouabain in vitro signal through Na/K-ATPase, which results in inhibition of transepithelial (22)Na(+) transport by redistributing Na/K-ATPase and NHE3. In the present study, we investigate the role of Na/K-ATPase signaling in renal sodium excretion and blood pressure regulation in vivo. In Sprague-Dawley rats, high salt diet activated c-Src and induced redistribution of Na/K-ATPase and NHE3 in renal proximal tubules. In Dahl salt sensitive (S) and resistant (R) rats given high dietary salt, we found different effects on blood pressure but, more interestingly, different effects on renal salt handling. These differences could be explained by different signaling through the proximal tubular Na/K-ATPase. Specifically, in Dahl R rats, high salt diet significantly stimulated phosphorylation of c-Src and ERK1/2, reduced Na/K-ATPase activity and NHE3 activity, and caused redistribution of Na/K-ATPase and NHE3. In contrast, these adaptations were either much less effective or not seen in the Dahl S rats. We also studied the primary culture of renal proximal tubule isolated from Dahl S and R rats fed a low salt diet. In this system, ouabain induced Na/K-ATPase/c-Src signaling and redistribution of Na/K-ATPase and NHE3 in the Dahl R rats, but not in the Dahl S rats. Our data suggested that impairment of Na/K-ATPase signaling and consequent regulation of Na/K-ATPase and NHE3 in renal proximal tubule may contribute to salt-induced hypertension in the Dahl S rat.

Protein-enriched diet increases water absorption via the aquaporin-2 water channels in healthy humans

According to animal experiments, a protein-enriched diet increased renal absorption of sodium and water. We wanted to test the hypothesis that a protein-enriched diet would increase the expression of the aquaporin-2 water channels and the epithelial sodium channels in the distal part of the nephron using biomarkers for the activity of the two channels. We performed a randomized, placebo controlled crossover study in 13 healthy humans to examine the effect of a protein-enriched diet on renal handling of water and sodium during baseline condition and during hypertonic saline infusion. We measured the effect of the protein-enriched diet on urinary excretions of aquaporin-2 (u-AQP2), the beta-fraction of the epithelial sodium channels (u-ENaC(beta)), free water clearance (C(H2O)), fractional excretion of sodium and vasoactive hormones. During baseline conditions, u-AQP2 increased, and C(H2O) decreased during the protein-enriched diet, whereas u-ENaC(beta) was unchanged, although the urinary sodium excretion increased. During hypertonic saline infusion, the response in the effect variables did not deviate between protein-enriched and normal diet. Plasma concentrations of angiotensin II and aldosterone increased as well as pulse rate. Vasopressin in plasma was unchanged, and prostaglandin E(2) fell during the protein-enriched diet. The protein-enriched diet increased water absorption via an increased transport via the aquaporin-2 water channels. The increased u-AQP2 might be due to a reduced prostaglandin level. The increase in renal sodium excretion seems to be mediated in another part of the nephron than the epithelial sodium channels.

Hypothalamic paraventricular nucleus mediates sodium-induced changes in cardiovascular and renal function in conscious sheep

