Renal medulla in hypertension

Abstract: Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years.

Naringen's Effects on Diuresis and Prevention of Urolithiasis in Hypertensive Rats.

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.

8-Aminopurines in the Cardiovascular and Renal Systems and Beyond.

Screening of compounds comprising 8-substituted guanine revealed that 8-aminoguanosine and 8-aminoguanine cause diuresis/natriuresis/glucosuria, yet decrease potassium excretion. Subsequent investigations demonstrated that 8-aminoguanosine's effects are mediated by its metabolite 8-aminoguanine. The mechanism by which 8-aminoguanine causes diuresis/natriuresis/glucosuria involves inhibition of PNPase (purine nucleoside phosphorylase), which increases renal interstitial inosine levels. Additional evidence suggests that inosine, via indirect or direct adenosine A2B receptor activation, increases renal medullary blood flow which enhances renal excretory function. Likely, 8-aminoguanine has pleiotropic actions that also alter renal excretory function. Indeed, the antikaliuretic effects of 8-aminoguanine are independent of PNPase inhibition. 8-Aminoguanine is an endogenous molecule; nitrosative stress leads to production of biomolecules containing 8-nitroguanine moieties. Degradation of these biomolecules releases 8-nitroguanosine and 8-nitro-2'-deoxyguanosine which are converted to 8-aminoguanine. Also, guanosine and guanine per se may contribute to 8-aminoguanine formation. 8-Aminoinosine, 8-aminohypoxanthine, and 8-aminoxanthine likewise induce diuresis/natriuresis/glucosuria, yet do not reduce potassium excretion. Thus, there are several pharmacologically active 8-aminopurines with nuanced effects on renal excretory function. Chronic treatment with 8-aminoguanine attenuates hypertension in deoxycorticosterone/salt rats, prevents strokes, and increases lifespan in Dahl salt-sensitive rats on a high salt diet and attenuates the metabolic syndrome in rats; 8-aminoguanosine retards progression of pulmonary hypertension in rats and anemia and organ damage in sickle cell mice. 8-Aminoguanine reverses age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines represent a new class of agents (and potentially endogenous factors) that have beneficial effects on the cardiovascular system and kidneys and may turn back the clock in age-associated diseases.

8-Aminoguanine and Its Actions on Renal Excretory Function.

BACKGROUND: The endogenous purine 8-aminoguanine induces diuresis/natriuresis/glucosuria by inhibiting PNPase (purine nucleoside phosphorylase); however, mechanistic details are unknown. METHODS: Here, we further explored in rats 8-aminoguanine's effects on renal excretory function by combining studies using intravenous 8-aminoguanine, intrarenal artery infusions of PNPase substrates (inosine and guanosine), renal microdialysis, mass spectrometry, selective adenosine receptor ligands, adenosine receptor knockout rats, laser doppler blood flow analysis, cultured renal microvascular smooth muscle cells, HEK293 cells expressing A2B receptors and homogeneous time resolved fluorescence assay for adenylyl cyclase activity. RESULTS: Intravenous 8-aminoguanine caused diuresis/natriuresis/glucosuria and increased renal microdialysate levels of inosine and guanosine. Intrarenal inosine, but not guanosine, exerted diuretic/natriuretic/glucosuric effects. In 8-aminoguanine-pretreated rats, intrarenal inosine did not induce additional diuresis/natriuresis/glucosuria. 8-Aminoguanine did not induce diuresis/natriuresis/glucosuria in A2B-receptor knockout rats, yet did so in A1- and A2A-receptor knockout rats. Inosine's effects on renal excretory function were abolished in A2B knockout rats. Intrarenal BAY 60-6583 (A2B agonist) induced diuresis/natriuresis/glucosuria and increased medullary blood flow. 8-Aminoguanine increased medullary blood flow, a response blocked by pharmacological inhibition of A2B, but not A2A, receptors. In HEK293 cells expressing A2B receptors, inosine activated adenylyl cyclase, and this was abolished by MRS 1754 (A2B antagonist). In renal microvascular smooth muscle cells, 8-aminoguanine and forodesine (PNPase inhibitor) increased inosine and 3',5'-cAMP; however, in cells from A2B knockout rats, 8-aminoguanine and forodesine did not augment 3',5'-cAMP yet increased inosine. CONCLUSIONS: 8-Aminoguanine induces diuresis/natriuresis/glucosuria by increasing renal interstitial levels of inosine which, via A2B receptor activation, increases renal excretory function, perhaps in part by increasing medullary blood flow.

