Sodium Excretion Rate Research Articles

Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin–angiotensin–aldosterone system in normotensive men

Cytochrome P450 (CYP) 2C9 gene polymorphisms have been implicated in regulation of the renin-angiotensin-aldosterone system (RAAS) and salt sensitivity in hypertensive patients. We tested the relevance of CYP2C9 genotypes for regulation of plasma renin activity (PRA), plasma aldosterone concentrations and blood pressure (BP) in response to changes in salt intake in normotensive individuals. Three hundred and ten normotensive men (mean age 24.9 ± 0.1) were studied after a standardized low = 20 mmol/day or high = 220 mmol/day sodium intake for 7 days. Individuals were classified as salt sensitive when the mean arterial BP was more than 3 mmHg higher after high compared with low-salt exposure. CYP2C9*2 and CYP2C9*3 alleles were not associated with salt-sensitivity status or BP phenotypes; CYP2C9*2 had no effect on PRA or plasma aldosterone. CYP2C9*3 carriers showed a significantly lower PRA compared with CYP2C9*1/*1 individuals in the overall study cohort (high salt: 0.39 ± 0.05 vs. 0.62 ± 0.04 ng/ml per h, P = 0.009; low salt: 2.19 ± 0.27 vs. 2.87 ± 0.13 ng/ml per h, P = 0.013). Salt-sensitive CYP2C9*3 carriers exhibited the lowest PRA values and significantly lower 24 h sodium excretion rates during high-salt intake (P = 0.005 vs. CYP2C9*1/*1). Lower plasma aldosterone concentrations were only observed in salt-resistant CYP2C9*3 carriers under low salt (P = 0.039). The present study confirms an association between CYP2C9 polymorphism and activity of the RAAS. Specifically, we detected an overall effect of CYP2C9*3 on lower PRA, but not on salt-sensitive BP regulation in normotensive men. Further studies are needed to analyze the long-term effects of CYP2C9*3 for salt sensitivity and hypertensive diseases.

Diuretic and potassium-sparing effect of isoquercitrin—An active flavonoid of Tropaeolum majus L.

Previous studies have shown that the extracts obtained from Tropaeolum majus L. exhibit pronounced diuretic effects supporting the ethnopharmacological use of this plant as diuretic. In the present work, phytochemical investigation, guided by bio-assay in spontaneously hypertensive rats (SHR), was carried out in order to identify the compounds responsible for diuretic action. Chromatographic fractionation of the hydroethanolic extract yielded an active fraction (TMLR) rich in isoquercitrin. TMLR (25-100mg/kg) and isoquercitrin (5-10mg/kg), as well the reference drug hydrochlorothiazide (10mg/kg) were orally administered in a single dose or daily for 7 days to SHR. The urine excretion rate, pH, density, conductivity and content of sodium (Na(+)) and potassium (K(+)) electrolytes were measured in the urine of saline-loaded animals. The urinary excretion rate was dose-dependently increased in both TMLR and isoquercitrin groups, as well as Na(+). Despite the changes in urinary excretion of electrolytes, the plasmatic levels of Na(+) and K(+) had not been changed. In addition, we did not find any evidence of renal toxicity or other adverse effects in these animals, even after prolonged treatment with TMLR or isoquercitrin. This research supports and extends the ethnomedicinal use of T. majus as diuretic. This activity seems to be associated to the presence of the flavonol isoquercitrin.

Vasopressin V2 receptors, ENaC, and sodium reabsorption: a risk factor for hypertension?

