Sodium Depletion Research Articles

β-Endorphinergic system involvement in the inhibitory action of clonidine on induced sodium appetite

In the present study, we investigated the degree to which β-endorphin plays a role in the alpha 2-adrenergic/imidazoline receptor agonist attenuation of salt appetite. In order to evaluate whether the inhibitory action of clonidine (an α2-adrenergic/imidazoline receptor agonist) on induced sodium intake is mediated by the β-endorphinergic system, we used a β-endorphin deficient mouse line. β-endorphin knockout (βend−/−), heterozygous (βend+/−) and wild-type (βend+/+) mice were submitted to acute sodium depletion by a combined treatment of furosemide and low sodium diet and, 20h later, were administered with clonidine (0.5mg/kg). An hour later, the animals were subjected to a two-bottle choice test (water/2% NaCl). The results indicate that clonidine administration during the first stage of the test exerts an equivalent inhibition on sodium intake regardless of the genotype; however, in the final stage of the test, a reversal of the inhibitory response on induced sodium appetite becomes evident in the mice lacking β-endorphin. Moreover no differences in dipsogenic response were observed between the genotypes. Considering these results and the fact that plasma half-life of clonidine at the dose administered is approximately 3h, it is possible to speculate that the inhibitory effect of clonidine on sodium appetite may be independent of β-endorphin modulation during the first stage; however, the long-lasting inhibitory effect of clonidine may be mediated by the β-endorphinergic system. This evidence supports the existence of adrenergic and β-endorphinergic system interaction in the osmoregulatory response to achieve sodium balance.

Parabrachial and hypothalamic interaction in sodium appetite

Rats with bilateral lesions of the lateral hypothalamus (LH) fail to exhibit sodium appetite. Lesions of the parabrachial nuclei (PBN) also block salt appetite. The PBN projection to the LH is largely ipsilateral. If these deficits are functionally dependent, damaging the PBN on one side and the LH on the other should also block Na appetite. First, bilateral ibotenic acid lesions of the LH were needed because the electrolytic damage used previously destroyed both cells and axons. The ibotenic LH lesions produced substantial weight loss and eliminated Na appetite. Controls with ipsilateral PBN and LH lesions gained weight and displayed robust sodium appetite. The rats with asymmetric PBN-LH lesions also gained weight, but after sodium depletion consistently failed to increase intake of 0.5 M NaCl. These results dissociate loss of sodium appetite from the classic weight loss after LH damage and prove that Na appetite requires communication between neurons in the LH and the PBN.

Primary Molecular Disorders and Secondary Biological Adaptations in Bartter Syndrome

Bartter syndrome is a hereditary disorder that has been characterized by the association of hypokalemia, alkalosis, and the hypertrophy of the juxtaglomerular complex with secondary hyperaldosteronism and normal blood pressure. By contrast, the genetic causes of Bartter syndrome primarily affect molecular structures directly involved in the sodium reabsorption at the level of the Henle loop. The ensuing urinary sodium wasting and chronic sodium depletion are responsible for the contraction of the extracellular volume, the activation of the renin-aldosterone axis, the secretion of prostaglandins, and the biological adaptations of downstream tubular segments, meaning the distal convoluted tubule and the collecting duct. These secondary biological adaptations lead to hypokalemia and alkalosis, illustrating a close integration of the solutes regulation in the tubular structures.

Purinergic mechanisms of lateral parabrachial nucleus facilitate sodium depletion-induced NaCl intake

Purinergic receptors are present in the lateral parabrachial nucleus (LPBN), a pontine structure involved in the control of sodium intake. In the present study, we investigated the effects of α,β-methyleneadenosine 5′-triphosphate (α,β-methylene ATP, selective P2X purinergic agonist) alone or combined with pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS, P2X purinergic antagonist) or suramin (non-selective P2 purinergic antagonist) injected into the LPBN on sodium depletion-induced 1.8% NaCl intake. Male Holtzman rats with stainless steel cannulas implanted into the LPBN were used. Sodium depletion was induced by treating rats with the diuretic furosemide (20mg/kg of body weight) followed by 24h of sodium-deficient diet. Bilateral injections of α,β-methylene ATP (2.0 and 4.0nmol/0.2μl) into the LPBN increased sodium depletion-induced 1.8% NaCl intake (25.3±0.8 and 26.5±0.9ml/120min, respectively, vs. saline: 15.2±1.3ml/120min). PPADS (4nmol/0.2μl) alone into the LPBN did not change 1.8% NaCl intake, however, pretreatment with PPADS into the LPBN abolished the effects of α,β-methylene ATP on 1.8% NaCl intake (16.9±0.9ml/120min). Suramin (2.0nmol/0.2μl) alone into the LPBN reduced sodium depletion-induced 1.8% NaCl intake (5.7±1.9ml/120min, vs. saline: 15.5±1.1ml/120min), without changing 2% sucrose intake or 24h water deprivation-induced water intake. The combination of suramin and α,β-methylene ATP into the LPBN produced no change of 1.8% NaCl intake (15.2±1.2ml/120min). The results suggest that purinergic P2 receptor activation in the LPBN facilitates NaCl intake, probably by restraining LPBN mechanisms that inhibit sodium intake.