The contribution of the paraventricular nucleus of the hypothalamus (PVN) in mediating cardiovascular, renal, hormonal, and sympathetic nerve responses to increased cerebrospinal fluid (CSF) [Na(+)] was investigated in conscious sheep. Intracerebroventricular hypertonic NaCl (0.5 mol/l, 20 microl/min for 60 min) increased arterial blood pressure [AP; +13.4 (sd 2.0) mmHg, P < 0.001] and central venous pressure [CVP; +2.8 (sd 1.3) mmHg, P < 0.001], but did not significantly change heart rate or cardiac output (n = 6). Elevated CSF [Na(+)] also lowered plasma ANG II levels [-3.3 (sd 1.6) pmol/l, P = 0.004] and increased creatinine clearance [+31.5 (sd 32.7) ml/min, P = 0.03] and renal sodium excretion [+9.2 (sd 9.2) mmol/h, P = 0.003]. Lidocaine injection (1 microl, 2%) into the PVN prior to the ICV infusion had no apparent effect per se, but it abolished the AP, CVP, creatinine clearance, and ANG II responses to hypertonic NaCl, as well as reducing the increase in renal sodium excretion (n = 6). Subsequent studies were performed in conscious sheep with chronically implanted electrodes for measurement of renal sympathetic nerve activity (RSNA). The effects of ICV hypertonic NaCl on AP and RSNA were measured before and after PVN-injection of glycine (250 nmol in 500 nl artificial CSF). ICV NaCl increased AP and decreased RSNA (P < 0.001). These effects were significantly reduced by glycine (P = 0.02-0.001, n = 5). Saline injected into the PVN (n = 5) or lidocaine injected outside the PVN (n = 6) had no effect on the response to ICV hypertonic NaCl. These results indicate that the PVN is an important mediator of cerebrally induced homeostatic responses to elevated sodium concentration/hyperosmolality.

The increase in renal sodium excretion in response to Angiotensin II infusion in exercised female rats is dependent on a rise in renal perfusion pressure.

Prior studies in this lab have shown that chronically exercised female spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats excrete a greater amount of sodium in response to angiotensin II infusion than do sedentary rats. The current study determined if the difference in renal sodium excretion persisted when the renal perfusion pressure (RPP) was held constant. Female SHR and female WKY rats were separated into sedentary and exercise groups at 4 weeks of age. The exercise group voluntarily exercised for at least eight weeks using an exercise wheel and time/distance monitor. At 13 weeks of age or older, rats were anesthetized and catheters were placed into the jugular vein, and carotid and femoral arteries. A noose, placed around the abdominal aorta, was continually adjusted to maintain a constant RPP during Ang II infusion. Ang II was infused at 0, 0.125, 0.5, and 2µg/ml saline, each for 15 minutes. MAP and RPP were measured continually. Urine was collected during each 15 minute period and analyzed for sodium excretion. Sodium excretion did not significantly increase with the Ang II infusions when RPP was held constant, and no difference was found between the exercised and sedentary rats. The increase in renal sodium excretion observed in exercised female rats compared to sedentary appears to be due to a difference in the pressure natriuresis response. Funding: Department of Biological Sciences, MSU, M.

Glucagon-Like Peptide-1 Is Involved in Sodium and Water Homeostasis in Humans

In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. Methods: Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7 ± 0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7 ± 0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg × min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. Results: In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6 ± 0.3 (placebo) to 2.7 ± 0.2% (GLP-1; p = 0.0005). There was no difference in water consumption between the two treatments: 1,291 ± 69 (saline) vs. 1,228 ± 74 ml (GLP-1; p = 0.49). In part B, an oral salt challenge of 27.7 ± 0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6 ± 0.2% (placebo) to 2.0 ± 0.2% (GLP-1; p = 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848 ± 331 ml (placebo) vs. 1,181 ± 177 ml (GLP-1; p = 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p < 0.02). Conclusions: GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.

Renal denervation (RD) does not prevent the hypertensive response to chronic baroreceptor unloading (CBU) in the dog

We have reported that CBU causes a sustained increase in mean arterial pressure (MAP) in the dog (AJP 288: R863-R871, 2005). In the present study, we tested the hypothesis that the renal nerves are essential for the increase in MAP following CBU. Dogs (n=5) were housed in metabolism cages to determine daily sodium excretion and MAP was recorded continuously via telemetry (DSI International). After four control days, the carotid artery proximal to an innervated carotid sinus was ligated to produce CBU (all other baroreceptive areas previously denervated). After seven days of CBU, the ligature was removed. Subsequently, the kidneys were denervated bilaterally and at least 14 days later, the experimental protocol was repeated. The average MAP (in mmHg ± 1SE) in the Control, CBU and Recovery periods are shown in the table below. ANOVA indicated a significant effect of CBU on MAP but no effect of RD on the MAP response to CBU and no interaction between the CBU and RD factors. There was a significant increase in renal sodium excretion on the first day of CBU in both treatment conditions but sodium excretion returned to control levels thereafter. We conclude that the renal nerves are not required to sustain the increase in MAP caused by seven days of CBU in the dog. (Supported by HL 67329)