Excessive sodium reabsorption by the kidney has long been known to participate in the pathogenesis of some forms of hypertension. In the kidney, the final control of NaCl reabsorption takes place in the distal nephron through the amiloride-sensitive epithelial sodium channel (ENaC). Liddle's syndrome, an inherited form of hypertension due to gain-of-function mutations in the genes coding for ENaC subunits, has demonstrated the key role of this channel in the sodium balance. Although aldosterone is classically thought to be the main hormone regulating ENaC activity, several studies in animal models and in humans highlight the important effect of vasopressin on ENaC regulation and sodium transport. This review summarizes the effect of vasopressin V2 receptor stimulation on ENaC activity and sodium excretion in vivo. Moreover, we report the experimental and clinical data demonstrating the role of renal ENaC in water conservation at the expense of a reduced ability to excrete sodium. Acute administration of the selective V2 receptor agonist dDAVP not only increases urine osmolality and reduces urine flow rate but also reduces sodium excretion in rats and humans. Chronic V2 receptor stimulation increases blood pressure in rats, and a significant correlation was found between blood pressure and urine concentration in healthy humans. This led us to discuss how excessive vasopressin-dependent ENaC stimulation could be a risk factor for sodium retention and resulting increase in blood pressure.

The abuse of diuretics as performance‐enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis

Diuretics are drugs that increase the rate of urine flow and sodium excretion to adjust the volume and composition of body fluids. There are several major categories of this drug class and the compounds vary greatly in structure, physicochemical properties, effects on urinary composition and renal haemodynamics, and site and mechanism of action. Diuretics are often abused by athletes to excrete water for rapid weight loss and to mask the presence of other banned substances. Because of their abuse by athletes, diuretics have been included on The World Anti-Doping Agency's (WADA) list of prohibited substances; the use of diuretics is banned both in competition and out of competition and diuretics are routinely screened for by anti-doping laboratories. This review provides an overview of the pharmacology and toxicology of diuretics and discusses their application in sports. The most common analytical strategies currently followed by the anti-doping laboratories accredited by the WADA are discussed along with the challenges laboratories face for the analysis of this diverse class of drugs.

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Nonsteroidal anti-inflammatory drug usage has long revealed renoprotective prostaglandin actions on the renal microvasculature during increased pressor hormone influence, but whether increased cyclooxygenase (COX)-2 expression supports prostaglandin vasodilatory influence by interfering with the actions of ANG II remains unresolved. Therefore, we tested the hypothesis that COX-2 inhibition causes hemodynamic and excretory effects that are increased in proportion to ANG II activity. In anesthetized Sprague-Dawley rats having augmented cortical COX-2 expression but different ANG II activity, we conducted renal clearance experiments during acute inhibition of COX-2 with nimesulide (NMSLD) and inhibition of COX-1 with SC-560. In one series of experiments, acute captopril [acute angiotensin-converting enzyme (ACE) inhibitor (aACEi)] was administered alone (n = 13) or in combination with chronic captopril [chronic ACEi (cACEi)] pretreatment (n = 19). In another series of experiments, rats were fed a normal-sodium [0.4% (NS), n = 12] or a low-sodium [0.03% (LS), n = 18] diet. NMSLD did not alter mean arterial blood pressure in any group but, in the LS and cACEi groups, decreased renal plasma flow (from 3.99 ± 0.33 to 2.85 ± 0.26 and from 4.30 ± 0.19 to 3.22 ± 0.21 ml·min(-1)·g(-1)), cortical blood flow (-12 ± 8% and -13 ± 4%), and glomerular filtration rate (from 0.88 ± 0.04 to 0.65 ± 0.05 and from 0.95 ± 0.07 to 0.70 ± 0.05 ml·min(-1)·g(-1)). In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in NS (-24 ± 5%), LS (-27 ± 8%), aACEi (-16 ± 3.8%), and cACEi (-24 ± 4.2%) groups. Absolute and fractional sodium excretion rates were unchanged by NMSLD, except in the LS group (0.75 ± 0.05 μeq/min and 0.43 ± 0.15% and 0.51 ± 0.06 μeq/min and 0.26 ± 0.10%). SC-560 did not augment the effects of NMSLD. These results demonstrate an augmented COX-2-mediated vasodilation that is not contingent on ANG II, in contrast to COX-2-mediated augmented sodium excretion, where ANG II activity is requisite. Furthermore, the COX-2 effects on MBF are not contingent on ANG II or changes in cortical microvascular responses. These results reflect COX-2 continual regulation of MBF and adaptive opposition to ANG II prohypertensinogenic effects on renal plasma flow, cortical blood flow, glomerular filtration rate, and absolute and fractional sodium excretion.

