Search

The basolateral potassium channel KCNJ10 (Kir4.1), is expressed in the renal distal convoluted tubule and controls the activity of the thiazide-sensitive sodium chloride cotransporter. Loss-of-function mutations of KCNJ10 cause EAST/SeSAME syndrome with salt wasting and severe hypokalemia. KCNJ10 is also expressed in the principal cells of the collecting system. However, its pathophysiological role in this segment has not been studied in detail. To address this, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the collecting system (collecting system-Kcnj10-knockout). Collecting system-Kcnj10-knockout mice responded normally to standard and high potassium diet. However, this knockout exhibited a higher kaliuresis and lower plasma potassium than control mice when treated with thiazide diuretics. Likewise, collecting systemKcnj10-knockout displayed an inadequately high kaliuresis and renal sodium retention upon dietary potassium restriction. In this condition, these knockout mice became hypokalemic due to insufficient downregulation of the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) in the collecting system. Consistently, the phenotype of collecting system-Kcnj10-knockout was fully abrogated by ENaC inhibition with amiloride and ameliorated by genetic inactivation of ROMK in the collecting system. Thus, KCNJ10 in the collecting system contributes to the renal control of potassium homeostasis by regulating ENaC and ROMK. Hence, impaired KCNJ10 function in the collecting system predisposes for thiazide and low potassium diet-induced hypokalemia and likely contributes to the pathophysiology of renal potassium loss in EAST/SeSAME syndrome.

Active constituents from natural origin have long been used for the treatment of patients suffering from cardiovascular and renal diseases. This study therefore aimed to investigate the diuretic and natriuretic properties of nothofagin, a dihydrochalcone isolated from Leandra dasytricha (A. Gray) Cogn. leaves in normotensive and hypertensive rats. Male Wistar normotensive rats were orally treated with vehicle (1 ml/kg); hydrochlorothiazide (HCTZ; 25 mg/kg); ethyl acetate fraction from L. dasytricha (EALD; 3-30 mg/kg) and nothofagin (NOT; 0.3-3 mg/kg). Spontaneously hypertensive rats (SHR) received NOT (1 mg/kg), HCTZ (25 mg/kg) or vehicle. The cumulative diuretic index, urinary electrolytes excretion (Na+ and K+), pH, density and conductivity were measured at the end of the experiment (after 8 h). A7r5 and L929 cell lines were used to measure cell viability after exposure to NOT. Nitric oxide generation was quantified in A7r5 cell supernatant, and DPPH assay was used for evaluating the antioxidant properties of NOT. The urinary volume of normotensive rats were increased after the treatment with EALD, without any changes in Na+ or K+ excretion. NOT was able to induce diuresis and natriuresis, but not kaliuresis, in both normotensive and hypertensive rats. The reduction in prostanoids generation through cyclooxygenase inhibition, as well as the muscarinic receptor antagonism, fully avoided NOT-induced increases in diuretic index. NOT, which did not interfere with L929 or A7r5 cell viability, was able to stimulate nitric oxide generation in A7r5 cell, besides showing an antioxidant effect in scavenging the free-radical DPPH. Taken together, our study shows, for the first time, the diuretic, natriuretic and potassium-sparing effect of nothofagin in rats, which was associated with prostanoids generation, muscarinic receptor activation and antioxidant properties.

In humans, leptospiral acute kidney injury (AKI) is characterised by tubulointerstitial involvement and renal electrolyte losses, impacting clinical presentation and case management. The aim of this study was to evaluate urine chemistry findings in dogs with leptospirosis in order to identify characteristic patterns of tubular damage associated with this disease. Dogs with intrinsic AKI caused by leptospirosis and by other aetiologies were prospectively enrolled. Clinical and clinicopathological variables, including serum and urine chemistry, fractional excretion (FE%) of electrolytes, and urinary neutrophil gelatinase-associated lipocalin (NGAL), were evaluated in both groups and compared statistically. Dogs with leptospirosis (n = 38) had significantly higher serum creatinine concentration than dogs with AKI caused by other aetiologies (n = 37). Serum potassium and glucose concentrations were comparable between groups. Dogs with leptospiral AKI had significantly higher FE of potassium (median 100%, range 20–480 vs. median 68%, range 5–300; P = 0.048), as well as higher magnitude of glucosuria (urine glucose to creatinine ratio, median 0.64, range 0–26 vs. median 0.22, range 0–13; P = 0.023) and frequency of positive glucose dipstick reaction (59% vs. 18%; P = 0.002), than dogs with AKI of other aetiologies. Additional markers of tubular damage considered in this study, including FE of other electrolytes and urinary NGAL, did not differ between groups. In conclusion, when compared to other aetiologies of intrinsic AKI, canine leptospirosis was characterised by increased glucosuria and kaliuresis.

A gastrointestinal-renal kaliuretic signaling axis has been proposed to regulate potassium excretion in response to acute potassium ingestion independent of the extracellular potassium concentration and aldosterone. Here we studied this presumed axis in 32 individuals in our clinical pharmacology unit while on a 20 mmol sodium and 60 mmol potassium diet. The serum potassium concentration, potassium excretion, aldosterone, and insulin were measured following either a 35 mmol oral potassium load, a potassium- and sodium-deficient complex meal, or a potassium-deficient complex meal plus 35 mmol potassium. This design allowed determination of the component effects on potassium handling of the meal and potassium load separately. The meal plus potassium test was repeated following aldosterone blockade with eplerenone to specifically evaluate the role of aldosterone. In response to the potassium-deficient meal plus 35 mmol potassium, the serum potassium did not increase but the hourly mean potassium excretion increased sharply. This kaliuresis persisted following aldosterone blockade with eplerenone, further suggesting independence from aldosterone. Thus, a gastrointestinal-renal kaliuretic signaling axis exists in humans mediating potassium excretion independent of changes in the serum potassium concentration and aldosterone. The implication of this mechanism is yet to be determined but may account for a significant component of potassium excretion following a complex potassium-rich meal.

Hyperkalemia limits the use of renin-angiotensin-aldosterone axis (RAAS) blockers in patients with renal insufficiency. This can be managed by efforts to increase kaliuresis and by gastrointestinal potassium binding with sodium polystyrene sulfonate, a relatively ineffective agent. Now with the availability of patiromer, RAAS blockers can be used more liberally. In addition, potassium reduction decreases aldosterone, which may be beneficial. Adverse nonepithelial aldosterone effects such as endothelial dysfunction and cardiac fibrosis may be ameliorated.

A new understanding of renal potassium balance has emerged as the molecular underpinnings of potassium secretion have become illuminated, highlighting the key roles of apical potassium channels, renal outer medullary potassium channel (ROMK) and Big Potassium (BK), in the aldosterone-sensitive distal nephron and collecting duct. These channels act as the final-regulated components of the renal potassium secretory machinery. Their activity, number, and driving forces are precisely modulated to ensure potassium excretion matches dietary potassium intake. Recent identification of the underlying regulatory mechanisms at the molecular level provides a new appreciation of the physiology and reveals a molecular insight to explain the paradoxic actions of aldosterone on potassium secretion. Here, we review the current state of knowledge in the field.

In a variety of animal models, uroguanylin causes diuresis, natriuresis and kaliuresis and is found in larger concentrations in the urine compared to controls after oral salt intake or in conditions of excess salt and fluid retention. It has been proposed that uroguanylin functions as an intestinal natriuretic hormone following intake of meals high in salt content. In the present work, we examined if 10 days of salt ingestion resulted in an enhanced response to uroguanylin in the isolated perfused rat kidney. Rats were given normal water, 1% NaCl (HS1%), or 2% NaCl (HS2%) for 10 days, at which time the right kidneys were surgically removed and perfused with a modified Krebs-Henseleit solution for 30 min. After a 30-min control period, the kidneys were perfused with a modified Krebs-Henseleit solution containing 0.06 microM uroguanylin for an additional 90 min. Compared to vehicle-matched time controls, 0.06 microM uroguanylin perfusion of kidneys from rats maintained on HS2% resulted in a significantly increased urine flow (UF; from 0.17+/-0.01 to 0.23+/-0.01, after 60 min, n=6, P

Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Background Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na + , K + , and Cl − transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c ), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C (−/−) null). Results In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C (−/−) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C (−/−) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na + /K + ATPase γ-subunit and the Cl − channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C–independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na + /K + ATPase and ClC-K2.