Effect of BQ-123, an Endothelin Antagonist, on Renal Hemodynamics, Tubular Function, Vasoactive Hormones, and Blood Pressure in Healthy Humans: A Dose Response Study

Endothelin contributes to the maintenance of vascular tonus in both the systemic circulation and in regional vascular beds. The purpose of the study was to measure the effect of the endothelin A antagonist BQ-123 on renal hemodynamics, tubular function, vasoactive hormones, and blood pressure (BP) in healthy men. In a randomized, placebo-controlled, double-blind dose-response study of 11 healthy men we measured the effect of BQ-123 on glomerular filtrations rate (GFR), renal plasma flow (RPF), fractional excretion of sodium (FENa), lithium clearance (CLi), BP, and plasma concentrations of renin (PRC), angiotensin II (Ang II), atrial and brain natriuretic peptides (ANP, BNP), and vasopressin (AVP). BQ-123 was infused intravenously at the rate of 0.1, 0.2, and 0.3 mg/kg for 1 h, and the effects were measured before, during, and after infusion. The GFR and RPF were not significantly changed by BQ-123. The FENa was increased (20%, medium dose), and CLi was unchanged. Systolic BP remained constant, whereas diastolic BP decreased (-6.3%, medium dose), and pulse rate increased (7.1%, medium dose). BQ-123 increased both PRC (62%, medium dose) and Ang II (70%, medium dose). The changes in FENa, diastolic BP, pulse rate, and Ang II gradually increased up to medium dose, and in PRC up to high dose. The ANP, BNP, and AVP were practically unchanged by BQ-123. Infusion of an endothelin A antagonist resulted in an increase in renal sodium excretion despite a stimulation of the renin-angiotensin system and a decrease in diastolic BP.

Biphasic effects of ANP infusion in conscious, euvolumic rats: roles of AQP2 and ENaC trafficking

Atrial natriuretic peptide (ANP) acutely promotes water and sodium excretion, whereas subchronic effects involve water retention. Renal hemodynamics, water and sodium excretion, and aquaporin-2 (AQP2) and epithelial Na channel (ENaC) subcellular trafficking were determined in response to continuous ANP infusion in conscious rats, where body sodium and fluid balance was constantly maintained. ANP (0.5 microg x kg(-1) x min(-1)) evoked a transient (peak at 10 min) fivefold diuresis followed by reduced urine production to control levels (30- to 90-min period). The fractional distal water excretion was significantly increased initially and then decreased in response to ANP. There was no change in the subcellular localization of AQP2 and AQP2 phosphorylated in PKA consensus site S256 (p-AQP2) 10 min after ANP infusion. In contrast, after 90 min a marked increase in apical labeling of AQP2 and p-AQP2 was observed in the inner and outer medullary collecting ducts but not in cortical collecting ducts. In support of this, ANP induced plasma membrane targeting of AQP2 in transiently AQP2-transfected cells. ANP infusion evoked an instant increase in renal sodium excretion, which persisted for 90 min. Ten minutes of ANP infusion induced no changes in the subcellular localization of ENaC subunits, whereas a marked increase in apical targeting of alpha- and gamma-subunits was observed after 90 min. In conclusion, 1) ANP infusion induced a sustained natriuresis and transient diuresis; 2) there were no changes in the subcellular localization of AQP2 and ENaC subunits after 10 min of ANP infusion; and 3) there was a marked increase in apical targeting of AQP2, p-AQP2, and alpha- and gamma-ENaC after 90 min of ANP infusion. The increased targeting of ENaC and AQP2 likely represents direct or compensatory effects to increase sodium and water reabsorption and to prevent volume depletion in response to prolonged ANP infusion.