Nitric oxide(NO)合成慢性阻害時の血圧上昇機序に関する検討

Although the inhibition of nitric oxide (NO) synthesis is known to induce systemic hypertension, the underlying mechanisms mediating this type of hypertension are incompletely understood. In the present study we investigated the influence of sodium intake on the pressor effect of long-term administration of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 16 mg/dl in drinking fluid for 8 weeks), in conscious Sprague-Dawley rats. Urinary excretion rates of catecholamine during NO synthesis inhibition were also examined. Long-term administration of L-NAME produced a sustained elevation in tail-cuff pressure without altering urine flow, or sodium excretion rate. L-NAME-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites, NO2- and NO3-, and was aggravated when rats drank 0.9% saline in place of tap water. Thus, inhibition of NO synthesis resulted in a rightward shift of the pressure natriuresis relationship and a significant decrease in the slope of this relationship. Urinary excretion of epinephrine and norepinephrine, but not that of dopamine, in L-NAME-treated rats significantly increased within the first week of the study when compared with those observed in control rats. A natriuretic index of the sympathetic nervous system, the ratio of dopamine to norepinephrine excretion, was significantly less in L-NAME-treated rats than in control rats. After 8-week treatment with L-NAME, renal morphologic evaluation revealed significant narrowing and obliteration of the arterioles. L-arginine (2 g/dl in drinking fluid) completely reversed the elevation of blood pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment after 3 weeks of concomitant administration. These results suggest that the inhibition of chronic NO synthesis produces sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

PRENATAL MATERNAL FOOD RESTRICTION LEADS TO IMPAIRED RENAL SODIUM HANDLING IN ADULT RAT OFFSPRING: PP.9.361

Objective: Maternal food restriction (MFR) during pregnancy programmes the development of hypertension in the rat. The kidneys of MFR rats develop fewer nephrons suggesting that sodium retention may underlie the hypertension in this model. The aim of this study was to assess renal function in the MFR rat. Design and Methods: Control pregnant Wistar rats had access to food ad libitum (C n = 7); the food restricted group received 50% of the food consumed by control rats from day 1 of pregnancy until birth (MFR n = 6). Offspring had free access to food. At 9 weeks systolic blood pressure (SBP) and renal function were assessed in male rats housed in metabolism cages. Results and Conclusions: MFR offspring were significantly lighter at birth, but had caught up body weight by 9 weeks of age (Table 1). SBP was higher in the MFR animals. Food and water intake did not differ between MFR and control rats. Creatinine clearance was significantly lower in MFR rats, but neither urine flow nor sodium excretion rates were different from controls. However, fractional excretion of sodium was greater in MFR rats. These data suggest that renal tubular handling of sodium in MFR rats is altered. MFR rats filter less sodium than controls, but excrete proportionately more of the sodium that is filtered. Sodium retention may contribute to the higher SBP of these animals.