[A new equation to estimate daily natriuresis from parameters in plasma and spot urine sample in the Chilean population]. / Nueva ecuación para la estimación de la natriuresis diaria a partir de parámetros en plasma y orina aislada en población chilena.

BACKGROUND: Excessive sodium intake is associated with increased cardiovascular morbidity and mortality. Daily sodium intake is usually inferred from sodium excretion in a 24-hour urine collection, which is cumbersome and prone to errors. Different formulas have attempted to estimate 24-hour urinary sodium from a spot urine sample. Unfortunately, their concordances are insufficient and have not been tested in our population. AIM: To develop an equation to predict 24-hour urine sodium from parameters in plasma and spot urine samples. To validate the equation and compare it with other formulas in Chilean population. MATERIAL AND METHODS: Analysis of 24-hour urine collections, plasma sample and spot urine sample from 174 adult outpatients (81% females) with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2. These were collected between 2015 and 2019 using standardized methods and educating patients about the correct method to collect 24 h urine samples. In all these patients, creatinine and electrolytes were measured in plasma and urine. A new equation was developed using a multiple linear regression model. RESULTS: Twenty-four-hour urine sodium excretion was significantly correlated with age, weight, height, eGFR, plasma osmolarity, urine electrolytes and parameters obtained from spot urine sample, among others. The new equation had a linear correlation with 24-hour natriuresis of 0.91 and the concordance was 0.9. The predictive capacity of the new equation was better than the existing formulas. CONCLUSIONS: We developed a formula to accurately predict daily natriuresis in the Chilean population.

Tagetes erecta L. flowers, a medicinal plant traditionally used to promote diuresis, induced diuretic and natriuretic effects in normotensive and hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tagetes erecta L., known as marigold, belongs to the Asteraceae family and is mainly found in South America. Despite reports that T. erecta flowers are used in folk medicine to treat cardiovascular and renal diseases, there is no study regarding its diuretic effect. AIM: This study aimed to evaluate the chemical composition and the diuretic efficacy of the hydroethanolic extract from T. erecta (HETE) in normotensive (NTR) and hypertensive (SHR) rats. MATERIAL AND METHODS: The HETE was analyzed by liquid chromatography coupled to diode array detector and mass spectrometry (LC-DAD-MS). Female and male NTR and SHR received the treatment with vehicle, HETE (0.01 mg/kg, 0.1 mg/kg, and 1 mg/kg) or hydrochlorothiazide (HCTZ; 5 mg/kg) orally. The urinary parameters were measured at the end of the 8-h experiment. RESULTS: From HETE, saccharides and triterpenes were the main annotated compounds, such as erythrodiol and ß-amyrin. The urine volume was significantly increased in the groups treated with HETE, in both male and female NTR and SHR rats, compared to the respective vehicle-treated groups. Regarding electrolytes elimination, the treatment with HETE did not reveal significant changes in the urine levels of K+ or Cl-, but it showed a natriuretic and Ca2+-sparing effects. The HETE beneficial result in reducing Ca2+ excretion was confirmed through the protective effect found in front of the urinary calcium oxalate precipitation and crystallization. The combination with HCTZ, a classic diuretic and saluretic medicine, significantly enhanced HETE-induced diuresis, natriuresis, and the Ca2+-sparing effect. On the other hand, the K+-sparing action was improved in the combination of HETE with amiloride, a standard K+-sparing diuretic. In contrast, the combination of HETE with atropine (a non-selective muscarinic receptor antagonist) and indomethacin (an inhibitor of the cyclooxygenase enzyme), promoted an important reduction in urinary volume, but interestingly the natriuretic effect was maintained. CONCLUSION: This study contributed to the preclinical validation of the diuretic efficacy of T. erecta, highlighting this species as promising for the development of new pharmacological strategies for the management of kidney disorders.

1,3,5,6-tetrahydroxyxanthone promotes diuresis, renal protection and antiurolithic properties in normotensive and hypertensive rats.