Effect of BQ-123, an endothelin antagonist, on renal hemodynamics, tubular function, vasoactive hormones and blood pressure in healthy man. A dose response study

The importance of endothelin for renal hemodynamics and tubular function during baseline conditions is not clarified, and the interaction with vasoactive hormones is unknown. The purpose of the study was to measure the effect of the endothelin A antagonist, BQ-123, on renal hemodynamics, tubular function, vasoactive hormones and blood pressure in healthy men. In a randomized, placebo-controlled, double blind dose response study in 11 healthy men we measured the effect of the endothelin A antagonist BQ-123 on glomerular filtrationsrate (GFR), renal plasmaflow (RPF), fractional excretions of sodium (FENa) and lithium clearance (CLi), blood pressure (BP), and plasma concentrations of renin (PRC) and angiotensin II (Ang. II). BQ-123 was infused intravenously in 0.1 mg/kg (low dose), 0.2 mg/kg (medium dose) and 0.3 mg/kg (high dose) during one hour, and the effect variables were measured before, during and after infusion. Renal hemodynamics were determined by the constant infusion clearance method using 51Cr-EDTA and 125I-hippuran as reference substances. Hormones were measured by radioimmunoassays. GFR and RPF were not significantly changes by BQ-123, but FENa was increased (20%, medium dose). CLi was unchanged. Systolic BP were unchanged, whereas diastolic BP decreased (-6.3%, medium dose), and pulse rate increased (7.1%, medium dose) during BQ-123 infusion. BQ-123 increased both PRC (62%, medium dose) and Ang II (70%, medium dose). The changes in FENa, diastolic BP, pulse rate and Ang II gradually increased till medium dose. Infusion of an endothelin A antagonist resulted in an increase in renal sodium excretion despite a stimulation of the renin-angiotensin system and a decrease in diastolic blood pressure. These results show that endothelin plays a role during baseline conditions both in vascular tone in the systemic circulation and in the regulation of renal sodium excretion. Blockade of the endothelin A effects can resist and to some extent antagonize the vascular and renal effects of the renin-angiotensin system on the cardiovascular homeostasis and sodium balance.

Role of the paraventricular nucleus in renal excretory responses to acute volume expansion: role of nitric oxide.

Acute volume expansion (VE) produces a suppression of renal sympathetic nerve discharge (RSND) resulting in diuresis and natriuresis. Recently, we have demonstrated that the endogenous nitric oxide (NO) system within the paraventricular nucleus (PVN) produces a decrease in RSND. We hypothesized that endogenous NO in the PVN is involved in the suppression of RSND leading to diuretic and natriuretic responses to acute VE. To test this hypothesis, we first measured the VE-induced increase in renal sodium excretion and urine flow with and without blockade of NO, with microinjection of NG-monomethyl-L-arginine (L-NMMA; 200 pmol in 200 nl), within the PVN of Inactin-anesthetized male Sprague-Dawley rats. Acute VE produced significant increases in urine flow and sodium excretion, which were diminished in rats treated with L-NMMA within the PVN. This effect of NO blockade within the PVN on VE-induced diuresis and natriuresis was abolished by renal denervation. Consistent with these data, acute VE induced a decrease in RSND (52% of the baseline level), which was significantly blunted by prior administration of L-NMMA into the PVN (28% of the baseline level) induced by a comparable level of acute VE. Using the push-pull perfusion technique, we found that acute VE induced a significant increase in NOx concentration in the perfusate from the PVN region. Taken together, these results suggest that acute VE induces an increase in NO production within the PVN that leads to renal sympathoinhibition, resulting in diuresis and natriuresis. We conclude that NO within the PVN plays an important role in regulation of sodium and water excretions in the volume reflex via modulating renal sympathetic outflow.

Rosiglitazone Treatment Restores Renal Dopamine Receptor Function in Obese Zucker Rats

Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.