RENAL ACTIONS OF UROTENSIN II DURING THE DEVELOPMENT OF ESSENTIAL HYPERTENSION IN THE RAT: PP.9.373

Objective: The peptide hormone urotensin II (UII) has been implicated in human cardiovascular and renal disease, but its precise role has yet to be fully established. Recently we have shown an exaggerated renal response to infusion of rat UII in the adult spontaneously hypertensive rat (SHR) compared to control Wistar-Kyoto (WKY) rats (Abdel-Razik et al., 2008, Am J Physiol 295:F1239–47). The aim of the current study was to establish the renal actions of UII during the development of hypertension. Design and Methods: Young 4–5-week-old WKY and pre-hypertensive SHR were prepared for standard renal clearance experiments. Inactin-anaesthetised animals were initially infused i.v. with 0.154 M NaCl for 2 h 45 min before being randomly assigned to receive either vehicle (saline) or the UT receptor antagonist SB706375 at 0.01 mg.min-1. 100 g bwt-1 for 1 h 15 min. Urine samples were collected every 15 min and two carotid artery blood samples were taken for measurement of electrolytes. Results and conclusions: All measured variables were in a steady state before UT antagonist infusion. As expected SHR had elevated mean arterial pressures (97 ± 5 vs 82 ± 5 mmHg, P < 0.05) and lower basal renal filtered load and flow rates compared to WKY rats. Compared with the vehicle-infused groups UT-antagonist infusion had no effect on renal parameters in the WKY rats (Table 1). In contrast, UT-antagonist infusion led to a significant increase in urine flow and sodium excretion rates in SHR compared to vehicle-treated animals (Table 1). Neither glomerular filtration rate nor fractional sodium excretion were affected by the UT-antagonist. These data suggest that endogenous rUII has no effect on the young WKY kidney but has a tonic influence on renal function in the young SHR. The antagonist-induced diuresis and natriuresis in the young SHR appear to be independent of a change in filtered load. These results suggest that the UII system may contribute to the well documented retention of sodium and water during the development of hypertension in the SHR.

Time-Course for Recovery of Renal Function After Unilateral (Single-Tract) Percutaneous Access in the Pig

The immediate (1-5 hours) response to percutaneous renal access (PERC) in pigs is vasoconstriction in the treated kidney. The present study determined the longer-term (72 hours) consequences of this surgical procedure. Adult female pigs were anesthetized, and bilateral glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urine flow rate, and sodium excretion rate were measured before and 1 hour after sham PERC or unilateral, single-tract PERC using a balloon dilator system. Animals were allowed to regain consciousness and were then anesthetized 72 hours later for final measurements of bilateral renal hemodynamic and excretory function together with renal para-aminohippuric acid (PAH) extraction (a measure of tubular organic anion transport efficiency). Bilateral renal hemodynamics were unchanged in the sham-PERC-treated pigs over the 72-hour observation period. In contrast, both GFR and ERPF were reduced by approximately 55% in the PERC-treated kidney within 1 hour of access, and returned to pre-PERC levels within 72 hours. Renal hemodynamics were not significantly altered in the opposite, untreated kidney of the PERC-treated pigs. Renal PAH extraction was decreased in PERC-treated kidneys at 72 hours post-PERC. Both sham-PERC-treated and PERC-treated animals showed similar falls in urine flow rate and sodium excretion rate immediately after treatment and at 72 hours after PERC. Renal vasoconstriction characterized the acute response of the treated kidney to unilateral PERC, whereas impaired tubular function (reduced PAH extraction) with near-normal GFR and ERPF characterizes the later (72 hours) response to PERC.

Cisplatin increases urinary sodium excretion in rats: gender-related differences

OBJECTIVE. There are well-documented reports of cisplatin-associated hyponatremia in the literature, but there are no data on gender-dependent differences. The aim of the present study was to define characteristics of 24-hour urinary sodium excretion in young adult Wistar rats of both genders and to evaluate the gender-related effect of cisplatin. MATERIALS AND METHODS. Twelve control Wistar rats (6 males and 6 females) and 12 cisplatin-treated Wistar rats (6 males and 6 females) after a single and repeated injection of cisplatin (once a day for 3 days) at a dose of 2.5 mg/kg body weight into the caudal vein were examined. The experiment was carried out by measuring 24-h urinary sodium, potassium, chloride, magnesium, creatinine excretion and pH in the urine of age-matched male and female rats. RESULTS. The 24-h urinary sodium excretion, sodium/chloride ratio, and diuresis showed no gender-related differences in control rats. After a single administration of 2.5 mg/kg cisplatin, 24-h urinary sodium excretion was not significantly higher in cisplatin-treated rats than in gender-matched controls. After repeated cisplatin administration, 24-h urinary sodium excretion was significantly higher in cisplatin-treated male rats as compared to matched controls (P<0.05). No such effect was found in cisplatin-treated female rats. CONCLUSION. The study data show that cisplatin enhances urinary sodium excretion in male but not in female rats. The mechanism of such a gender-related effect is not yet clear. Further investigations are necessary to elucidate the mechanism of this pharmacological effect of cisplatin.