OBJECTIVES: This study investigated the prolonged diuretic and renal effects of 1,3,5,6- tetrahydroxyxanthone (THX) in rats. METHODS: Normotensive (NTR) and hypertensive rats (SHR) received orally the treatment with THX, hydrochlorothiazide or vehicle (VEH). Urine volume, urinary, plasma and kidney parameters were evaluated daily or at the end of 7 days of the experiment. KEY FINDINGS: The urinary volume of both NTR and SHR were significantly augmented with the THX treatment, an effect associated with increased levels of urinary Na+ and K+, besides a Ca2+-sparing effect. As well, THX decreased the quantity of monohydrate crystals in urines from NTR and SHR when compared with VEH-group. Regarding the renal analyses, the glutathione levels and the activities of superoxide dismutase, glutathione S-transferase and myeloperoxidase in kidney homogenates of the SHR group were decreased. In contrast, the generation of lipid hydroperoxides (LOOH) and catalase activity was significantly increased. THX reduced the content of LOOH and increased nitrite levels in kidney homogenates obtained from SHR. Additionally, THX also augmented the levels of nitrite in the plasma from the SHR group. CONCLUSIONS: Therefore, THX can be highlighted as a natural diuretic agent with renal protective properties and antiurolithic action.

Nueva ecuación para la estimación de la natriuresis diaria a partir de parámetros en plasma y orina aislada en población chilena / A new equation to estimate daily natriuresis from parameters in plasma and spot urine sample in the Chilean population

Background: Excessive sodium intake is associated with increased cardiovascular morbidity and mortality. Daily sodium intake is usually inferred from sodium excretion in a 24-hour urine collection, which is cumbersome and prone to errors. Different formulas have attempted to estimate 24-hour urinary sodium from a spot urine sample. Unfortunately, their concordances are insufficient and have not been tested in our population. Aim: To develop an equation to predict 24-hour urine sodium from parameters in plasma and spot urine samples. To validate the equation and compare it with other formulas in Chilean population. Material and Methods: Analysis of 24-hour urine collections, plasma sample and spot urine sample from 174 adult outpatients (81% females) with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2. These were collected between 2015 and 2019 using standardized methods and educating patients about the correct method to collect 24 h urine samples. In all these patients, creatinine and electrolytes were measured in plasma and urine. A new equation was developed using a multiple linear regression model. Results: Twenty-four-hour urine sodium excretion was significantly correlated with age, weight, height, eGFR, plasma osmolarity, urine electrolytes and parameters obtained from spot urine sample, among others. The new equation had a linear correlation with 24-hour natriuresis of 0.91 and the concordance was 0.9. The predictive capacity of the new equation was better than the existing formulas. Conclusions: We developed a formula to accurately predict daily natriuresis in the Chilean population.

Treatment with Mesenchymal Stem Cells Improves Renovascular Hypertension and Preserves the Ability of the Contralateral Kidney to Excrete Sodium.

BACKGROUND: Mesenchymal stem cells (MSC) improve renal function and renovascular hypertension in the 2-kidney 1-clip model (2K-1C). While MSC play an immunomodulatory role, induce neoangiogenesis, and reduce fibrosis, they do not correct sodium loss by the contra-lateral kidney. OBJECTIVES: We investigated the tubular function of both stenotic and contralateral kidneys and the effect of MSC treatment by evaluating diuresis, natriuresis, and the expression of the main water and sodium transporters. METHOD: Adult Wistar rats were allocated into four groups: control (CT), CT+MSC, 2K-1C, and 2K-1C+MSC. MSC (2 × 105) were infused through the tail vein 3 and 5 weeks after clipping. Systolic blood pressure (SBP) was monitored weekly by plethysmography. Six weeks after clipping, 24-hour urine and blood samples were collected for biochemical analysis. Gene expression of the Na/H exchanger-3, epithelial sodium channel, Na/K-ATPase, Na/K/2Cl cotransporter, and aquaporins 1 and 2 (AQP1 and AQP2) were analyzed by RT-PCR. Intrarenal distribution of AQP1 and AQP2 was analyzed by immunohistochemistry. RESULTS: In hypertensive 2K-1C animals, MSC prevented additional increases in BP. AQP1, but not AQP2, was suppressed in the contralateral kidney, resulting in significant increase in urinary flow rate and sodium excretion. Gene expressions of sodium transporters were similar in both kidneys, suggesting that the high perfusing pressure in the contralateral kidney was responsible for increased natriuresis. Contralateral hypertensive kidney showed signs of renal deterioration with lower GFR in spite of normal RPF levels. CONCLUSIONS: MSC treatment improved renal function and enhanced the ability of the contralateral kidney to excrete sodium through a tubular independent mechanism contributing to reduce SBP.