Cooperative mechanisms of acute antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus

The exact mechanism underlying thiazides-induced paradoxical antidiuresis in diabetes insipidus is still elusive, but it has been hypothesized that it is exerted either via Na+-depletion activating volume-homeostatic reflexes to decrease distal delivery, or direct stimulation of distal water reabsorption. This study examined how these two proposed mechanisms actually cooperate to induce an acute bendroflumethiazide (BFTZ)-antidiuretic effect in nephrogenic diabetes insipidus (NDI). Anaesthetized rats with lithium (Li)-induced NDI were prepared in order to measure their renal functional parameters, and in some of them, bilateral renal denervation (DNX) was induced. After a 30 min control clearance period, we infused either BFTZ into 2 groups, NDI+BFTZ and NDI/DNX+BFTZ, or its vehicle into a NDI+V group, and six 30 min experimental clearance periods were taken. During BFTZ infusion in the NDI+BFTZ group, transiently elevated Na+ excretion was associated with rapidly increased urinary osmolality and decreased free water clearance, but Li clearance and urine flow declined in the later periods. However, in the NDI/DNX+BFTZ group, there was persistently elevated Na+ excretion with unchanged Li clearance and urine flow during the experimental period, while alterations in free water clearance and urinary osmolality resembled those in the NDI+BFTZ group. In conclusion, BFTZ initially exerted two direct effects of natriuresis-diuresis and stimulating free water reabsorption at the distal nephron in NDI, which together elevated Na+ excretion and urinary osmolality but kept the urine volume unchanged in the first hour. Thereafter, the resultant sodium depletion led to the activation of neural reflexes that reduced distal fluid delivery to compensate for BFTZ-induced natriuresis-diuresis which, in cooperation with the direct distal BFTZ-antidiuretic effect, resulted in excretion of urine with a low volume, high osmolality, and normal sodium.

Effect of low sodium intake and β-blockade on renin synthesis and secretion in mice with unilateral ureteral ligation

We previously reported that sodium depletion increased renin secretion from the normal kidney in mice. We postulated that the combined procedures of sodium depletion and β-adrenoceptor blockade would affect the activity of the renin-angiotensin system. To test this hypothesis, we investigated the interaction of low sodium intake (LSI) and propranolol (PRO) on renin synthesis and secretion. To prevent the influence of tubule flow on renin secretion, mice with a left hydronephrotic kidney were used. LSI increased plasma renin concentration (PRC) 5.6-fold in the right renal vein (P<0.01). There was no net increase of PRC in the left renal vein. Tissue renin concentration (TRC) was elevated 3.6-fold and 1.3-fold in the right and left kidneys (P<0.01), respectively. After administration of PRO, PRC decreased by 34% in the right renal vein and 47% in the aorta (P<0.05); TRC was reduced by 37.5% in the right and 29.3% in the hydronephrotic kidneys (P<0.05). The combination of LSI and PRO increased PRC 3.4-fold and 1.8-fold in the right (P<0.01) and left renal veins (P<0.05), respectively. TRC increased 3.4-fold in the right (P<0.01) but only 61% in the left kidneys (P<0.05). The pattern in change of renin mRNA levels was similar to TRC but the absolute amount was smaller. There were correlations between PRC and renin mRNA, and between TRC and renin mRNA in both kidneys (P<0.001). Thus, LSI increased renin synthesis in both kidneys. However, there was no apparent renin secretion in the hydronephrotic kidney. PRO treatment suppressed renin synthesis and renin secretion, irrespective of hydronephrosis and LSI. The macula densa is critical for renin secretion under all of the circumstances studied.