The ROMK (Kir1.1; Kcnj1) gene is believed to encode the apical small conductance K(+) channels (SK) of the thick ascending limb (TAL) and cortical collecting duct (CCD). Loss-of-function mutations in the human ROMK gene cause Bartter's syndrome with renal Na(+) wasting, consistent with the role of this channel in apical K(+) recycling in the TAL that is crucial for NaCl reabsorption. However, the mechanism of renal K(+) wasting and hypokalemia that develop in individuals with ROMK Bartter's syndrome is not apparent given the proposed loss of the collecting duct SK channel. Thus, we generated a colony of ROMK null mice with approximately 25% survival to adulthood that provides a good model for ROMK Bartter's syndrome. The remaining 75% of null mice die in less than 14 days after birth. The surviving ROMK null mice have normal gross renal morphology with no evidence of significant hydronephrosis, whereas non-surviving null mice exhibit marked hydronephrosis. ROMK protein expression was absent in TAL and CCD from null mice but exhibited normal abundance and localization in wild-type littermates. ROMK null mice were polyuric and natriuretic with an elevated hematocrit consistent with mild extracellular volume depletion. SK channel activity in TAL and CCD was assessed by patch clamp analysis in ROMK wild-type ROMK(+/+), heterozygous ROMK(+/-), and null ROMK(-/-) mice. In 313 patches with successful seals from the three ROMK genotypes, SK channel activity in ROMK (+/+ and +/-) exhibited normal single channel kinetics. The expression frequencies are as follows: 67 (TAL) and 58% (CCD) in ROMK(+/+); about half that of the wild-type in ROMK(+/-), being 38 (TAL) and 25% (CCD); absent in both TAL or CCD in ROMK(-/-) between 2 and 5 weeks in 15 mice (61 and 66 patches, respectively). The absence of SK channel activity in ROMK null mice demonstrates that ROMK is essential for functional expression of SK channels in both TAL and CCD. Despite loss of ROMK expression, the normokalemic null mice exhibited significantly increased kaliuresis, indicating alternative mechanisms for K(+) absorption/secretion in the nephron.

Acute renal failure is one the most common systemic complications after snakebite, however, its pathogenesis remains obscure. In this study we evaluated the renal effects of Bothrops moojeni venom and its myotoxins (Bmtx-I and BmtxII) in rat isolated perfused kidneys. The myotoxins were purified by ion-exchange chromatography and reverse phase HPLC. The whole venom (10 μg/ml) and myotoxins (5 μg/ml) were added to the perfusion system 30 min after the beginning of each perfusion. The renal effects were compared to a control group perfused with modified Krebs–Henseleit solution alone. B. moojeni venom decreased the perfusion pressure (PP), renal vascular resistance (RVR), and the percent sodium, potassium and chloride tubular transport (%TNa + , %TK + , %TCl − ). In contrast, the venom increased the urinary flow (UF), glomerular filtration rate (GFR), and the sodium, potassium and chloride excretion (ENa + , EK + , ECl − ). The renal effects of myotoxin I was very similar to those of the whole venom, but there was an increase rather than a decrease in the PP and RVR. Myotoxin II had no effect on renal physiology, except for a transient decrease in %TK + . In conclusion, B. moojeni venom caused intense alterations in renal physiology, including a drop in vascular resistance associated with diuresis, natriuresis and kaliuresis. Bmtx-I had an opposite effect when compared to whole venom, showed in the parameters of PP and RVR. Bmtx-II had a mild effect in %TK + . The apparent inability of Bmtx-II to induce the renal effect similarly to Bmtx-I should be explained by the absence in the Bmtx-II of the C-terminal lysine rich region.

In this work we studied in rat the diuretic activity of Opuntia ficus indica (L.) Mill. (Cactaceae) waste matter. The cladodes, flowers and non commerciable fruits were collected in S. Cono (CT, Sicily) cultivation. Acute and chronic diuretic activity of 15% infusion of cladodes, flowers and fruits were assayed. Natriuresis, kaliuresis and the activity on fructose-induced hyperuricemia was also studied. The results show that O. ficus indica cladode, fruit and flower infusions significantly increase diuresis. This effect is more marked with the fruit infusion and it is particularly significant during the chronic treatment. The fruit infusion shows also antiuric effect. In all experiments cladode, flower and fruit infusions showed a modest but not significant increase in natriuresis and kaliuresis.

Introduction AGT is the substrate upon which renin acts to generate angiotensin (ANG); it is rate-limiting in pregnancy. AGT synthesis has recently been identified in renal proximal tubular epithelial cells. With the rate of renal excretion being proportional to intrarenal generation and independent of circulating (systemic) concentrations. Regulation of the systemic renin-angiotensin system (RAS) in pre-eclampsia (PE) differs from that in normotensive pregnancies; there are minimal data relating to regulation of intrarenal RAS in PE. Objective: To investigate urine AGT and electrolyte concentrations and relate these to glomerular volume (GV) and renal AGT localisation in women with normotensive or hypertensive pregnancy. Patients and methods Urine samples were collected from normotensive controls (NT), gestational hypertensive (GH) and PE women at renal biopsy (mean 34 weeks”gestation). AGT was measured by ELISA and potassium by inductively-coupled plasma mass spectrometry. All data were normalised to creatinine. The mean GV was estimated in biopsies containing at least 6 glomerular sections by a computer-assisted stereological algorithm. Protein AGT localisation in renal biopsies was established by immunohistochemistry. Results Table 1 summarises AGT and potassium concnetrations. Overall, there was a positive relationship between urinary potassium and AGT (r = 0.828; P = 0.001). Higher GVs tended to track with higher urinary AGT. AGT protein was present in glomerulus and proximal tubular lumen, but absent from distal tubules in NT. In contrast, AGT was absent from all renal cells in GH and PE patients. Conclusions Raised intrarenal generation of ANG could result in sodium retention and kaliuresis, if AGT is rate-limiting in kidneys of pregnant women, then higher AGT would result in higher ANG II, which evokes sodium reabsorption, largely in exchange for potassium, the excretion of which will thus rise. Our data suggest that inappropriate activation of intrarenal RAS may contribute to the pathogenesis of pregnant hypertension and renal injury.

Interactions of mineralocorticoids and glucocorticoids in epithelial target tissues. Background In Na + -transporting epithelial target tissues, such as mammalian kidney and the isolated toad bladder, glucocorticoids (GCs) do not normally elicit Na + retention. In mammalian kidney, however, they do cause kaliuresis. The presence of 11β-hydroxysteroid dehydrogenase isoform 2 (11β-HSD2) in these target tissues inactivates the GCs, preventing them from accessing mineralocorticoid receptors (MRs) and stimulating Na + transport. Results The usually observed Na + retention elicited by the mineralocorticoid aldosterone was blunted when the GC corticosterone was coadministered along with aldosterone. However, when corticosterone was administered along with a 11β-HSD2 inhibitor, a strong Na + transport was elicited by an MR-mediated mechanism. 11-Dehydrocorticosterone also blunted aldosterone-elicited Na + transport in these target tissues. Conclusions 11β-HSD2 appears to play two important roles in the epithelial target tissues, kidney and toad bladder. The first is to protect GC access to MR, and the second involves the product of the enzyme to regulate the magnitude of aldosterone-induced Na + retention.

We determined the effects of losartan and CGP42112A (selective ligands of the AT1 and AT2 angiotensin receptors, respectively) and salarasin (a relatively nonselective angiotensin receptor antagonist) on urinary volume and urinary sodium and potassium excretion induced by administration of angiotensin II (ANG II) into the paraventricular nucleus (PVN) of conscious rats. Both the AT1 and AT2 ligands and salarasin administered in the presence of ANG II elicited a concentration-dependent inhibition of urine excretion, but losartan inhibited only 75% of this response. The IC50 for salarasin, CGP42112A, and losartan was 0.01, 0.05, and 6 nM, respectively. Previous treatment with saralasin, CGP42112A and losartan competitively antagonized the natriuretic responses to PVN administration of ANG II, and the IC50 values were 0.09, 0.48, and 10 nM, respectively. The maximum response to losartan was 65% of that obtained with saralasin. Pretreatment with saralasin, losartan, and CGP42112A injected into the PVN caused shifts to the right of the concentration–response curves, but the losartan concentrations were disproportionately greater compared with salarasin or CGP42112A. The IC50 values were 0.06, 0.5, and 7.0 for salarasin, CGP42112A, and losartan, respectively. These results suggest that both AT1 and AT2 receptor subtypes in the PVN are involved in ANG II-related urine, sodium, and potassium excretion, and that the inhibitory responses to AT2 blockade are predominant.