Effects of myricetin-3-O-α-rhamnoside (myricitrin) treatment on urinary parameters of Wistar rats.

OBJECTIVES: This study aimed to investigate the diuretic efficacy of myricetin-3-O-α-rhamnoside (myricitrin), a common naturally occurring plant-derived flavonoid, obtained from Marlierea eugeniopsoides (D.Legrand & Kausel) D.Legrand leaves in rats. METHODS: For that, female Wistar rats were treated by oral route with the different treatments and kept in metaboloic cages for 8-h or 24-h experiment. The volume and urinary parameters were measured at the end of the period and compared between groups. KEY FINDINGS: When orally given to rats and compared to the vehicle-treated group, myricitrin (0.3 and 1 mg/kg) was able to stimulate rat diuresis, natriuresis and kaliuresis. The combination myricitrin plus hydrochlorothiazide, but not plus furosemide or amiloride, potentiated the urinary volume when compared to the effects of drugs alone. Besides, the 8-h renal effects of myricitrin were prevented in the presence of a cyclooxygenase inhibitor and a muscarinic receptor antagonist. However, all groups treated with myricitrin showed a significant reduction in Cl- excretion. In addition, a reduction in the urinary excretion of Cl- and HCO 3 - was detected on 24-h analysis, a result that showed to be associated with an increase of these anions in the blood samples from the myricitrin-treated group. Despite these alterations, no changes in urinary or blood pH were detected. CONCLUSIONS: Taking together, although the results of this study point to the diuretic potential of myricitrin, the reduction in urinary Cl- and HCO 3 - excretion should be considered in future approaches, as well as for therapeutic applicability.

Angiotensin-(1-7) inhibits sodium transport via Mas receptor by increasing nitric oxide production in thick ascending limb.

Sodium transport in the thick ascending loop of Henle (TAL) is tightly regulated by numerous factors, especially angiotensin II (Ang II), a key end-product of the renin-angiotensin system (RAS). However, an alternative end-product of the RAS, angiotensin-(1-7) [Ang-(1-7)], may counter some of the Ang II actions. Indeed, it causes vasodilation and promotes natriuresis through its effects in the proximal and distal tubule. However, its effects on the TAL are unknown. Because the TAL expresses the Mas receptor, an Ang-(1-7) ligand, which in turn may increase NO and inhibit Na+ transport, we hypothesized that Ang-(1-7) inhibits Na transport in the TAL, via a Mas receptor/NO-dependent mechanism. We tested this by measuring transport-dependent oxygen consumption (VO2 ) in TAL suspensions. Administering Ang-(1-7) decreased VO2 ; an effect prevented by dimethyl amiloride and furosemide, signifying that Ang-(1-7) inhibits transport-dependent VO2 in TAL. Ang-(1-7) also increased NO levels, known inhibitors of Na+ transport in the TAL. The effects of Ang-(1-7) on VO2 , as well as on NO levels, were ameliorated by the Mas receptor antagonist, D-Ala, in effect suggesting that Ang-(1-7) may inhibit transport-dependent VO2 in TAL via Mas receptor-dependent activation of the NO pathway. Indeed, blocking NO synthesis with L-NAME prevented the inhibitory actions of Ang-(1-7) on VO2 . Our data suggest that Ang-(1-7) may modulate TAL Na+ transport via Mas receptor-dependent increases in NO leading to the inhibition of transport activity.

Efeito agudo da drenagem linfática manual sobre a natriurese e lipólise de mulheres jovens / Acute effect of manual lymphatic drainage on natriuresis and lipolysis in young women

Fundamentos: A importância da validação científica de técnicas coadjuvantes a diversos tratamentos de saúde é inquestionável. Desta forma, a influência da drenagem linfática manual (DLM) na natriurese e na lipólise sob interação de anticoncepcional oral precisa ser investigada. Objetivos: Avaliar o efeito agudo da DLM sobre a natriurese e lipólise de mulheres jovens usuárias ou não de anticoncepcional oral. Método: Participaram 29 mulheres não usuárias de anticoncepcional oral e 29 usuárias, autodeclaradas saudáveis, sedentárias e eutróficas. As análises foram realizadas em dois dias distintos, Controle (C), sem intervenção terapêutica e DLM. Nos dias C e DLM coletamos 4 amostras de urina com intervalos de 60 min. Seguimos o método de Leduc, abdomem e membros inferiores, durante 45 min. Analisamos o fluxo urinário e excreção urinária e sódio, glicerol e peptideo natriurético atrial. A normalidade dos dados foi analisada pelo teste Shapiro-Wilk. Os dados que não obedeceram à normalidade foram apresentados em mediana e intervalo interquartil (25%-75%), enquanto os que obedeceram foram apresentados em média ± erro padrão. O teste de Mann-Whitney foi usado para dados não pareados e Wilcoxon para dados pareados. Dados com normalidade foram avaliados pelo teste t-Student não pareado. O nível de significância estatística adotado foi de 5%. Resultados: O efeito agudo de uma sessão de DLM promove aumento da natriurese em mulheres não usuárias de anticoncepcional oral, por outro lado, em usuárias induz aumento na liberação de glicerol e de ANP

Background: The importance of scientific validation of supporting techniques to various treatments is unquestionable. In this context, the influence of manual lymphatic drainage (MLD) on natriuresis and lipolysis and its interaction with oral contraceptives still need to be investigated. Objectives: To evaluate the acute effect of MLD on natriuresis and lipolysis in young women using or not oral contraceptives. Methods: Twenty-nine non-users of oral contraceptives and 29 oral contraceptive users, self-reported healthy, sedentary, normal weight women were enrolled. Analyses were conducted on two different days ­ control (C), without therapeutic intervention and MLD day. Four urine samples were collected at 60-minute intervals. MLD was performed in lower limbs and abdomen for 45 min following the Leduc method. Urinary flow rat e and urinary sodium, glycerol and atrial natriuretic peptide excretion were analyzed. Data normality was tested by the Shapiro-Wilk test. Data without normal distribution were expressed as median and interquartile range (25%-75%), while normally distributed data were expressed as mean ± standard error. Mann-Whitney test was used for unpaired data and Wilcoxon test for paired data. Data with normal distribution were evaluated by the unpaired t-Student test. Statistical significance was set at 5%. Results: One MLD session had an acute effect on both groups, increasing natriuresis in non-users of oral contraceptives and glycerol and atrial natriuretic peptide excretion in oral contraceptive users. Conclusion: Oral contraceptives influence the effect of MLD on natriuresis

Serum Cortisol and Cortisone as Potential Biomarkers of Partial 11ß-Hydroxysteroid Dehydrogenase Type 2 Deficiency.

BACKGROUND: Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11ßHSD2 deficiency in those heterozygous subjects. METHODS: We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS: The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21-3.69] and 2.54 [2.35-2.88], and in adults were 4.42 [3.70-4.90] and 2.23 [1.92-2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION: Serum F/E ratio and cortisone allow to identify partial 11ßHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.

Geraniin is a diuretic by inhibiting the Na+-K+-2Cl- cotransporter NKCC2.

Geranium seemannii Peyr is a perennial plant endemic to central Mexico that has been widely used for its diuretic effect, but the responsible compound of this effect is unknown as well as the mechanism by which the diuretic effect is achieved. Geraniin is one of the compounds isolated from this kind of geranium. This study was designed to determinate whether geraniin possesses diuretic activity and to elucidate the mechanism of action. Geraniin was extracted and purified from Geranium seemannii Peyr. Male Wistar rats were divided into four groups: 1) Control, 2) 75 mg/kg of geraniin, 3) 20 mg/kg of furosemide, and 4) 10 mg/kg of hydrochlorothiazide. Each treatment was administered by gavage every 24 h for 7 days. The urinary excretion of electrolytes and the fractional excretion of sodium (FENa) were determined. To uncover the molecular target of geraniin, Xenopus laevis oocytes were microinjected with cRNAs encoding the Na+-Cl- cotransporter (NCC) and the Na+-K+-2Cl- cotransporter NKCC2 to functionally express these cotransporters. Geraniin significantly increased diuresis, natriuresis, and calciuresis to a similar extent as was observed in the furosemide-treated rats. Consistent with the furosemide-like effect, in X. laevis oocytes, geraniin significantly reduced the activity of NKCC2, with no effect on NCC activity. In contrast to furosemide, the effect of geraniin on NKCC2 was irreversible, apparently due to its inhibitory effect on heat shock protein 90. Our observations suggest that geraniin could have a potential role in the treatment of hypertension or edematous states.

Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature.

Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.

Patrones de excreción urinaria de Sodio en población adulta en muestras de orina espontánea / Urinary sodium excretion patterns in adult population in spot urine samples

Introducción: El presente estudio describe los patrones de natriuresis según las características clínicas y sociodemográficas en una población adulta de Asunción. Métodos: Estudio transversal tipo encuesta y toma de muestra de orina a personas que acudieron al Mercado de Abasto y al Policlínico Municipal durante los meses de junio-setiembre del 2014. Se estimó natriuria en muestras de orina espontánea a primera hora de la mañana y en ayunas. Se incluyeron sujetos de 18 a 65 años. Se compararon las medianas de los valores de natriuria en mmol/L, utilizándose el test U de Mann-Whitney para comparar las variables de dos categorías y Kruskal-Wallis para las que tienen más de dos categorías. Resultados: Se aplicó la encuesta y se tomó muestra de orina a 463 personas. El 69,5% (322) eran mujeres. La media de edad fue 50,5 años (DE: 14,2). El 26,6% (123) negó antecedentes patológicos. La mediana de natriuria global fue 97,5 mmol/L (RIC: 59,3­139,3). Los niveles de natriuria no presentaron diferencias por sexo. Las personas menores de 30 años, con bajo consumo de verduras y mayor consumo de frituras presentaron valores de natriuria altos y estadísticamente significativos. El grupo de sujetos sanos mostró mayor excreción de sodio que los que refirieron diabetes o hipertensión arterial. Conclusiones: La mayor excreción de sodio en orina observada se presenta en personas jóvenes, sin antecedentes patológicos y, al mismo tiempo son los que también presentan los peores hábitos alimenticios. Estos resultados muestran la necesidad de intervención en el ámbito de la salud pública a fin de prevenir la patología cardiovascular y renal del futuro.

Introduction: The present study describes natriuresis patterns according to clinical and sociodemographic characteristics in adult population of Asuncion. Methods: Cross-sectional study of convenience sampling to people who attended the Mercado de Abasto and the Municipal Polyclinic during June to September 2014. People from 18 to 65 years old were included. Sodium was estimated from urine samples of spot urine taken in the morning and fasting. Median values of natriuresis in mmol/L were compared using the test Mann-Whitney and Kruskal-Wallis. Results: 463 people participated. 69.5% (322) were women. The mean age was 50.5 years (SD 14.2). 26.6% (123) denied pathological medical history. The median overall natriuresis was 97.5 mmol/L (IQR: 59.3-139.3). Natriuresis levels did not differ by sex. High values with statistically significant were presented in people under 30 years old, with low consumption of vegetables and increased consumption of fried food. The group of healthy subjects showed increased sodium excretion than those who reported diabetes or high blood pressure. Conclusions: The increased natriuresis occurs in young people without having pathological medical history and also having the worst eating habits. Public health policies must focus at this level to prevent future cardiovascular and renal disease it is at this level where public health must intervene to prevent future cardiovascular and renal disease.

Concerted regulation of renal plasma flow and glomerular filtration rate by renal dopamine and NOS I in rats on high salt intake.

Under high sodium intake renal dopamine (DA) increases while NOS I expression in macula densa cells (MD) decreases. To explore whether renal DA and NOS I, linked to natriuresis and to the stability of the tubuloglomerular feedback, respectively, act in concert to regulate renal plasma flow (RPF) and glomerular filtration rate (GFR). Male Wistar rats were studied under a normal sodium intake (NS, NaCl 0.24%) or a high sodium intake (HS, NaCl 1% in drinking water) during the 5 days of the study. For the last two days, the specific D1-like receptor antagonist SCH 23390 (1 mg kg bwt-1 day-1, sc) or a vehicle was administered. HS intake increased natriuresis, diuresis, and urinary DA while it decreased cortical NOS I expression (P < 0.05 vs. NS), Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in MD (P < 0.001 vs. NS) and cortical nitrates+nitrites (NOx) production (NS 2.04 ± 0.22 vs. HS 1.28 ± 0.10 nmol mg protein-1, P < 0.01). Treatment with SCH 23390 to rats on HS sharply decreased hydroelectrolyte excretion (P < 0.001 vs. HS) while NOS I expression, NADPH-d activity and NOx production increased (P < 0.05 vs. HS for NOS I and P < 0.001 vs. HS for NADPH-d and NOx). SCH 23390 increased RPF and GFR in HS rats (P < 0.01 HS+SCH vs. HS). It did not cause variations in NS rats. Results indicate that when NS intake is shifted to a prolonged high sodium intake, renal DA through the D1R, and NOS I in MD cells act in concert to regulate RPF and GFR to stabilize the delivery of NaCl to the distal nephron.

Adverse effects of tempol on hidrosaline balance in rats with acute sodium overload.

We studied the effects of tempol, an oxygen radical scavenger, on hydrosaline balance in rats with acute sodium overload. Male rats with free access to water were injected with isotonic (control group) or hypertonic saline solution (0.80 mol/l NaCl) either alone (Na group) or with tempol (Na-T group). Hydrosaline balance was determined during a 90 min experimental period. Protein expressions of aquaporin 1 (AQP1), aquaporin 2 (AQP2), angiotensin II (Ang II) and endothelial nitric oxide synthase (eNOS) were measured in renal tissue. Water intake, creatinine clearance, diuresis and natriuresis increased in the Na group. Under conditions of sodium overload, tempol increased plasma sodium and protein levels and increased diuresis, natriuresis and sodium excretion. Tempol also decreased water intake without affecting creatinine clearance. AQP1 and eNOS were increased and Ang II decreased in the renal cortex of the Na group, whereas AQP2 was increased in the renal medulla. Nonglycosylated AQP1 and eNOS were increased further in the renal cortex of the Na-T group, whereas AQP2 was decreased in the renal medulla and was localized mainly in the cell membrane. Moreover, p47-phox immunostaining was increased in the hypothalamus of Na group, and this increase was prevented by tempol. Our findings suggest that tempol causes hypernatremia after acute sodium overload by inhibiting the thirst mechanism and facilitating diuresis, despite increasing renal eNOS expression and natriuresis.

Diastolic dysfunction is associated with low urinary sodium excretion in patients with decompensated cirrhosis.

BACKGROUND/AIM: The pathogenesis and the clinical impact of diastolic dysfunction (DD) in cirrhosis remain unclear. Our aim was to investigate the factors significantly associated with the presence of DD in patients with decompensated cirrhosis on the waiting list for liver transplantation. MATERIAL AND METHODS: consecutive patients with decompensated cirrhosis, who admitted for transplant assessment, were prospectively evaluated. We assessed the independent factors associated with the presence of DD, while their discriminative ability was evaluated by AUC curve. The diagnosis of DD was based on Doppler echocardiography and classified into three categories according to the current guidelines. RESULTS: we evaluated 115 consecutive patients. Sixty six patients (57.3%-group 1) had DD and 49 (42.7%-group 2) had not DD. The 2 groups had similar Child-Pugh/MELD scores and survival. In multivariable logistic regression analysis, pulse rate (OR: 1.082, 95% CI: 1.03-1.15, p = 0.004), and UNa24h (OR: 0.98, 95% CI: 0.97- 0.99, p = 0.004) were the only variables independently associated with the presence of DD. In the subgroup of consecutive patients (n = 31) with evaluation of cytokines, those (n = 22) with DD, compared to those (n = 9) without DD, had significantly higher levels of inteleukin-6 [145 (45-2000) vs. 56 (10-149)pg/mL, p = 0.043]. CONCLUSIONS: We found that DD was independently associated with lower 24-hour urine sodium. Although no correlation was found between DD and severity of liver disease or survival, further studies are needed for final conclusions.

Atrial natriuretic factor: is it responsible for hyponatremia and natriuresis in neurosurgery? / Fator natriurético atrial: ele é o responsável pela hiponatremia e natriurese em neurocirurgia?

OBJECTIVE: To evaluate the presence of hyponatremia and natriuresis and their association with atrial natriuretic factor in neurosurgery patients. METHODS: The study included 30 patients who had been submitted to intracranial tumor resection and cerebral aneurism clipping. Both plasma and urinary sodium and plasma atrial natriuretic factor were measured during the preoperative and postoperative time periods. RESULTS: Hyponatremia was present in 63.33% of the patients, particularly on the first postoperative day. Natriuresis was present in 93.33% of the patients, particularly on the second postoperative day. Plasma atrial natriuretic factor was increased in 92.60% of the patients in at least one of the postoperative days; however, there was no statistically significant association between the atrial natriuretic factor and plasma sodium and between the atrial natriuretic factor and urinary sodium. CONCLUSION: Hyponatremia and natriuresis were present in most patients after neurosurgery; however, the atrial natriuretic factor cannot be considered to be directly responsible for these alterations in neurosurgery patients. Other natriuretic factors are likely to be involved.