Regulation of WNK1 Expression by miR-192 and Aldosterone

WNK1 and WNK4 encode two members of the WNK serine-threonine kinase subfamily. Greater WNK1 expression associates with higher BP. A combination of promoters, enhancers, repressors, and insulators regulate WNK1 expression, but whether microRNAs also modulate WNK1 expression is unknown. Here, computational analysis revealed the presence of a target sequence for miR-192 and miR-215 at the same site in the 3' untranslated region of the ubiquitous L- and the kidney-specific KS-WNK1. We functionally validated this target sequence by transient transfection and reporter assays. Although we observed expression of both miRs along the distal nephron, only miR-192 regulated endogenous WNK1 ex vivo. Furthermore, a potassium load, sodium depletion, and aldosterone infusion each significantly reduced miR-192 expression in the kidney. Taken together, these results suggest a miR-driven mechanism of gene regulation by aldosterone and a role for miR-192 in the regulation of sodium and potassium balance in the kidney.

Area postrema projects to FoxP2 neurons of the pre-locus coeruleus and parabrachial nuclei: Brainstem sites implicated in sodium appetite regulation

The area postrema (AP) is a circumventricular organ located in the dorsal midline of the medulla. It functions as a chemosensor for blood-borne peptides and solutes, and converts this information into neural signals that are transmitted to the nucleus tractus solitarius (NTS) and parabrachial nucleus (PB). One of its NTS targets in the rat is the aldosterone-sensitive neurons which contain the enzyme 11 β-hydroxysteroid dehydrogenase type 2 (HSD2). The HSD2 neurons are part of a central network involved in sodium appetite regulation, and they innervate numerous brain sites including the pre-locus coeruleus (pre-LC) and PB external lateral-inner (PBel-inner) cell groups of the dorsolateral pons. Both pontine cell groups express the transcription factor FoxP2 and become c-Fos activated following sodium depletion. Because the AP is a component in this network, we wanted to determine whether it also projects to the same sites as the HSD2 neurons. By using a combination of anterograde axonal and retrograde cell body tract-tracing techniques in individual rats, we show that the AP projects to FoxP2 immunoreactive neurons in the pre-LC and PBel-inner. Thus, the AP sends a direct projection to both the first-order medullary (HSD2 neurons of the NTS) and the second-order dorsolateral pontine neurons (pre-LC and PB-el inner neurons). All three sites transmit information related to systemic sodium depletion to forebrain sites and are part of the central neural circuitry that regulates the complex behavior of sodium appetite.

Sodium Depletion Increases Sympathetic Neurite Outgrowth and Expression of a Novel TMEM35 Gene-Derived Protein (TUF1) in the Rat Adrenal Zona Glomerulosa

The adrenal zona glomerulosa (ZG) secretes aldosterone to regulate sodium balance. Chronic sodium restriction increases aldosterone accompanied by ZG expansion. The ZG is innervated by sympathetic, vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY), and sensory, calcitonin gene-related peptide, nerves. It is unclear whether innervation is affected by ZG growth. Therefore, we measured neurite outgrowth in the ZG of adult male rats after dietary sodium manipulation. In response to 1 wk sodium restriction, VIP and NPY fibers elongated in parallel with expansion of the ZG, shown by aldosterone synthase (AS) expression, but calcitonin gene-related peptide fibers were not affected. Sodium repletion resulted in parallel regression in VIP and NPY fiber length and AS expression. These results show that sympathetic, but not sensory, innervation is coordinated with ZG growth. Mediators underlying changes in innervation are unknown; therefore, we characterized a novel gene TMEM35 [termed the unknown factor-1 (TUF1) due to its unknown function] that shows extensive overlap with AS in ZG. After sodium restriction, TUF1 expanded in parallel with the ZG. TUF1 bound the low-affinity neurotrophin receptor, p75NTR, which was expressed in NPY fibers and showed a response similar to TUF1 after sodium manipulation. TUF1- p75NTR binding was competitively displaced by nerve growth factor but not by TUF1 lacking the p75NTR binding motif. Moreover, TUF1 mRNA in rat ZG cells increased after angiotensin II exposure in vitro. Collectively, these findings suggest that TMEM35/TUF1 is a candidate for modulating neurite outgrowth in the ZG after sodium depletion.