Texto completo: acesso restrito. p.176–184 Submitted by Suelen Reis (suelen_suzane@hotmail.com) on 2013-01-18T11:08:37Z No. of bitstreams: 1 Silva.pdf: 257229 bytes, checksum: 726a11e8b6867f6f8665f2016da6652a (MD5) Made available in DSpace on 2013-01-18T11:08:37Z (GMT). No. of bitstreams: 1 Silva.pdf: 257229 bytes, checksum: 726a11e8b6867f6f8665f2016da6652a (MD5) Previous issue date: 1999 The aim of the present study was to investigate the effect of acute third ventricle injections of zinc on the brain control of renal sodium and potassium excretion. Adult Wistar male rats received third ventricle injections of zinc acetate in three different doses (0.03, 0.3 and 3.0 nmol/rat). Third ventricle administration of zinc acetate provoked a significant intensification of natriuresis and kaliuresis as compared to sodium acetate-treated controls. When rats were pretreated with losartan, a selective angiotensin II AT1 receptor antagonist (10.8 nmol/rat into the third ventricle 10 min before central zinc injection) the increase in both natriuresis and kaliuresis was abolished. Furthermore, pretreatment with gadolinium, a calcium channel blocker (0.3 nmol/rat into the third ventricle 20 min before central zinc injection), also blunted the increase in renal sodium and potassium excretion seen in animals receiving zinc alone. In a group of rats receiving the same water load used in the previous experiments, the injection of zinc acetate into the third ventricle (3.0 nmol/rat) did not modify arterial blood pressure. It is suggested that zinc in the central nervous system may be involved in the control of renal sodium and potassium excretion by a mechanism unrelated to blood pressure increase. It is also shown that both natriuretic and kaliuretic actions of zinc depend on AT1 receptor activation. Whatever should be the mechanism(s) related to the central effects of zinc here evidenced, the functional integrity of calcium channels is required.

Torsemide inhibited aldosterone secretion by adrenal cells from rats, cows, and guinea pigs stimulated in vitro by potassium, angiotensin, dibutyryl cyclic AMP, ACTH, or corticosterone. Inhibitory concentrations for adrenal cells (micromolar) were comparable with those reported to inhibit ion transport in isolated renal tubules. Inhibition of aldosterone secretion could reduce kaliuresis, and that may explain why torsemide causes less kaliuresis than other diuretics.

Aldosterone and potassium homeostasis. The presently accepted regulators of the homeostatic excretion of potassium are the plasma concentrations of aldosterone and potassium. Evidence for a role of aldosterone is reviewed, and it is pointed out that aldosterone is kaliuretic at supraphysiologic levels but has little kaliuretic activity within its normal secretory range. Elevation of plasma potassium above its normal range enhances the kaliuretic action of aldosterone. Elevation of plasma potassium above, but not within, its normal range is strongly kaliuretic. In sheep the kaliuresis induced by intake of a potassium rich meal cannot be explained by changes in aldosterone or plasma potassium. A kaliuretic reflex arising from receptors in the gut, portal vein or liver has been proposed the explain the meal-induced kaliuresis. This putative reflex involves the central nervous system and efferent kaliuretic factors other than aldosterone and plasma potassium. Evidence for the involvement of the central nervous system and undetermined kaliuretic regulatory factors can be found in studies of the physiologic circadian rhythm of renal potassium excretion. This rhythmic excretion does not appear to depend on changes in either aldosterone or plasma potassium.

The present experiments were conducted to investigate the role of the alpha 1-, alpha 2- and beta-adrenergic receptors of the median preoptic area (MnPO) on the water intake and urinary electrolyte excretion, elicited by central injections of angiotensin II (ANG II). Prazosin (an alpha 1-adrenergic receptor antagonist) and yohimbine (an alpha 2-adrenergic receptor antagonist) antagonized the water ingestion, Na+, K+, and urine excretion induced by ANG II. Administration of propranolol, a beta-adrenergic receptor antagonist increased the Na+, K+, and urine excretion induced by ANG II. Previous treatment with prazosin and yohimbine reduced the pressor responses to ANG II. These results suggest that the adrenergic neurotransmission in the MnPO may actively participate in ANG II-induced dipsogenesis, natriuresis, kaliuresis, diuresis and pressor responses in a process that involves alpha 1-, alpha 2-, and beta-adrenoceptors.

We previously reported that the renal arterial infusions of non-hypotensive doses of calcitonin gene-related peptide (CGRP) caused renal vasodilatation and increases in glomerular filtration rate at a low dose, but renal vasoconstriction, natriuresis and kaliuresis at a high dose. In the present study, we examined the effects of the specific CGRP 1 receptor antagonist CGRP-(8–37) (1 and 10 nmol/kg) and the putative CGRP receptor antagonist, [Tyr 0 ]CGRP-(28–37) (3 and 30 nmol/kg), on the renal vascular and tubular effects of CGRP in inactin-anaesthetized Sprague-Dawley rats. Renal arterial infusion of single doses of CGRP (0.3–300 pmol/kg per min) did not significantly alter mean arterial pressure or heart rate. However, during the continuous renal arterial infusion of either CGRP-(8–37) or [Tyr 0 ]CGRP-(28–37), a high dose of CGRP (300 pmol/kg per min) paradoxically reduced arterial pressure and increased heart rate. CGRP-(8–37) completely but [Tyr 0 ]CGRP-(28–37) incompletely inhibited the vasodilatation and increments in glomerular filtration rate elicited by low doses of CGRP. Both blockers abolished the renal vasoconstriction but did not inhibit diuresis, natriuresis and kaliuresis elicited by a high but non-hypotensive dose of CGRP. On the basis that CGRP-(8–37) is a competitive CGRP 1 receptor antagonist, our results suggest: (1) the renal vascular effect of CGRP is completely mediated via the activation of CGRP 1 receptors, (2) the renal tubular effects of CGRP are not mediated via CGRP 1 receptors, and (3) [Tyr 0 ]CGRP-(28–37) is a CGRP 1 receptor antagonist with potency and efficacy less than those of CGRP-(8–37).

Biologic and physical characteristics of the non-peptidic, non-digitalis-like natriuretic hormone. At least three independent groups of natriuretic hormones have been isolated over the past ten years. Two, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), are proteins and the third is made up of digitalis-like substances (DLS). The present report concerns the isolation, substantial purification and biologic actions of an entirely different natriuretic hormone (NH) which appears to be steroidal in nature and an isomer of cortisone. The source of NH was uremic urine. Purification involved successive chromatographic steps including gel filtration and multiple HPLC runs through C-18 resins. A translucent crystal ultimately was obtained. The product was examined using mass spectroscopy with trimethylsilyl derealization. Only one compound was identifiable. The characteristics of the molecule include: a molecular weight, 360.4; a molecular formula, C 21 H 28 O 5 ; a steroidal nucleus; UV absorption at 220 and 290 nm; and intrinsic fluorescence. The onset of action occurs within minutes both in the rat and, as previously shown, in several in vitro systems including the frog skin, toad bladder, fibroblasts and renal tubular epithelial cells grown in culture and isolated perfused cortical collecting tubules. In contrast to DLS, NH has been previously shown not to cross react with digoxin antibodies. Moreover, when given to intact rats, it produces a profound natriuresis but little or no kaliuresis. In contrast to ANF and BNP the compound is active orally as well as intravenously. It is clearly different from cortisone, based both on its biologic and mass spectroscopic characteristics.