Effects of fresh and seawater ingestion on osmoregulation in Atlantic bottlenose dolphins (Tursiops truncatus)

Bottlenose dolphins (Tursiops truncatus) are marine mammals with body water needs challenged by little access to fresh water and constant exposure to salt water. Osmoregulation has been studied in marine mammals for a century. Research assessing the effects of ingested fresh water or seawater in dolphins, however, has been limited to few animals and sampling times. Nine 16- to 25-h studies were conducted on eight adult dolphins to assess the hourly impact of fresh water, seawater, and seawater with protein ingestion on plasma and urine osmolality, urine flow rate (ufr), urinary and plasma solute concentrations, and solute clearance rates. Fresh water ingestion increased ufr. Fresh water ingestion also decreased plasma and urine osmolality, sodium and chloride urine concentrations, and solute excretion rates. Seawater ingestion resulted in increased ufr, sodium, chloride, and potassium urine concentrations, sodium excretion rates, and urine osmolality. Seawater with protein ingestion was associated with increased ufr, plasma osmolality, sodium excretion, and sodium, chloride, potassium, and urea urine concentrations. In conclusion, bottlenose dolphins appear to maintain water and plasma solute balance after ingesting fresh water or seawater by altering urine osmolality and solute clearance. Ingestion of protein with seawater appears to further push osmoregulation limits and urine solute concentrations in dolphins.

The effect of spironolactone on sweat and urinary sodium excretion during exercise in humans

This study examined the effect of spironolactone on urinary ([Na(+)](urine)) and sweat sodium concentration ([Na(+)](sweat)) when controlling for sweat rate. Fifteen healthy subjects were required to complete two 90-min exercise bouts (three 30-min ordered exercise bouts at 60%, 70%, and 80% of the subjects' age-predicted maximum heart rate) in a 35 degrees C and 40% relative humidity environmental chamber, once after administration of 300 mg spironolactone, and once after administration of 300 mg placebo. Both the drug and placebo were taken over an 18 h period, with the second 100 mg dose taken 6 h prior to exercise, and the first 200 mg dose taken 12 h prior to the second dose. Sweat rate was measured during each of the three exercise bouts using a Macroduct sweat collector affixed to the flexor surface of the forearm. Urine sodium excretion rate was calculated for the three hour period immediately prior to each exercise bout. Urinary and sweat sodium concentrations were analyzed via flame photometry. Spironolactone had no effect on [Na(+)](sweat) at the different sweat rates. However, the urinary sodium excretion rate was significantly higher with spironolactone use (P<0.05). These results demonstrate that spironolactone caused the expected natriuresis, but greater sodium excretion was not observed in the sweat gland. Since the mineralocorticoid receptors (MR) in the sweat gland were not antagonized by spironolactone in the same manner as those in the kidney, this suggests that different isoforms of the MR exist in the kidney and the sweat gland of humans.

Intrarenal Aminopeptidase N Inhibition Restores Defective Angiotensin II Type 2-Mediated Natriuresis in Spontaneously Hypertensive Rats

The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (U(Na)V), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs). Although renal interstitial infusion of Ang II type 1 receptor blocker candesartan increased U(Na)V in WKYs from a baseline of 0.05+/-0.01 to 0.17+/-0.04 micromol/min (P<0.01), identical infusions failed to increase U(Na)V in hypertensive SHRs. Coinfusion of AT(2)R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT(2)R-mediated effect. AT(2)R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.05+/-0.01 to 0.11+/-0.03 micromol/min; P<0.05). The defects in sodium excretion were present before the onset of hypertension in SHRs, because young WKYs demonstrated double the U(Na)V of SHRs (0.04+/-0.006 versus 0.02+/-0.003 micromol/min; P<0.01) at baseline. The increased U(Na)V of young WKYs was attributed to reduced renal proximal tubule sodium reabsorption, because increases in fractional excretion of sodium were paralleled by increases in fractional excretion of lithium. Renal interstitial PC-18 infusion ameliorated defective AT(2)R-mediated natriuresis in young SHRs by increasing fractional excretion of sodium and fractional excretion of lithium without changing the glomerular filtration rate. Thus, increased renal proximal tubule sodium retention is observed before the onset of hypertension in SHRs, and inhibition of the metabolism of Ang III ameliorates this pathophysiologic defect in sodium excretion.

Urinary dopamine excretion and renal responses to fenoldopam infusion in blacks and whites.

Dopamine is an endogenous natriuretic amine that contributes to the maintenance of sodium homeostasis. Deficiencies in the renal production of dopamine and the action of dopamine on renal tubular receptors have been observed in human hypertension and may contribute to salt sensitivity of blood pressure. Ethnic differences in the sodium-to-dopamine relationship may contribute to the higher prevalence of salt sensitivity in blacks. The authors assessed dopaminergic activity in two studies. In the first, daytime and nighttime excretion of sodium and dopamine were compared in 11 black and 17 white normotensive patients. No racial difference in the rate of sodium or dopamine excretion during either period was observed. In the second study, a graded infusion of the dopamine-1 receptor agonist, fenoldopam, was performed in 14 black and 17 white normotensive patients. There was no racial difference in the natriuretic responses. Previously described lower rates of renal free water clearance and potassium excretion in blacks compared with whites were maintained during fenoldopam infusion, suggesting that dopamine is not a mediator of those differences. The authors conclude that there are no race-related differences in dopamine excretion or activity in normotensive patients.

Impaired renal calcium absorption in mice lacking calcium channel β3 subunits

Transgenic mice lacking calcium channel beta3 subunits (CaVbeta3) were used to determine the involvement of a multimeric calcium channel in mediating stimulated renal calcium absorption. We measured the ability of calcium channel beta3 subunit-null (CaVbeta3-/-) and wild-type (CaVbeta3+/+) mice to increase renal calcium absorption in response to the calcium-sparing diuretic chlorothiazide (CTZ). Control rates of fractional sodium excretion were comparable in CaVbeta3-/- and CaVbeta3+/+ mice and CTZ increased sodium excretion similarly in both groups. CTZ enhanced calcium absorption only in wild-type CaVbeta3+/+ mice. This effect was specific for diuretics acting on distal tubules because both CaVbeta3-/- and CaVbeta3+/+ mice responded comparably to furosemide. The absence of beta3 subunits resulted in compensatory increases of TrpV5 calcium channels, the plasma membrane Ca-ATPase, NCX1 Na/Ca exchanger protein, and calbindin-D9k but not calbindin-D28k. We conclude that TrpV5 mediates basal renal calcium absorption and that a multimeric calcium channel that includes CaVbeta3 mediates stimulated calcium transport.

Gitelman Syndrome

Gitelman Syndrome

Local Renal Delivery of a Natriuretic Peptide: A Renal-Enhancing Strategy for B-Type Natriuretic Peptide in Overt Experimental Heart Failure

The purpose of this study was to test the hypothesis that local renal delivery of B-type natriuretic peptide (BNP) will overcome renal resistance to BNP without systemic hypotension. BNP has vasodilating, natriuretic, and renin-inhibiting properties. In overt heart failure (HF), there is development of renal resistance to BNP. We defined the cardiorenal and humoral effects of systemic (n = 6) or local renal (n = 7) administration of canine BNP (0.01 microg/kg/min) in 2 separate groups of dogs with pacing-induced subacute overt HF complicated by renal dysfunction. We used a commercially available small (3.1-F) bifurcated renal catheter (FlowMedica Inc., Fremont, California) for direct bilateral infusion of BNP into both renal arteries. With systemic BNP at this clinically used dose (without the bolus), urine flow increased, but there was only a trend for an increase in urinary sodium excretion and glomerular filtration rate (GFR). In contrast, local renal delivery of BNP resulted in significant diuresis and natriuresis and an increase in GFR. These diuretic and natriuretic responses were greater with local renal BNP compared with systemic BNP, and were associated with increased delivery of BNP to the renal tubules as evident by a greater urinary BNP excretion resulting in a decrease in distal reabsorption of sodium. Importantly, local renal BNP did not result in a significant decrease in mean arterial pressure that was observed with systemic BNP. We conclude that local renal BNP delivery is a novel strategy that may overcome renal assistance to BNP in overt HF by increasing local delivery of BNP to the renal tubules.

Effects of uroguanylin on natriuresis in experimental nephrotic rats

Uroguanylin, isolated from human and opossum urine, is a candidate intestinal natriuretic hormone that controls the sodium and water balance between the intestine and the kidneys. Levels of immunoreactive (ir)-uroguanylin in the plasma and urine are increased in rats and humans with nephrotic syndrome, which is physiologically characterized by sodium retention with massive proteinuria. The present study evaluates the effect of natriuresis induced by uroguanylin on nephrotic rats. Normal rats and rats rendered nephrotic by injections of puromycin aminonucleoside (PAN) were treated with uroguanylin (0.5 nmol/h, delivered by an osmotic pump) or with vehicle during the sodium retention phase. All rats consumed the same quantity of sodium. Uroguanylin did not increase urinary excretion of sodium and water in normal rats, but significantly increased urinary sodium excretion during the sodium retention phase in nephrotic rats (untreated vs uroguanylin-treated nephrotic rats in mmol/mmol creatinine; 2.92 +/- 0.65 vs 8.93 +/- 2.53 on day 6, P < 0.05; 3.55 +/- 0.47 vs 10.37 +/- 1.73 on day 7, P < 0.01; 14.88 +/- 2.32 vs 24.47 +/- 2.86 on day 8, P < 0.05). Plasma levels of ir-uroguanylin in uroguanylin-treated nephrotic rats on day 6 were significantly increased compared with those in uroguanylin-treated control and untreated nephrotic rats. Uroguanylin increased urinary sodium excretion in rats with PAN-induced nephrosis, and might be useful for treating sodium retention in patients with nephrotic syndrome.

Medial Septal Area Vasopressin Receptor Subtypes in the Regulation of Urine and Sodium Excretion in Rats

The present study aimed to determine the effects of selective antagonists of V(1a), V(2), and V(1a)/V(2) (Conivaptan; Astellas Pharma Inc., Tokyo, Japan) arginine vasopressin (AVP) receptors on the flow of urine and sodium excretion induced by AVP, by means of microinjections into the medial septal area (MSA) of the rat brain. Male Holtzman rats had a guide cannula implanted into the dorsal surface of the MSA. Intravenous infusion of hypotonic saline was used to promote urinary flow, which was collected for 4 h. Pretreatment with the V(1a) antagonist decreased, and the V(2) antagonist and Conivaptan (a V(1a)/V(2) antagonist) increased, the urinary flow induced by AVP. Administration of AVP increased sodium excretion. Pretreatment with V(2) or V(1a) antagonists decreased, and Conivaptan abolished, the sodium excretion induced by AVP. These results indicate that the V(1a) and V(2) receptors of the MSA are important in the central regulation of urine and sodium excretion.

Diuretics: An Update on the Pharmacology and Clinical Uses

Diuretics are among the most commonly used drugs. They increase the rate of urine flow and sodium excretion and are used to induce negative fluid and sodium balance in a variety of clinical situations, including hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis. It is essential for clinicians to understand the mechanism of action of various diuretics to be able to maximize the efficacy of these agents when used as monotherapy and in combination with agents that have different targets of action in the kidney. The pharmacology of commonly used diuretics and the renal anatomy and physiology relevant to diuretic effects are reviewed.