Sodium appetite in adult rats following ω-3 polyunsaturated fatty acid deficiency in early development

We examined the effect of ω-3 polyunsaturated fatty acid (PUFA) deficiency during development on sodium appetite. Being raised on an ω-3 PUFA deficient diet increased the intake of 0.5 M NaCl following furosemide-induced sodium depletion by 40%. This occurred regardless of the diet they were maintained on later in life, and the increased consumption persisted for 3 days. In a second study, animals were administered furosemide and low-dose captopril. Sodium consumption of deficient raised animals was again higher than that of the control raised. Fos immunoreactivity in brain areas associated with sodium appetite and excretion were not influenced by diet. Our findings indicate that inadequate dietary ω-3 PUFA during development results in an exaggerated sodium appetite later in life.

Nucleus accumbens neurons encode the enhanced palatability of hypertonic saline following sodium depletion

Nucleus accumbens neurons encode the enhanced palatability of hypertonic saline following sodium depletion

SUPERIORITY OF LOW DOSE DIURETICS COMBINATION OVER RENIN-ANGIOTENSIN BLOCKERS COMBINATION IN RESISTANT HYPERTENSION: PP.16.89

In case of resistant essential hypertension (RH), guidelines recommend to increase the treatment, especially diuretics, without precision of use. Objective: To compare in RH patients (pts), over a three-month period, the efficacy and the safety of 2 stepped care strategies chosen to limit counter regulations: either to increase sodium depletion by combining low doses of diuretics acting at different sites of the renal tubule (D group) or to combine renin-angiotensin system blockers (RASB, R group). Methods: In a PROBE study, after a standardized 4-week (W) 3 drug-regimen (irbesartan 300 mg/d, hydrochlorothiazide 12.5 mg/d, amlodipine 5 mg/d), pts with mean day-time ambulatory BP (dABP) > 135 and/or 85mmHg were randomized to receive, on top of these 3 drugs, either spironolactone 25 mg/d (D) or ramipril 5 mg/d (R) for 4 weeks. Then, treatment was increased either on W4, W8 or W10 if home BP was >135 and/or 85 mmHg: in D, furosemide 20 mg/d then 40 mg/d then amiloride 5 mg/d; in R, ramipril 10 mg/d, then bisoprolol 5 mg/d then 10 mg/d. Results: 169 pts were included: sex ratio M/F: 3.1; age 55 ± 10 years; BMI 29 ± 4 kg/m2; eGFR 82 ± 18 ml/mn; dABP 150 ± 13/92 ± 10 mmHg (no intergroup difference). At W12: dABP was 128 ± 11/80 ± 9 mmHg in D and 141 ± 17/85 ± 10 mmHg in R; difference between groups (mmHg): 11.5 [CI95% 7.6–15.4] / 4.7 [2.2–7.2] (p < 0.001/0.0003); 68% were controlled (dABP < 135/85 mmHg) in D vs 28% in R (p < 0.0001). 19% needed up-titration until last step in D vs 55% in R (p < 0.0001). 7 pts in D and 5 in R discontinued the study due to drug related adverse events. At W12, only eGFR differed between D (69 ± 18 ml/mn) and R (83 ± 17 ml/mn) (p < 0.0001). Conclusions: Increasing sodium depletion by combining low doses of several diuretics induces a large and safe reduction in BP in resistant hypertension, and is more effective than RASB combination.

Role of serotonergic 5-HT 1A and oxytocinergic receptors of the lateral septal area in sodium intake regulation

Several reports have revealed a high density of 5-HT 1A receptors in the lateral septal area (LSA), as well as a subpopulation of oxytocin (OT) receptors. Increasing evidence shows that 5-HT 1A and OT neurons inhibit sodium urinary excretion. The aim of this study was to investigate the part played by serotonergic (5-HT 1A) and oxytocinergic receptors in the LSA in the sodium intake induced in rats by sodium depletion followed by 24 h deprivation. Cannulae were implanted bilaterally into the LSA of rats to enable the introduction of receptor ligands into that brain area. Serotonergic injections of 5-HT (10, 20, and 40 μg/0.2 μL) reduced 1.8% NaCl solution intake, but injections (1, 2, and 4 μg/0.2 μL) of 8-OH-DPAT, a 5-HT 1A agonist, were more effective than 5-HT in reducing 1.8% NaCl intake. Pretreatment of the LSA with the 5-HT 1A antagonist pMPPF partially reduced the inhibitory effect of 5-HT and totally reversed the effects of 8-OH-DPAT on 1.8% NaCl intake induced by sodium depletion. Previous treatment with the potent oxytocin receptor antagonist d(CH 2) 5[Tyr(Me) 2Thr 4, Orn 5, Tyr(NH 2) 9]-vasotocin also totally blocked the inhibitory effects of 5-HT or 8-OH-DPAT on 1.8% NaCl intake. These results show that 5-HT 1A serotonergic receptors in the LSA, including some that interact with the oxytocinergic system, modulate sodium intake induced by sodium loss in rats.