The excretion of potassium (K+) decreased by 50% (30 v 63 mEq/d, P < .01) when subjects consumed a diet that was low in K+ for 3 days. Although part of this conservation of K+ was achieved in part by suppressing the release of aldosterone, nevertheless providing exogenous mineralocorticoids did not lead to a large kaliuresis when there was a modest degree of K+ depletion. Accordingly, the purpose of this study was to evaluate possible mechanisms for this antikaliuretic response to mineralocorticoids. The renal handling of K+ was examined by independent analysis of the two factors that influence its excretion, the driving force to secrete K+ and the urine volume. This driving force is reflected in a noninvasive fashion by the transtubular [K+] gradient (TTKG). Stimuli to increase the rate of excretion of K+ in subjects on a normal and a low-K+ diet included the administration of 200 micrograms fludrocortisone (9 alpha F), the induction of a high urine flow rate (9 alpha F+furosemide), the induction of bicarbonaturia (9 alpha F+acetazolamide), and the excretion of Cl(-)-poor urine (< 15 mEq/L). On the low-K+ diet, the peak value for the TTKG 3 to 4 hours after 9 alpha F was less than half that while on the normal diet (6.4 v 14, P < 0.01). In contrast, the TTKG was not significantly different on either diet when there was bicarbonaturia or the excretion of a Cl(-)-poor urine (18 v 17 and 17 v 16, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Nephron segment-specific inhibition of Na+/K+-ATPase activity by cyclosporin A. Decreased kaliuresis and hyperkalemia are common complications of cyclosporin A (CsA) therapy. If CsA significantly inhibits renal tubular Na+/K+-ATPase activity, the alteration in transepithelial K+ secretion and K+ homeostasis could result in hyperkalemia. To investigate this possibility, we tested the effects of CsA on Na+/K+-ATPase activity in microdissected rat tubules. CsA, at a “toxic” concentration of 600 ng/ml, significantly inhibited Na+/K+-ATPase in cortical collecting ducts (CCD), medullary thick ascending limbs (mTAL), and outer medullary collecting ducts from the outer stripe (OMCDos) by 35%, 53%, and 39%, respectively. Cremophore, the commercial vehicle for CsA, did not change Na+/K+-ATPase activity in any nephron segment tested. To determine whether CsA inhibits Na+/K+-ATPase activity in a dose-dependent manner, microdissected CCD's were incubated with 300, 600, and 2500 ng/ml of CsA for 30 minutes. Na+/K+-ATPase activity was inhibited at 600 and 2500 ng/ml, but not at 300 ng/ml. No further inhibition of enzyme activity was noted at 2500 ng/ml. CsA did not change Na+/K+-ATPase activity in proximal tubule S1, S2, and S3 subsegments; cortical thick ascending limbs (cTAL), connecting tubules (CNT), or outer medullary collecting ducts from the inner stripe (OMCDis). Prolonging the incubation of CsA with S2 subsegments to 60 minutes did not result in inhibition of Na+/K+-ATPase activity. Ouabain-insensitive ATPase activity was unaffected by CsA or its vehicle in any nephron segment tested. In summary, CsA specifically inhibits Na+/K+-ATPase activity in the CCD, mTAL, and OMCDos. In the CCD, inhibition of Na+/K+-ATPase activity was dose-dependent and occurred at concentrations commonly associated with clinical CsA toxicity (600 to 2500 ng/ml). CsA-induced inhibition of Na+/K+-ATPase activity in the CCD and OMCDos could decrease K+ secretion and contribute to clinical hyperkalemia.

Eleven term neonates treated with extracorporeal membrane oxygenation received bumetanide to treat volume overload. All patients had stable renal function, no history of prior diuretic therapy, and no overt evidence of hepatobiliary disease or hypoalbuminemia. Pretreatment creatinine clearance was 35.2 +/- 4.5 ml/min per 1.73 m2 (range, 20.3 to 57.5). Bumetanide, 0.095 +/- 0.003 mg/kg, was administered for 2 minutes into the postmembrane side of the extracorporeal membrane oxygenation circuit. Serial plasma and urine samples were collected for measurement of bumetanide and electrolyte concentrations. Total plasma and renal clearances for bumetanide were 0.63 +/- 0.11 and 0.16 +/- 0.04 ml/min per kilogram, respectively. The steady-state volume of distribution (0.44 +/- 0.03 L/kg) and the elimination half-life (13.2 +/- 3.8 hours) were greater than similar values reported in previous studies of bumetanide disposition in premature and term neonates who were not treated with extracorporeal membrane oxygenation. At observed rates of bumetanide excretion, the diuretic, natriuretic, and kaliuretic responses were linear. Significant diuresis, natriuresis, and kaliuresis were observed, although the duration of these effects was less than expected given the prolonged renal elimination of bumetanide. Nonrenal elimination of bumetanide was variable (47.2% to 96.9%) but higher than expected; this may explain the relatively brief diuretic and kaliuretic response.

The effects of exposure to competitive mental stressors on rates of excretion of sodium (Na), potassium (K) and fluid, together with cardiovascular responses, were evaluated in 14 black and 14 white normotensive men after 3 days of controlled diet (200 mEq Na, 100 mEq K daily). In the first hour of a 5-hr protocol, subjects ingested a standard dinner and drank 1 liter of water. In hours 2-5, they voided to provide urine collections every 30 min, and drank 200 ml additional water after each collection. Hours 1-2 were for stabilization of excretion, hour 3 was baseline, hour 4 was stress and hour 5 was post-stress rest. During stress, 20 men showed faster natriuresis and 8 showed slower natriuresis than at baseline. These subgroups did not differ in any excretion measure at baseline. During stress, the slow stress natriuresis group showed slower excretion of potassium and fluid as well as sodium; slow natriuresis and kaliuresis persisted 30 min after stress. Creatinine clearance rate was also decreased, but only during the first 30 min of stress. Slow stress natriuresis subjects were found to have higher blood pressures during baseline and stress, greater heart rate and cardiac output increases during stress, and a larger percentage had hypertensive parents (63 vs 37%) compared to fast stress natriuresis subjects. Slow stress natriuresis was observed in 50 vs 17% of men with resting diastolic levels above vs below 80 mmHg, and in 43% of blacks vs 18% of whites tested. Overall, black subjects tended to excrete sodium more slowly than whites at baseline, and showed significantly lesser increases in sodium excretion rate when pressures rose during stress.

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.

The present study investigated the effect of selective muscarinic antagonists on natriuresis, kaliuresis and antidiuresis induced by intracerebroventricular (i.c.v.) injection of carbachol in the rat. The muscarinic antagonists were given by i.c.v. injection 1 min before carbachol (1 μg/rat). 4-Diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a rather selective M1 and M3 receptor antagonist, was the most potent inhibitor of carbachol-induced natriuresis, kaliuresis and antidiuresis, its ID50 being respectively 0.12,0.04 and 0.56 nmol/rat. Pirenzepine, a selective m1 antagonist, potently inhibited the above mentioned carbachol effects, its 1050 being 1.85, 3.25 and 1.49 nmol/rat, respectively. On the other hand, the M2-selective antagonist methoctramine and the M3-selective antagonist p-fluoro-nexahydro-sila-difenidol were very weak inhibitors. Methoctramine at doses up to 60 nmol/rat produced non statistically significant inhibition of carbachol-induced natriuresis, kaliuresis and antidiuresis. Parafluoro-hexahydro-sila-diphenidol showed an ID50 of 64.4 nmol/rat on carbachol-induced natriuresis, while at the maximum dose employed, 100 nmol/rat, the inhibition of carbachol-induced kaliuresis and antidiuresis was lower than 50%. The rank order of potency of the antagonists tested proved to be related to their pA2 values for muscarinic M1 receptors, suggesting that this receptor subtype mediates the central effects of cholinergic mechanisms on water and electrolyte excretion.

Early and late adjustment to potassium loading in humans. We studied the adaptation to early (72 hr) and late (20 days) K loading (400 mmol/day, 4 equal meals every 6 hour) in six healthy humans. Throughout the study, each single K meal was followed by an acute transient rise in plasma K, aldosterone and kaliuresis. “K balance” (urinary K excretion ∼80% of intake) was achieved in the second 24 hour period of K loading. This was associated with elevated plasma K and aldosterone, slightly negative sodium (Na) balance and stimulated plasma renin activity. At 20 days of K loading Na loss had been compensated. Plasma renin activity and aldosterone had returned to baseline, although the latter kept increasing after each single K meal. Compared to the first K meal, the K meals at 72 hours and 20 days of K loading were followed by more kaliuresis, while the natriuretic effect had disappeared. Abrupt discontinuation of K loading was followed by negative K balance, lasting only 24 hour, and by Na retention, lasting 72 hours. In conclusion, switching to a high K diet in humans is immediately followed by increased renal K excretion, and by Na loss. K excretion increases over a few days, while Na loss is halted. This can be explained by the rise in plasma aldosterone, secondary to elevated plasma K and renin activity. After weeks, renal adaptation forms an additional factor promoting K excretion and preventing natriuresis. The latter appears specifically from the Na retention which occurs after discontinuation of K loading in the absence of persistent aldosterone stimulation.

International audience; Rat atrial natriuretic factor (125I-rANF, 99-128) is hydrolysed by pure enkephalinase (EC 3.4.24.11) in vitro at a rate similar to that of 125I-hANF. Trichloroacetic precipitated radioactivity was significantly elevated in the kidneys of rats pretreated with acetorphan, an enkephalinase inhibitor, and receiving 125I-rANF, indicating that the exogenous hormone was protected against degradation. A single oral administration of acetorphan elicited diuretic and natriuretic effects in conscious normotensive rats and natriuretic effects in spontaneously hypertensive rats, effects which were not accompanied by significant changes in kaliuresis. The diuretic and natriuretic effects were still observed in conscious normotensive rats after three days of repeated administration of the drug. In conscious or anesthetized rats in which volume expansion was elicited by hydroelectrolytic loads, the initial rate of urinary elimination of water and sodium was nearly doubled by treatment with enkephalinase inhibitors. This effect was prevented by coadministration of an ANF antiserum, which suggests that the effect was mediated by endogenous ANF. These various observations suggest that enkephalinase inhibitors protect endogenous ANF from degradation and thereby enhance the typical renal effects of the hormone.

Diuretic drugs have been the mainstay of treatment for heart failure. Specific elucidation of the effects of diuretics on electrolytes, however, has been difficult, since the heart failure state itself may alter the electrolyte balance. Nevertheless, it is noteworthy that the natriuretic effect of loop diuretics is greater in edematous patients than in healthy volunteers; yet, the initial kaliuresis is minimal--perhaps because aldosterone levels are low. With continued treatment (or after the edema has been cleared), however, the natriuretic action of loop diuretics is less than that seen in controls, but loss of potassium occurs. The addition of a thiazide to a loop diuretic enhances its natriuretic effect. Both loop and thiazide diuretics can induce depletion of magnesium. Potassium-sparing diuretic drugs augment the natriuresis induced by loop or thiazide diuretics but limit or prevent the loss of potassium or magnesium in the urine, at least in the short term. However, potassium-sparing diuretics can exacerbate the development of hyponatremia.

Congestive heart failure is characterized by both disturbances in electrolyte homeostasis and neuro-hormonal regulation. Total body potassium is reduced, and this reduction bears a modest relation to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Patients with decompensated heart failure show increases in both plasma epinephrine and plasma norepinephrine, whereas patients with chronic stable heart failure usually have an increase only in plasma norepinephrine. High levels of circulating epinephrine may contribute to the development of hypokalemia by activating skeletal muscle and liver membrane beta 2-adrenergic receptors, which in turn stimulate intracellular cyclic adenosine monophosphate to activate the membrane-bound Na+K(+)-adenosine triphosphatase pump. The net result is that potassium flux across the cell membrane from the extracellular to the intracellular space increases, setting the stage for hypokalemia and possibly serious ventricular arrhythmias. Other mechanisms that may contribute to the development of hypokalemia in heart failure include the kaliuresis brought on by excessive levels of aldosterone. Moreover, it is likely that the activity of facilitated by concomitant activation of the renin-angiotensin system. Increased sympathetic nerve activity may then release additional renin from the kidney (by way of a beta 2-adrenergic mechanism). Therefore, both the sympathetic nervous system and the adrenal medulla may interact to cause hypokalemia in patients with heart failure. Because hypokalemia is known to predispose patients to ventricular arrhythmias, it may be prudent to aggressively maintain serum potassium levels in patients with heart failure in the range of 4 to 5 mEq/liter.

The syndrome of primary aldosteronism produces few signs or symptoms. The diagnosis should be suspected when either spontaneous hypokalemia or easily provoked hypokalemia is found in a patient with hypertension. Hypokalemia in association with inappropriate kaliuresis, low plasma renin activity, and a high plasma aldosterone concentration/plasma renin activity ratio are the findings on initial screening tests that should suggest primary aldosteronism. The diagnosis must be confirmed by demonstrating nonsuppressible aldosterone excretion in conjunction with normal cortisol excretion. The choice of therapy is based on distinguishing unilateral from bilateral adrenal disease. With a unilateral adrenal adenoma, surgical removal reverses the hypokalemia and frequently cures the hypertension. In most patients with bilateral adrenal hyperplasia who are treated surgically, however, hypertension persists; thus, the initial treatment in these patients should be pharmacologic.

The effects of intraseptal injection of carbachol on natriuresis, kaliuresis and diuresis has been studied in conscious, unrestrained water-loaded male rats. Urinary sodium and potassium excretion increased following injections into the septal area. The intensity of the natriuresis and kaliuresis was dose-related. An antidiuretic effect was also observed. The Na + /K + ratio increased with increasing doses of carbachol, indicating that the rise in urinary sodium exceeded that of potassium. Systematic mapping of the septal area yielded about the same results for all sites, excepting a zone located in the anterior-dorsal part of the medial nucleus which appeared more sensitive. The natriuretic effect of intraseptal carbachol in adrenalectomized rats demonstrated the secondary role played by the adrenals. Contrariwise the decrease of the natriuretic effect observed either in hypophysectomized rats or in rats bearing a median eminence lesion receiving intraseptal carbachol showed the important participation of these structures in urinary Na + excretion. Adrenalectomy or median eminence lesions did not modify the kaliuretic response while hypophysectomy produced a transitory diminution. This fact favours the hypothesis of different mechanisms involved in Na + and K + excretion following intraseptal carbachol. These results leave open the question as to mechanism of action but suggest a possible role of the pituitary in mediating the responses. Also, the possibility of a role played by hemodynamic shifts is suggested.

It is unknown whether diabetic patients without renal failure or aldosterone deficiency respond normally to potassium administration. Acute oral potassium-loading was carried out in eight diabetic patients with modestly reduced creatinine clearance (Ccr) and in 11 diabetic patients and 13 controls with normal clearances. Only one diabetic patient manifested an inappropriately low upright plasma aldosterone level (6 ng/dL). The percentage of potassium excreted in 4 hour by both groups of diabetic patients was significantly less than that of the controls (decreased Ccr:21% +/- 6%, normal Ccr:36% +/- 5%, controls:54% +/- 5%; p less than 0.01 and 0.05 respectively). On the other hand, the estimated amount of potassium translocated intracellularly tended to be greater in the diabetic patients (18 +/- 3 mmol; 11 +/- 3 mmol) than controls(7 +/- 2 mmol; p less than 0.005 and 0.1 respectively), and the ratio of the increase in plasma (K) to the amount of potassium retained, was lower in diabetic patients, probably indicating enhanced intracellular potassium translocation. The authors conclude that diabetic patients with normal or only slightly reduced renal function (and no aldosterone deficiency) may have a reduced capacity to excrete an acute potassium load but an enhanced capacity to transfer potassium intracellularly.

Prolonged infusion of vanadate (VO-3) (51 ng/microliter/hr during 15 hr), an in vitro inhibitor of Na,K-ATPase activity, into the 3rd brain ventricle (3BV) increased diuresis, sodium and potassium excretion in normal rats (p less than 0.001). Since the animals did not receive food or water during the infusion period, the effect of VO-3 was not related to hydration or volume expansion. A single injection of ouabain (a specific inhibitor of the sodium pump) 1 microliter, 50 pg/microliter, followed by a single injection of vanadate (1 microliter/51 ng/microliter) 1, 5 or 10 minutes after ouabain, prevented the diuretic and natriuretic effect of VO-3. When vanadate injections were delayed 20 or 30 minutes, diuresis reappeared. Ouabain (50 pg) decreased sodium intake induced by sodium depletion, an effect that lasted for 10 to 15 minutes after injection, a time coincident with the inhibition of the natriuretic effect of VO-3 by OUA. Then the life-span of ouabain effect on prevention of VO-3-induced diuresis as well as on inhibition of sodium intake, lasted between 10 to 15 minutes. These results provide further evidence for the powerful diuretic, natriuretic and kaliuretic effect of centrally injected vanadate. However, the finding that ouabain suppresses this effect, does not support the suggestion that the active transport system might be involved.

Natriuresis, kaliuresis and diuresis have been studied in rats following water loading and cholinergic stimulation in the MSA before and after bilateral electrolitic lesion of the habenula, or medullary stria, or supraoptic nucleus or paraventricular nucleus, or fornix. Carbachol injection in MSA elicited an increase of natriuresis and kaliuresis. These responses were blocked by bilateral electrolytic lesion of the habenula, medullary stria, or supraoptic nucleus but not of the paraventricular nucleus or the fornix. Urinary output plotted as a function of time showed antidiuresis in periods of 20 and 40 minutes after carbachol injection into the MSA. The lesion of the supraoptic nucleus inhibited this antidiuresis and natriuresis. The lesion of the habenula or medullary stria blocked natriuresis but not antidiuresis suggesting an independence between the mechanisms of antidiuretic hormone release and natriuresis regulation. The integrity of the habenula, medullary stria and supraoptic nucleus seems to be important in the mediation of the natriuretic response induced by carbachol injection into the MSA.

The microinjection of hypertonic sodium chloride into the third ventricle elicits natriuresis and kaliuresis in rats following water loading. These responses were blocked by atropine or phentolamine microinjection into the MSA. The data suggest the interaction between periventricular areas sensible to changes of sodium concentration in the cerebrospinal fluid (CSF) and MSA. Cholinergic and alpha-adrenergic synapses of MSA are involved in this interaction which regulates renal sodium excretion.

To examine the effects of increasing dietary sodium intake on natriuresis, filtration rate, and renal blood flow following rapid volume expansion, we infused 2-liter normal saline over 2 hr into normal men in balance at 10, 300, 600, and 800 mEq/day sodium intake. Natriuresis and kaliuresis were related to prior sodium intake. Fractional excretion of sodium (6%-7%) was maximal at the 600 mEq/day sodium intake and increased no further at the 800 mEq/day sodium intake. Although blood pressure increased with rapid saline infusion, natriuresis and blood pressure were not associated. Creatinine clearance decreased or remained constant, while PAH clearance decreased during saline infusion at each level. The data suggest that although natriuresis following rapid saline infusion is dependent upon prior sodium intake, under given circumstances it may be independent of glomerular filtration rate, renal blood flow, or blood pressure.

The more potent "loop" diuretics are being used with increasing frequency. The elderly constitute a growing portion of the population undergoing treatment with diuretics. The alterations in renal function and pharmacokinetics in the elderly (over 60 years of age) may result in the development of certain adverse effects. In patients over 70 years old, there is a progressive decline in overall renal function, resulting in a more than 50% decrease in glomerular filtration rate. Most of the pharmacokinetic changes in the elderly consist of alterations resulting in enhanced plasma levels of any given drug; diminished hepatic drug extraction, detoxification/metabolism or prodrug conversion; decreased renal excretion of drug; and diminished volume of distribution of drug. Adverse reactions to diuretics may be grouped into metabolic changes (e.g., hypokalemia), physiologic alteration (e.g., volume contraction), toxic manifestation (e.g., interstitial nephritis) and allergic or idiosyncratic phenomena (e.g., rash or thrombocytopenia). There is general agreement that significant hypokalemia, particularly among elderly patients receiving digitalis glycosides, is significant and requires therapy. Diuretic-associated hypokalemia reflects the potency and duration of action of a diuretic, factors modulating potassium balance including dietary intake and concurrent medical processes. The short duration of action and greater natriuresis relative to kaliuresis characteristic of loop diuretics may result in a lesser degree of hypokalemia than that seen with traditional thiazide diuretics.

Metabolic alkalosis was induced in adult Yucatan miniature boars by subcutaneous implantation of desoxycorticosterone-acetate impregnated silicone rubber strips. Serum pH, bicarbonate, and PaCO2 increased rapidly and consistently following implantation. As in the dog and the rat, hypokalemia was accompanied by hypochloremia. As in the rabbit, hypokalemia developed in the presence of a decreased urinary output of potassium and apparent absence of kaliuresis. The pig is resistant to the paralytic effects of hypokalemia. Implantation of DOCA is an effective means of producing chronic metabolic alkalosis in the pig which is characterized by hypokalemia and hypochloremia.

The effect of peritoneovenous shunting on body composition has been studied in 7 cirrhotic patients undergoing a successful shunt and 3 patients in whom the shunt was unsuccessful. In the 7 patients with functioning shunts, their weight had decreased by a mean of 9 kg (p less than 0.001) by 6 wk after initial diuresis, natriuresis, and kaliuresis, and was associated with a decrease in total body potassium (TBK) but not total body nitrogen (TBN). This resulted in a significant decrease in the TBK/TBN ratio from 2.12 +/- 0.74 to 1.66 +/- 0.20 (p less than 0.01). By a mean of 14 mo, in these 7 patients there was a significant increase in mean TBN (from 1.54 +/- 0.10 to 1.84 +/- 0.10, p less than 0.005) associated with an improvement in the mean nitrogen index (from 0.74 +/- 0.04 to 0.88 +/- 0.04, p less than 0.005). These changes were associated with a significant increase in nonalcoholic calories, a nonsignificant increase in protein consumption, and a positive nitrogen balance. After the initial kaliuresis, mean potassium balance remained constantly positive (+22.7 +/- 3.4 mmol/day), serum aldosterone levels normalized, and TBK increased. In contrast, 3 patients with failed peritoneovenous shunting continued to lose weight significantly despite the presence of ascites; TBN and nitrogen index also decreased. In conclusion, body composition studies appear to have confirmed the clinical observation that cirrhotic patients with massive ascites have depleted body protein which is gradually repleted only after successful shunting. In this situation TBK, long used as a measure of lean body mass, is less satisfactory than TBN and nitrogen index. This improvement in body protein appears to be explained by an increased dietary intake associated with improved nitrogen balance, but these changes are not found in patients in whom the shunt failed.

Hypotonic and isotonic solutions into the LHA of unrestrained rats caused no alteration in renal water and electrolyte excretion. Similar results were obtained after injecting hypo, iso and hypertonic glucose solutions. On the other hand, a hypertonic NaCl solution produced an increase in natriuresis and kaliuresis immediately after being injected into the LHA. The carbachol elicited an increase in natriuresis and kaliuresis as well as a decrease in urine output in the first urine samples collected after the injection being injected into the LHA. This response was not modified when the same dose of carbachol was injected associated with NaCl or glucose solutions. The observation of a lack of summation between the effects of carbachol and hypertonic NaCl, as well as the maintenance of the natriuretic and kaliuretic effects in response of the injection of the hypertonic solution even in the presence of blocked cholinergic pathways (atropine), suggests a dissociation between the mechanisms activated by the hypertonic solution and the cholinergic stimulation of the LHA.

Administration of angiotensin usually produces dual effects in normotensive man and other mammals: antidiuresis and antinatriuresis in relatively small doses and natriuresis at higher doses. Infusions of angiotensin II-amide and semipurified natural eel angiotensin into freshwater-adapted and saline-loaded American eels, Anguilla rostrata, produced vasopressor, diuretic, and natriuretic responses. Increased glomerular filtration, as estimated from inulin clearances (CIN), apparently caused the diuresis. Diuresis occurred only after clear vasopressor doses of angiotensins. There was no clear correlation, however, between the increase in dorsal aortic pressure and the increase in CIN. Norepinephrine increased dorsal aortic pressure as did the angiotensins, but urine flow and CIN decreased. Marked natriuresis and kaliuresis accompanied angiotensin diuresis. Increases in Na and K excretion rates were well correlated with increases in CIN. The amount of Na filtered and reabsorbed increased, although the percentage of the filtered Na reabsorbed decreased. Natriuresis thus may reflect impaired “glomerulo-tubular balance,” that is, the renal tubules failed to reabsorb Na in proportion to the increased filtered Na load. There was no apparent difference in the mode and magnitude of renal responses to synthetic angiotensin II-amide and to natural eel angiotensin, when these were compared on the basis of equivalent vasopressor activities determined by rat bioassays.

Mineralocorticoid–stimulated renal acidification: The critical role of dietary sodium. Recent in vitro studies of isolated distal nephron segments have demonstrated that 1) mineralocorticoid hormone stimulates H + secretion by both Na + -dependent and Na + -independent mechanisms, and 2) the Na + -independent acidification mechanism has a greater capacity. These in vitro data suggest that mineralocorticoid administration in vivo might increase renal acid excretion when an augmentation in distal Na + reabsorption is precluded by rigid restriction of dietary Na + ; under these circumstances, virtually all Na + delivered to the distal nephron is reabsorbed in the basal state. In the present studies, prolonged (12 days) administration of DOC (15 mg/day) was undertaken in both Na + -fed and rigidly Na + -restricted dogs with chronic HCl acidosis. Na + -fed animals responded to DOC administration with a large increment in net acid excretion and complete correction of metabolic acidosis. Marked hypokalemia and significant kaliuresis also occurred. Na + -restricted dogs experienced no changes in renal acid excretion, systemic acid–base equilibrium, plasma [K + ] or K + balance. These results suggest that both renal H + and K + excretory responses to prolonged mineralocorticoid hormone administration in vivo are critically dependent on the availability for reabsorption of surplus Na + within the distal nephron; this requirement is met when the diet, and hence the final urine, contains Na + but cannot be satisfied when dietary Na + is rigidly restricted.

Mineralocorticoid activity and the excretion of an oral potassium load in normal man. In six healthy males on a fixed sodium/potassium (Na/K) intake, we studied the relation between plasma K and urine K and Na excretion after an oral K load. Studies were repeated during fludrocortisone (0.5mg bid) or spironolactone (50mg qid), that is, after escape from the Na-retaining and Na-excreting effects of these drugs. A steep positive relation between plasma K (ordinate) and urine Kor Na (abscissa) was found, compatible with a strong influence of changes in plasma K on K and Na excretion. Fludrocortisone reset the relation to a lower level of plasma K. Spironolactone, on the other hand, had little effect on these relations, although a tendency towards a higher plasma K could be recognized. Paradoxically, the K load was excreted less efficiently during fludrocortisone, probably due to enhanced cellular K deposition. Prolonged kaliuresis relative to the transient rise in plasma K and natriuresis was found only without medication. Only in this situation aldosterone rose and fell parallel to plasma K. We conclude that: 1) chronic mineralocorticoid increase shifts the set point of both K and Na excretion following a K load to a lower plasma K, compatible with resetting of the positive influence of plasma K on distal solute delivery towards a lower plasma K; 2) total kaliuresis is paradoxically low due to enhanced cellular K uptake; 3) blockade of endogenous aldosterone action has relatively little influence on these relations between plasma K and urine K or Na; 4) the contribution of acute aldosterone stimulation to the excretion of a single oral K load can be recognized as a delayed kaliuresis extending beyond the peak in plasma K.

Renal handling of potassium in dogs with chronic renal insufficiency. The dynamics of potassium excretion were examined in normal dogs and dogs with chronic renal insufficiency of at least 4 weeks' duration (remnant model). All animals, in balance on diets providing 15, 50, or 100mEq of potassium and 100mEq of sodium, were challenged with 50mEq of potassium chloride. Immediately thereafter, hourly clearances were obtained for 5 hours. Irrespective of dietary potassium, mean fasting serum potassium and urinary potassium excretion (UKV) were similar in normal and remnant dogs with mean GFR's of 57 ± 3 and 16 ± 3 ml/min, respectively. After orogastric administration of 50mEq potassium, serum potassium rose significantly more in remnant (2.2 to 2.5 mEq/liter) than in normal (0.9 to 1.2 mEq/liter) groups (P < 0.001). Conversely, UKV increased significantly less, 70 to 96 vs. 151 to 194 µEq/min, respectively (P < 0.001). In 5 hours, normal animals excreted 61 to 67% of the load, but remnant dogs only 30 to 37% (P < 0.001). In all groups, UKV correlated directly with serum potassium concentration. But this relationship was markedly attenuated in the remnant groups (P < 0.001) and independent of dietary potassium. In contrast, the same slope describes the relationship between UKV/GFR and serum potassium for all, normal and remnant, animals. The blunted kaliuresis occurred despite the more severe hyperkalemia in remnant than in normal dogs; it was not associated with significant changes in acid-base, diuresis, natriuresis, serum glucose, insulin, and glucagon concentrations and occurred despite prolonged hyperaldosteronism. The results demonstrate a severe limitation of the remnant kidney's ability to rapidly excrete a potassium load. Changes in serum potassium, or a consequence thereof, are important for the urinary excretion of potassium following its acute administration.Comportement rénal du potassium chez les chiens en insuffisance rénale chronique. L'excrétion de potassium a été étudiée chez des chiens normaux et des chiens en insuffisance rénale chronique depuis au moins 4 semaines. Tous les animaux, en bilan avec des alimentations apportant 15, 50, ou 100mEq de potassium et 100mEq de sodium ont reçu 50mEq de chlorure de potassium. Immédiatement après des clearances horaires ont été obtenues pendant 5 heures. La concentration moyenne de potassium sérique à jeun et UKV étaient semblables, indépendamment de l'alimentation, chez les chiens normaux et ceux en insuffisance rénale avec des débits de filtration moyens de 57 ± 3 et 16 ± 3 ml/min, respectivement. Après l'administration orale de 50mEq de potassium, le potassium sérique a augmenté significativement plus chez ceux en insuffisance rénale (2,2 à 2,5 mEq/litre) que chez les normaux (0,9 à 1,2 mEq/litre) (P < 0,001). Inversement UKV a augmenté significativement moins, 70 à 96 vs 151 à 194 μEq/min respectivement (P < 0,001). En 5 heures les animaux normaux ont excrété 61 à 67% de la charge et ceux en insuffisance rénale seulement 30 à 37% (P < 0,001). Dans tous les groupes UKV était directement corrélé avec la concentration sérique du potassium. Cette relation, cependant, était très atténuée dans le groupe des animaux en insuffisance rénale (P < 0,001) et indépendante du potassium alimentaire. Au contraire, la même courbe décrit la relation entre UKV GFR et le potassium sérique pour tous les animaux. L'atténuation de la kaliurèse/est survenue chez les animaux en insuffisance rénale malgré une hyperkaliémie plus importante que chez les animaux normaux. Cela n'était pas associé à des modifications significatives de l'équilibre acido-basique, de la diurèse, de la natriurèse, du glucose sérique, des concentrations d'insuline et de glucagon et survenait malgré un hyperaldostéronisme prolongé. Les résultats démontrent une limitation sévère de la capacité d'excréter une charge de potassium par le rein réduit. Les modifications du potassium sérique, ou une de ses conséquences, sont importantes pour l'excrétion urinaire de potassium après son administration aiguë.

The microinjection of carbachol into the medial preoptic area (MPO) of the rat induced natriuresis, kaliuresis and anti-diuresis in a dose-related manner. Atropine blocked all responses to carbachol. Hexamethonium impaired the dose-response effect of carbachol on kaliuresis, but had no effect on natriuresis and enhanced the antidiuretic effect of carbachol. Nicotine alone had no effects, but pre-treatment with nicotine enhanced the responses to carbachol. These data show that activity of the muscarinic receptors of the MPO increases renal electrolyte and reduces water excretion. They also suggest that nicotinic receptors have an inhibitory effect on water excretion. Nicotine could act through mechanisms unrelated to nicotinic receptors to enhance the effect of the carbachol.

The effect of 4 h intracerebroventricular (i.c.v.) infusion of various solutions on the renal excretion of Na and K and urinary flow rate was examined in conscious unrestrained rats not water-loaded. I.c.v. infusion of iso- or hypo-osmotic solutions with low [Na] induced a diuresis but did not alter renal excretion of Na or K. I.c.v. infusion of hyperosmotic solutions with normal or elevated [Na] induced a natriuresis and kaliuresis. Hyperosmotic mannitol solutions caused a diuresis but hyperosmotic NaCl or sucrose solutions caused a diuresis only when the rats drank water and/or sodium solution during the infusion period. I.c.v. infusion of hyperosmotic NaCl but not hyperosmotic mannitol increased blood pressure. The results are consistent with the involvement of cerebral osmosensors in the control of urinary excretion of Na and K, and of cerebral Na sensors in the control of urinary flow rate. Increased blood pressure, as occurred during i.c.v. infusion of hyperosmotic NaCl, may also contribute to the increased excretion of Na and K.

Renal sodium and potassium handling, plasma aldosterone and cortisol concentrations, and urine free norepinephrine excretion were determined every 4 h for 24 h in 15 cirrhotics (7 without ascites, group 1; 8 with ascites, group 2) and 7 healthy controls during controlled salt intake and recumbency. Renal sodium excretion was significantly reduced in group 2, whereas it exceeded threefold the salt intake in group 1. Its circadian rhythm was disrupted in both groups of patients. Significant inverse correlations with plasma aldosterone were found erratically in controls, never in group 1, and at every 4-h interval in group 2. In the latter, the indexes of tubular activity and effectiveness of aldosterone were also significantly increased. Urine norepinephrine excretion was never related to sodium excretion in either controls or patients; in group 2 it was directly correlated with glomerular filtration rate in many instances. The cortisol-related circadian rhythm of kaliuresis was retained only in group 1. The 24-h renal potassium excretion of controls and patients was comparable, in spite of the striking hyperaldosteronism, and the more than doubled contribution of aldosterone to kaliuresis shown in group 2. The influence of aldosterone on potassium excretion was also witnessed by the direct correlation between these variables found in group 1 and, when kaliuresis was corrected by the distal sodium delivery, group 2. Renal sodium handling in cirrhosis is altered even before ascites formation and compensated patients can undergo "spontaneous natriuresis." Aldosterone is the main cause of sodium retention in nonazotemic ascitic patients, while sympathoadrenergic hyperactivity may contribute to preserve renal perfusion. The influence of aldosterone on kaliuresis is enhanced, but renal potassium wasting in patients with ascites and hyperaldosteronism is prevented by reduced distal tubular availability of sodium.

We examined renal function and Na + balance in a patient with congestive heart failure who was treated with demeclocycline (DMC) on three separate occasions under strict metabolic balance conditions. Natriuresis and reversible renal insufficiency, which could not be explained solely on the basis of negative Na + balance, developed on each occasion. In contrast to reports of an association between elevated serum DMC levels and renal insufficiency in patients with cirrhotic edema, the renal insufficiency in this patient with cardiac edema occurred in the absence of high DMC levels. Consequently, markedly elevated serum DMC levels do not appear to be a prerequisite for the development of natriuresis or renal insufficiency in edematous patients receiving this drug. In an attempt to clarify the mechanism of the natriuresis, we also examined the effects of DMC on Na + transport in an invitro model system, the toad urinary bladder. DMC inhibited aldosterone-stimulated Na + transport, but had no effect on Na + transport when the latter was jointly stimulated by ADH and theophylline. Despite this selective inhibition of the natriferic effect of aldosterone in-vitro, it is unlikely that such a mechanism completely accounts for the natriuresis observed in-vivo since the natriuresis is generally of large magnitude and is usually accompanied by some degree of kaliuresis, and DMC had no consistent effect on urinary aldosterone excretion. Consequently, other mechanisms must be sought to explain the natriuretic effect of DMC in edematous patients. Likewise, mechanisms other than negative Na + balance (perhaps primary alterations in renal hemodynamics) must underly the development of renal insufficiency in such individuals.

Effects of unclipping and converting enzyme inhibition on bilateral renal function in Goldblatt hypertensive rats. Previous studies have demonstrated that blockade of the renin-angiotensin system in two-kidney, one clip Goldblatt hypertensive rats induced arterial pressure associated reductions in the function of the renin rich, clipped kidney even though the renin-depleted, contralateral kidney exhibited enhanced renal hemodynamics and excretory function. This study was performed to evaluate the influence of inhibition of the activity of the renin-angiotensin system on the function of each kidney following the unclipping of the clipped kidney. Renin-angiotensin system blockade was accomplished by intravenous infusion of converting enzyme inhibitor (CEI, SQ 20881, 3 mg/hr · kg), either before (group 1, N = 15) or after (group 2, N = 16) removal of the clip. CEI infusion before unclipping decreased arterial blood pressure (BP), from 157 ± 3 to 124 ± 3mm Hg and led to increases in renal blood flow (RBF), GFR, urinary volume and sodium excretion in the nonclipped kidney. When the clip was still in place, renal function decreased in the clipped kidney during CEI infusion. Upon removal of the clip, there were immediate increases in RBF and GFR, and pronounced diuresis; natriuresis and kaliuresis ensued despite a further reduction of BP from 124 ± 3 to 110 ± 3mm Hg. In group 2, unclipping of the clipped kidney prior to administration of CEI reduced BP from 161 ± 4 to 118 ± 3mm Hg within 2hr. Nevertheless, RBF, GFR, urine flow, and sodium and potassium excretion rates increased in this newly undipped kidney. Subsequent infusion of CEI decreased BP further, but RBF, GFR, and urinary excretion rates of both kidneys increased significantly. These results suggest that hemodynamic and excretory function of both the nonclipped and clipped kidneys are influenced substantially by the renin-angiotensin system; however, this influence on the clipped kidney can be unmasked only after the clip has been removed.Effets de l'ablation du clip et de l'inhibition de l'enzyme de conversion sur la fonction rénale bilatérale chez des rats hypertendus selon Goldblatt. Les études antérieures ont démontré que le blocage du système rénine-angiotensine chez des rats hypertendus selon Goldblatt à deux reins et un clip entrainait des réductions de la fonction du rein riche en rénine clippé, en rapport avec la pression artérielle, bien que le rein contralatéral, déplété en rénine, ait une augmentation de l'hémodynamique et de la fonction excrétoire rénales. Cette étude a été entreprise afin d'évaluer l'influence de l'inhibition de l'activité du système rénine-angiotensine sur la fonction de chaque rein après ablation du clip du rein clippé. Le blocage du système rénine-angiotensine a été effectué par perfusion intra-veineuse de l'inhibiteur de l'enzyme de conversion (CEI, SQ 20881, 3 mg/hr · kg) soit avant (groupe 1, N = 15) soit après (groupe 2, N = 16) ablation du clip. La perfusion de CEI avant l'ablation du clip a abaissé la pression artérielle (BP) de 157 ± 3 à 124 ± 3mm Hg, et a augmenté le flux sanguin (RBF), le GFR, le volume urinaires et l'excrétion sodée du rein non clippé. Lorsque le clip était encore en place, la fonction rénale diminuait du côté du rein clippé pendant la perfusion de CEI. Lors de l'ablation du clip, il y avait des augmentations immédiates du RBF et de GFR et une diurèse; une natriurèse et une kaliurèse prononcées se produisaient malgré une réduction supplémentaire de la BP de 124 ± 3 à 110 ± 3mm Hg. Dans le groupe 2, l'ablation du clip avant l'administration de CEI a réduit la BP du rein clippé de 161 ± 4 à 118 ± 3mm Hg en 2hr. Cependant, le RBF, le GFR, le débit urinaire, et l'excrétion de sodium et de potassium se sont élevés dans ce rein dont le clip a été récemment enlevé. La perfusion ultérieure de CEI diminuait BP plus mais RBF, GFR, et les excrétions urinaires des deux reins ont augmenté significativement. Ces résultats suggèrent que les fonctions hémodynamique et excrétoire des reins clippés et non-clippés sont substantiellement influencées par le système rénine-angiotensine; cependant, cette influence sur le rein clippé ne peut être démasquée qu'après ablation du clip.