Genotype–phenotype analysis of angiotensinogen polymorphisms and essential hypertension: the importance of haplotypes

To better understand the relationship between angiotensinogen (AGT) genetic variation and essential hypertension, AGT genotypes and haplotypes were tested for association with hypertensive endophenotypes and essential hypertension. Two hundred and fifty-six Hypertensive Pathotype (HyperPATH)/Specialized Center of Research (SCOR) cases and 126 controls were genotyped for 24 single-nucleotide polymorphisms (SNPs) in the AGT gene. SNPs and AGT haplotypes were tested for association with plasma AGT, renal plasma flow (RPF), and essential hypertension. New associations between essential hypertension, plasma AGT, and RPF are reported for alleles -1178G, 6066A, 6152A, 6233C, and 12822C. The maximum odds ratio for association of hypertension and AGT genetic variation was 2.3 [95% confidence interval (CI) 1.5-3.8; P < 0.0003] for allele 6233C. Previous associations for -1074T, -532T, -217A, -6A, and 4072C are confirmed (P < 0.05). Sodium depletion enhances associations between AGT SNPs and plasma AGT. Most individually associated SNPs, including -6A and 4072C, are found on a common complete AGT haplotype, H4 (frequency = 0.09). Individuals with haplotype H4 have significantly higher plasma AGT and reduced RPF (P < 0.003 and P < 0.0002, respectively). Other common haplotypes are not associated with increased plasma AGT levels in this data set despite the presence of the -6A and 4072C alleles, suggesting that AGT haplotype H4 is more predictive of elevated plasma AGT than is -6A or 4072C. This study demonstrates the importance of analyzing haplotypes in addition to single genotypes in association studies. By demonstrating the dependence of AGT associations on sodium depletion status, it helps to explain previous conflicting association results.

Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite.

Our laboratory has reported that manipulations that provoke a robust sodium appetite (e.g., sodium depletion, deoxycorticosterone acetate) decrease lateral hypothalamic self-stimulation (LHSS) reward if rats are denied access to hypertonic saline solutions. The following studies investigated the interaction between chronic sodium appetite and the renin-angiotensin-aldosterone system on LHSS reward. In Experiment 1, animals treated with the diuretic furosemide (20 mg/kg) when denied access to saline exhibited an increase in the current required to produce 50% of the maximum LHSS response rate (ECu50) 48 hr after extracellular volume depletion. Furosemide-depleted rats that were allowed to drink 0.3 M saline after depletion, or that were treated with the selective mineralocorticoid receptor (MR) antagonist spironolactone, which significantly reduced sodium appetite, did not show ECu50 changes. In Experiment 2 chronic intracerebroventricular administration of the selective MR antagonist RU 28318 (10 microg/microl/hr) prevented decreases in the ECu50 induced by deoxycorticosterone acetate-no salt treatment. We conclude that an unresolved sodium appetite will reduce responding for rewards and that experimental manipulations that reduce sodium appetite (e.g., access to saline or blockade of MR) decrease hedonic deficits.

New Developments in the Field of RAS Inhibition

The renin-angiotensin system (RAS) was extensively investigated and characterized throughout the first half of the 20th century. However, its contribution to the maintenance of high blood (BP) in essential hypertension and to the development of hypertensive cardiac complications remained under debate until the advent of the first pharmacologic probes capable of blocking its actions, namely the angiotensin receptor blocker (ARB) saralasin and the angiotensin-converting enzyme inhibitor (ACEI) teprotide in the early 1970’s. Using these probes, we could demonstrate that even in normal-renin and low-renin hypertension, blockade of the RAS produced a fall in BP. And this fall was maximized if the patient had been previously submitted to sodium depletion by diuretics or low salt diet, which might produce only a small and possibly insignificant BP fall by itself, but rendered the hypertension RAS-dependent and far more responsive to RAS blockade. In parallel, we had found that excess angiotensin II, either exogenous (in experimental animals) or endogenous, in various clinical settings, could produce significant cardiac and renal tissue damage, because the vasculature of these organs is particularly sensitive to the constricting effects of angiotensin. In particularly, angiotensin excess was shown to produce widespread foci of necrosis and scarring of the myocardium, leading to replacement of myocardial tissue by fibrotic tissue, eventually progressing to ischemic cardiomyopathy and heart failure. Early clinical trials found that treatment of heart failure with ACEIs or ARBs leads to significant hemodynamic improvement in terms of increased cardiac output, decreased peripheral arterial resistance, decreased heart rate, increased coronary blood flow and diminished myocardial oxygen consumption. Subsequent large randomized long-term outcome trials with ACEIs or ARBs, such as the HOPE, EUROPA, LIFE, CHARM, etc., confirmed the functional and structural benefits of these therapeutic approaches and have now established treatment with an ACEI or ARB as mandatory therapy for patients with ischemic heart disease, as well as congestive or chronic heart failure. It is also now universally accepted that initiation of RAS-suppressing therapy with an ACEI or ARB in patients with multiple cardiovascular risk factors, even not necessary including hypertension, offers long-term protection from ischemic heart disease, diastolic and systolic cardiac dysfunction, arrhythmias, as well as protection from renal insufficiency, cerebrovascular accidents and new onset type 2 diabetes mellitus. Drugs that inhibit the RAS now include, in addition to the ACEIs and ARBs, a new class, the direct renin inhibitors (DRIs), of which only aliskiren is commercially available to date. Several clinical trials have shown aliskiren to be equally effective to ACEIs and ARBs in terms of BP lowering, cardioprotection and nephroprotection. A large body of literature has now reported additional benefits of ACEI+ARB combination in selected patients, i.e., those with resistant hypertension on multidrug ATHENS CARDIOLOGY UPDATE 2010

Activation of lateral parabrachial afferent pathways and endocrine responses during sodium appetite regulation

Modulation of salt appetite involves interactions between the circumventricular organs (CVOs) receptive areas and inhibitory hindbrain serotonergic circuits. Recent studies provide support to the idea that the serotonin action in the lateral parabrachial nucleus (LPBN) plays an important inhibitory role in the modulation of sodium appetite. The aim of the present work was to identify the specific groups of neurons projecting to the LPBN that are activated in the course of sodium appetite regulation, and to analyze the associated endocrine response, specifically oxytocin (OT) and atrial natriuretic peptide (ANP) plasma release, since both hormones have been implicated in the regulatory response to fluid reestablishment. For this purpose we combined the detection of a retrograde transported dye, Fluorogold (FG) injected into the LPBN with the analysis of the Fos immunocytochemistry brain pattern after sodium intake induced by sodium depletion. We analyzed the Fos-FG immunoreactivity after sodium ingestion induced by peritoneal dialysis (PD). We also determined OT and ANP plasma concentration by radioimmunoassay (RIE) before and after sodium intake stimulated by PD. The present study identifies specific groups of neurons along the paraventricular nucleus, central extended amygdala, insular cortex, dorsal raphe nucleus, nucleus of the solitary tract and the CVOs that are activated during the modulation of sodium appetite and have direct connections with the LPBN. It also shows that OT and ANP are released during the course of sodium satiety and fluid reestablishment. The result of this brain network activity may enable appropriate responses that re-establish the body fluid balance after induced sodium consumption.

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.

Evaluation of salt supplementation in CF infants

Background CF infants may be at increased risk of sodium depletion which may lead to impaired growth. The objective of this study was to evaluate their sodium supplementation requirements. Methods Ten CF infants had serial measurements of weight and plasma/urine sodium and creatinine. Sodium supplementation was adjusted with the aim of maintaining fractional excretion (FENa) between 0.5% and 1.5% and urinary sodium > 10 mmol/L. Results Urine sodium:creatinine (UNa:Cr) ratio strongly correlated with FENa [UNa:Cr (mmol/mmol) = 35.0 × FENa ( r = 0.99)]. The FENa target range corresponded to UNa:Cr 17–52 mmol/mmol. All infants required sodium supplementation to achieve UNa:Cr >17 mmol/mmol. Sodium supplement requirements (mean ± SD) at ages 0–3, 3–6, 6–9 and 9–12 months were 1.9 ± 0.5, 1.8 ± 0.8, 1.9 ± 0.9 and 0.8 ± 0.4 mmol/kg/d. No infant required calorie supplementation to achieve expected weight gain. Conclusions Using current UK guidelines, many cases of sodium depletion may be overlooked. Some infants require more than the recommended 1–2 mmol/kg/d. UNa:Cr ratio is a useful non-invasive measure to monitor sodium supplementation.

Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome

Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor-mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 microg/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and alpha1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress.