Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments.

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

Hacia el esclarecimiento del rol del anión cloruro en la hipertensión arterial: / Towards the Elucidation of the Role of the Chloride Anion in Arterial Hypertension:

RESUMEN Introducción: Se desconoce el papel del anión cloruro en los efectos deletéreos del consumo excesivo de sal (NaCl) y si sus efectos son independientes de la presencia del sodio. Objetivo: Demostrar que tanto una sobrecarga de cloruro como una sobrecarga de sodio en la dieta producen efectos deletéreos, en forma independiente, sobre la presión arterial sistólica (PAS), la función renal y los marcadores de estrés oxidativo en el riñón. Materiales y métodos: Ratas Wistar macho fueron divididas en cuatro grupos (n = 8/grupo) y fueron alimentadas con diferentes dietas durante tres semanas: C: control (dieta estándar), NaCl: hipersódica-hiperclórica, Na: hipersódica sin cloruro, Cl: hiperclórica sin sodio. Se determinaron la presión arterial sistólica (PAS) y la función renal y en la corteza renal, se evaluó la producción de especies reactivas del ácido tiobarbitúrico (en inglés: TBARS) y la actividad y la expresión de las enzimas superóxido dismutasa (SOD), catalasa (CAT) y glutatión peroxidasa (GPx). Resultados: Al cabo de tres semanas, la PAS aumentó (*) en los dos grupos alimentados con cloruro. La excreción fraccional de sodio y de cloruro aumentó (*) en los grupos NaCl y Na. La diuresis y los TBARS en la corteza renal aumentaron (*) con las tres dietas, sin cambios en la actividad y en la expresión de SOD y CAT. La actividad de la GPx aumentó (*) en los dos grupos que recibieron cloruro; (*p < 0,05 vs C). Conclusión: Tanto la sobrecarga de sodio como la de cloruro se asocian a mayor estado oxidativo caracterizado por un incremento en la peroxidación lipídica en la corteza renal. Sin embargo, solo el exceso de cloruro se asocia a mayor actividad de la GPx y de la hipertensión, sin cambios en la excreción urinaria de cloruros, sugiriendo un mayor estado prooxidante renal en comparación con el grupo Na.

ABSTRACT Introduction: The role of the chloride anion on the deleterious effects of excessive consumption of salt (NaCl) and whether its effects are independent each other of the presence of sodium remains to date, unknown and unclear. Objective: To demonstrate that both a chloride overload and a sodium overload in the diet produce deleterious effects, by different mechanisms, on systolic blood pressure (SBP), renal function and markers of oxidative stress in the kidney. Materials and Methods: Male Wistar rats were divided into four groups (n = 8 / group) and fed with different diets for three weeks: C: control (standard diet), and diets: NaCl: hypersodic-hyperchloric; Na: hypersodic without chloride and Cl: hyperchloric without sodium. Systolic blood pressure (SBP) and renal function were determined, and the production of thiobarbituric acid reactive species (TBARS) and the activity and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes were evaluated in renal cortex tissue. Results: SBP increased (*) in the two groups fed with chloride. The fractional excretion of sodium and chloride increased (*) in the NaCl and Na groups. increased (*) in the renal cortex with the three diets. No changes were observed in the activity and expression of SOD and CAT. GPx activity increased (*) in the two groups that received chloride; (* p <0.05 vs C). Conclusion: Both sodium and chloride overload are associated with a higher oxidative state characterized by an increase in lipid peroxidation in the renal cortex. However, compared with Na group, only chloride overload is associated with higher GPx activity and hypertension without any changes in urinary chloride excretion, suggesting a higher renal pro-oxidant state in this experimental group.

Acute infusion of angiotensin II regulates organic cation transporters function in the kidney: its impact on the renal dopaminergic system and sodium excretion.

A close relationship between angiotensin II (ANG II) and the renal dopaminergic system (RDS) has been reported. Our aim was to study whether renal dopamine and ANG II can interact to modify renal sodium handling and then to elucidate the related mechanism. Anesthetized male Sprague-Dawley rats were used in experiments. ANG II, exogenous dopamine, and decynium-22 (or D-22, an isocyanine that specifically blocks electrogenic organic cation transporters, OCTs), were infused in vivo for 120 min. We analyzed renal and hemodynamic parameters, renal Na+, K+-ATPase levels, OCT activity, and urinary dopamine concentrations. We also evaluated the expression of D1 receptor, electroneutral organic cation transporters (OCTNs), and OCTs. ANG II decreased renal excretion of sodium in the presence of exogenous dopamine, increased Na+, K+-ATPase activity, and decreased the urinary dopamine concentration. D-22 treatment exacerbated the ANG II-mediated decrease in renal excretion of sodium and dopamine urine excretion but did not modify ANG II stimulation of Na+, K+-ATPase activity. The infusion of ANG II did not affect the expression of D1 receptor, OCTs, or OCTNs. However, the activity of OCTs was diminished by the presence of ANG II. Although ANG II did not alter the expression of D1 receptor, OCTs, and OCTNs in renal tissues, it modified the activity of OCTs and thereby decreased the urinary dopamine concentration, showing a novel mechanism by which ANG II decreases dopamine transport and its availability in the tubular lumen to stimulate D1 receptor. This study demonstrates a relationship between ANG II and dopamine, where both agents counteract their effects on sodium excretion.

Alteration of Renal Natriuretic Systems Is Associated with the Development of Hypertension and Precedes the Presence of Renal Damage in a Model of Metabolic Syndrome / La alteración de sistemas natriuréticos renales se asocia con el desarrollo de hipertensión arterial y precede en el tiempo a la aparición de daño renal en un modelo de síndrome metabólico

ABSTRACT: Background: The aim of this study was to determine the presence of alterations in the natriuretic systems of atrial natriuretic peptide and renal dopamine in a model of metabolic syndrome induced by fructose overload and to associate them with changes in systolic blood pressure, renal function, Na+/K+-ATPase status and microalbuminuria. Methods: Male Sprague-Dawley rats were divided into control (C) and fructose (F) groups receiving drinking water or a fructose so-lution (10% W/V), respectively, for 4, 8 and 12 weeks. L-dopa and dopamine, sodium, creatinine and albumin were measured in urine and ANP, insulin, sodium and creatinine in plasma. Systolic blood pressure was measured by indirect method and the renal activity and expression of Na+/K+-ATPase as well as the renal expression of A- and C-type natriuretic peptide receptors were assessed. results: Fructose overload was associated with a significant increase in insulinemia and systolic blood pressure levels and a decrease in urinary sodium excretion since week 4. A significant increase in L-dopa excretion and a decrease in dopamine excretion (increased urinary L-dopa/dopamine ratio) due to fructose overload were observed since week 4 with a decrease in plasma atrial natriuretic peptide at weeks 8 and 12. These changes were accompanied by increased activity and expression of Na+/ K+-ATPase, decreased A-type natriuretic peptide receptor and increased C-type natriuretic peptide receptor expression. Microalbuminuria was observed at week 12 of fructose overload.

RESUMEN: Objetivos: El objetivo del trabajo consistió en determinar la existencia de alteraciones en los sistemas natriuréticos del péptido natriurético atrial y dopamina renal en un modelo de síndrome metabólico por sobrecarga de fructosa y asociarlas con cambios en la presión arterial sistólica, función renal, estado de la Na+, K+-ATPasa y microalbuminuria. Material y Métodos: Ratas macho Sprague-Dawley fueron divididas en grupos control (C) y fructosa (F) con agua o solución de F (10%P/V) para beber durante 4, 8 y 12 semanas. En orina, se midió L-dopa y dopamina, sodio, creatinina y albúmina; y en plasma péptido natriurético atrial, insulina, sodio y creatinina. La presión arterial sistólica fue medida por método indirecto. Se midió la actividad y expresión de la Na+, K+-ATPasa así como la expresión del receptor de péptidos natriuréticos A y C renales. resultados: La sobrecarga de fructosa se asoció con el aumento de la insulinemia y la presión arterial sistólica, y con la disminución en la excreción urinaria de sodio desde la semana 4. La excreción urinaria de L-dopa se incrementó y la de dopamina disminuyó (cociente L-dopa/dopamina incrementado) por sobrecarga de fructosa desde la semana 4 y el péptido natriurético atrial plasmático se redujo en las semanas 8 y 12. Estos cambios fueron acompañados por un incremento de la actividad y expresión de la Na+, K+-ATPasa, disminución del receptor de péptidos natriuréticos A y aumento del C. La microalbuminuria se observó en la semana 12 de sobrecarga de fructosa. Conclusiones: Las alteraciones del péptido natriurético atrial y de la dopamina renal se asociaron con el desarrollo de hipertensión arterial y precedieron a la aparición de microalbuminuria, por lo que se pudo establecer una asociación temporal entre la alteración de ambos sistemas y el desarrollo de daño renal.

Short-term effects of a green coffee extract-, Garcinia c ambogia- and L-carnitine-containing chewing gum on snack intake and appetite regulation.

INTRODUCTION: Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. PURPOSE: The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. METHODS: This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. RESULTS: There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. CONCLUSION: This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.

Effects of chronic fructose overload on renal dopaminergic system: alteration of urinary L-dopa/dopamine index correlates to hypertension and precedes kidney structural damage.

Insulin resistance induced by a high-fructose diet has been associated to hypertension and renal damage. The aim of this work was to assess alterations in the urinary L-dopa/dopamine ratio over three time periods in rats with insulin resistance induced by fructose overload and its correlation with blood pressure levels and the presence of microalbuminuria and reduced nephrin expression as markers of renal structural damage. Male Sprague-Dawley rats were randomly divided into six groups: control (C) (C4, C8 and C12) with tap water to drink and fructose-overloaded (FO) rats (FO4, FO8 and FO12) with a fructose solution (10% w/v) to drink for 4, 8 and 12 weeks. A significant increase of the urinary L-dopa/dopamine ratio was found in FO rats since week 4, which positively correlated to the development of hypertension and preceded in time the onset of microalbuminuria and reduced nephrin expression observed on week 12 of treatment. The alteration of this ratio was associated to an impairment of the renal dopaminergic system, evidenced by a reduction in renal dopamine transporters and dopamine D1 receptor expression, leading to an overexpression and overactivation of the enzyme Na+, K+-ATPase with sodium retention. In conclusion, urinary L-dopa/dopamine ratio alteration in rats with fructose overload positively correlated to the development of hypertension and preceded in time the onset of renal structural damage. This is the first study to propose the use of the urinary L-dopa/dopamine index as marker of renal dysfunction that temporarily precedes kidney structural damage induced by fructose overload.

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion.

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

Synthesis and Biological Evaluation of New N-(4-Substituted phenyl)glycine Derivatives as Potential Anti-inflammatory Agents.

BACKGROUND: Designing new anti-inflammatory agents possessing safe therapeutic profiles and devoid of potential undesirable side effects is an active field in medicinal chemistry. Thus, a series of N-(4-substituted phenyl)glycine derivatives was designed and synthesized. The idea behind the design is to utilize the bifunctionality of 4-aminoacetophenone via converting the amino group into glycine derivative as a side arm to mimic the glycine amino acid enhancing the overall physicochemical and biological characteristics. In addition, the opposite acetyl group was used as a center for modification and derivatization. METHODS: The starting N-(4-acetylphenyl)glycine was converted into two intermediates: the chalcone analog 2 and the thiosemicarbazone derivative 8. Both 2 and 8 were derivatized and/or cyclized into different heterocyclic target derivatives (3-7 and 9-12). The target compounds were screened for anti-inflammatory activity using carrageenan-induced rat paw edema assay. RESULTS: The results showed that compounds 6, 7, and 3, were the most active among the tested compounds at 50 mg/kg dose level with % inhibition of edema of 51.82, 43.80, and 40.39, respectively. CONCLUSION: The authors succeeded to introduce a simple and versatile skeleton with a side arm resembling the glycine amino acid; imparting a potential improvement in physicochemical properties. We utilize the other side of the skeleton's aromatic ring as a center for derivatization. The chalcone analog and its cyclized heterocyclic derivatives were of remarkably higher anti-inflammatory activity than the thiosemicarbazone and its derivatives.

Role of angiotensin II and oxidative stress on renal aquaporins expression in hypernatremic rats.

The aim of this study was to assess whether endogenous Ang II and oxidative stress produced by acute hypertonic sodium overload may regulate the expression of aquaporin-1 (AQP-1) and aquaporin-2 (AQP-2) in the kidney. Groups of anesthetized male Sprague-Dawley rats were infused with isotonic saline solution (control) or with hypertonic saline solution (Na group, 1 M NaCl), either alone or with losartan (10 mg kg(-1)) or tempol (0.5 mg min(-1) kg(-1)) during 2 h. Renal function parameters were measured. Groups of unanesthetized animals were injected intraperitoneally with hypertonic saline solution, with or without free access to water intake, Na+W, and Na-W, respectively. The expression of AQP-1, AQP-2, Ang II, eNOS, and NF-kB were evaluated in the kidney by Western blot and immunohistochemistry. AQP-2 distribution was assessed by immunofluorescence. Na group showed increased natriuresis and diuresis, and Ang II and NF-kB expression, but decreased eNOS expression. Losartan or tempol enhanced further the diuresis, and AQP-2 and eNOS expression, as well as decreased Ang II and NF-kB expression. Confocal immunofluorescence imaging revealed labeling of AQP-2 in the apical plasma membrane with less labeling in the intracellular vesicles than the apical membrane in kidney medullary collecting duct principal cells both in C and Na groups. Importantly, our data also show that losartan and tempol induces a predominantly accumulation of AQP-2 in intracellular vesicles. In unanesthetized rats, Na+W group presented increased diuresis, natriuresis, and AQP-2 expression (112 ± 25 vs 64 ± 16; *p < 0.05). Water deprivation increased plasma sodium and diuresis but decreased AQP-2 (46 ± 22 vs 112 ± 25; §p < 0.05) and eNOS expression in the kidney. This study is a novel demonstration that renal endogenous Ang II-oxidative stress, induced in vivo in hypernatremic rats by an acute sodium overload, regulates AQP-2 expression.

Evaluation of the satiating properties of a nutraceutical product containing Garcinia cambogia and Ascophyllum nodosum extracts in healthy volunteers.

A nutraceutical product composed of a combination of Garcinia cambogia, l-carnitine and a seaweed extract of Ascophyllum nodosum has been recently developed. The aim of the present study was to characterize its effects on subjective satiety sensations and food preferences in healthy volunteers. In a crossover design, 28 subjects (21 females and 7 males, aged 31 ± 5, BMI 22.6 ± 1.7) were randomly assigned to receive the active treatment (LIS) or placebo (PL) over one week. At the end of each treatment period, subjects were instructed to consume ad libitum a test meal. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preferences Questionnaire and visual analog scales, before and after meal, over three hours. There were no differences in energy intake between study groups. LIS was associated with a reduction in subjective hunger sensations (p = 0.018) and to an increase in satiety (p = 0.02) and fullness (p = 0.01) ratings. The preference for high fat foods was reduced after consuming the test meal in both study groups. There was a significant effect of LIS treatment on food explicit liking and implicit wanting, as evidenced by an increase in preference for sweet foods (relative to savory foods; p = 0.03 and p = 0.004, respectively), but no differences were observed regarding the preference for low or high fat foods (NS). These results provide proof of principle for the satiating properties of a nutraceutical containing Garcinia cambogia, Ascophyllum nodosum extract and l-carnitine and suggest that it might be useful as an appetite modulator.

Urodilatin regulates renal dopamine metabolism.

BACKGROUND: Sodium and water transport across renal proximal tubules is regulated by diverse hormones such as dopamine and urodilatin. We have previously reported that urodilatin stimulates extraneuronal dopamine uptake in external renal cortex by activation of the type A natriuretic peptide receptor, coupled to cyclic guanylate monophosphate signaling and protein kinase G. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity in renal tubules. The aim of the present study was to evaluate whether urodilatin could also alter renal dopamine synthesis, release, catabolism and turnover. METHODS: The effects of urodilatin on dopamine synthesis, release, catabolism and turnover were measured in samples of renal cortex from Sprague Dawley rats. RESULTS: The results indicate that urodilatin increases L-DOPA decarboxylase activity and decreases catechol-o-methyl transferase and monoamine oxidase activity. Moreover, urodilatin does not affect either dopamine basal secretion or potassium chloride-induced dopamine release in external renal cortex, and reduces amine turnover. CONCLUSIONS: Both the present results and previous findings show that urodilatin modifies dopamine metabolism in external renal cortex of rats by enhancing dopamine uptake and synthesis and by decreasing catechol-o-methyl transferase and monoamine oxidase activity and dopamine turnover. Those effects taken together may favor dopamine accumulation in renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and, in turn, overinhibition of Na+, K+-ATPase activity, which results in decreased sodium reabsorption. Therefore, urodilatin and dopamine enhance natriuresis and diuresis through a common pathway.

Salt-induced downregulation of renal aquaporins is prevented by losartan.

AIMS: The purpose of this study was to investigate the expression of aquaporin-1 (AQP-1) and aquaporin-2 (AQP-2) in the renal tubule of rats fed with a high-salt diet and its modulation by the AT1 receptor blocker losartan. MAIN METHODS: The experiments were performed in four groups of rats fed for 3 weeks with the following diets: regular rat chow (NS); high-salt (8% NaCl) chow (HS), NS plus losartan (NS-L) and HS plus losartan (HS-L). Losartan (40 mg x kg(-1)) was administered in the drinking water. Systolic blood pressure (SBP) and renal function were evaluated. The intrarenal levels of angiotensin II (Ang II), TGF-ß(1), α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), AQP-1 and AQP-2 were determined by immunohistochemistry. AQP-1 and AQP-2 protein levels were measured by western blot analysis. KEY FINDINGS: A high-sodium diet downregulated AQP-1 and AQP-2 expression levels in the proximal tubule and collecting duct, respectively. The high-sodium diet also induced Ang II, TGF-ß(1) and α-SMA overexpression and decreased eNOS expression in the renal cortex and medulla. Losartan increased the diuresis and natriuresis, favoring urinary sodium concentration. Additionally, losartan prevented the profibrogenic response, decreasing Ang II, TGF-ß(1) and α-SMA levels and normalizing AQP-2 expression in the HS-L group. AQP-1 expression was upregulated by losartan in both the NS-L and HS-L groups. SIGNIFICANCE: These results show that increased intrarenal Ang II in rats fed with a high-salt diet downregulates renal AQP-1 and AQP-2 expressions. In addition, although losartan increased diuresis and natriuresis, it prevented the downregulation of aquaporins, favoring urinary sodium concentration.

Angiotensin-(1-7) through Mas receptor up-regulates neuronal norepinephrine transporter via Akt and Erk1/2-dependent pathways.

As angiotensin (Ang) (1-7) decreases norepinephrine (NE) content in the synaptic cleft, we investigated the effect of Ang-(1-7) on NE neuronal uptake in spontaneously hypertensive rats. [(3)H]-NE neuronal uptake was measured in isolated hypothalami. NE transporter (NET) expression was evaluated in hypothalamic neuronal cultures by western-blot. Ang-(1-7) lacked an acute effect on neuronal NE uptake. Conversely, Ang-(1-7) caused an increase in NET expression after 3 h incubation (40 ± 7%), which was blocked by the Mas receptor antagonist, a PI3-kinase inhibitor or a MEK1/2 inhibitor suggesting the involvement of Mas receptor and the PI3-kinase/Akt and MEK1/2-ERK1/2 pathways in the Ang-(1-7)-stimulated NET expression. Ang-(1-7) through Mas receptors stimulated Akt and ERK1/2 activities in spontaneously hypertensive rat neurons. Cycloheximide attenuated Ang-(1-7) stimulation of NET expression suggesting that Ang-(1-7) stimulates NET synthesis. In fact, Ang-(1-7) increased NET mRNA levels. Thus, we evaluated the long-term effect of Ang-(1-7) on neuronal NE uptake after 3 h incubation. Under this condition, Ang-(1-7) increased neuronal NE uptake by 60 ± 14% which was blocked by cycloheximide and the Mas receptor antagonist. Neuronal NE uptake and NET expression were decreased after 3 h incubation with an anti-Ang-(1-7) antibody. Ang-(1-7) induces a chronic stimulatory effect on NET expression. In this way, Ang-(1-7) may regulate a pre-synaptic mechanism in maintaining appropriate synaptic NE levels during hypertensive conditions.

Perfiles de síntesis y secreción de los péptidos natriuréticos durante la evolución de la hipertrofia cardíaca en ratas hipertensas DOCA-sal / Natriuretic Peptides Synthesis and Secretion Profiles during the Evolution of Cardiac Hypertrophy in DOCA-Salt Hypertensive Rats / Natriuretic Peptides Synthesis and Secretion Profiles during the Evolution of Cardiac Hypertrophy in DOCASalt Hypertensive Rats

Durante el desarrollo de la hipertensión arterial, las interacciones entre las sobrecargas de presión y de volumen conducen a diferentes patrones de hipertrofia cardíaca y a un aumento de los péptidos natriuréticos (PN). Los perfiles de síntesis y secreción de ANP y BNP se han investigado en modelos de hipertensión arterial; sin embargo, aún no se ha estudiado la evolución diferencial de estos perfiles durante períodos agudos y crónicos de la hipertrofia cardíaca producida por sobrecarga de volumen. Por este motivo estudiamos ratas Sprague- Dawley con el modelo DOCA-sal a las 2, 4, 6 y 12 semanas, correlacionando la evolución de dichos perfiles con la hipertrofia cardíaca y la hipertensión arterial. El grado de hipertrofia cardíaca se correlacionó positivamente con la expresión del ANP en el ventrículo izquierdo y con los niveles de ANP en plasma. La expresión del ANP aumentó a las 4 semanas de tratamiento, mientras que la de BNP se incrementó recién a las 6 semanas. Asimismo, el BNP plasmático se incrementó sólo en el grupo con 12 semanas de tratamiento, mientras que el ANP plasmático mostró un aumento a partir de las 2 semanas de tratamiento. Durante el desarrollo de la hipertrofia cardíaca producida en el modelo DOCA-sal, la síntesis y la secreción de los PN responden en forma diferencial, con incremento precoz del ANP. Además, el aumento de éste superó al de BNP en todos los grupos DOCA-sal, lo que permitiría considerar al ANP como un marcador más específico de la sobrecarga de volumen.

The interactions between pressure and volume overload that occur in hypertension lead to different patterns of cardiac hypertrophy and to increase in natriuretic peptides (NPs). The profiles of ANP and BNP synthesis and secretion have been investigated in models of hypertension; however, the different evolution of these profiles during the acute and chronic periods of pressure overload-induced cardiac hypertrophy is still unknown. For this reason, we studied DOCA-salt treated Sprague-Dawley rats at weeks 2, 4, 6 and 12 and correlated the evolution of these profiles with cardiac hypertrophy and hypertension. Cardiac hypertrophy had a positive correlation with ANP expression in the left ventricle and with ANP plasma levels. BNP expression increased after 4 weeks of treatment while ANP increased significantly after 6 weeks. In addition, BNP plasma levels increased only in the group treated for 12 weeks, while ANP plasma levels increased from week 2. NP secretion has a differential response in the early stages of the development of cardiac hypertrophy induced by the DOCA-salt model, with an early increase in ANP. As ANP levels were exceeded to those of BNP in all the DOCA-salt groups, ANP might be considered a more specific marker of volume overload.

Urodilatin increases renal dopamine uptake: intracellular network involved

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Dopamine and urodilatin promote natriuresis and diuresis through a common pathway that involves reversible deactivation of renal Na+, K+-ATPase. We have reported that urodilatin enhances dopamine uptake in outer renal cortex through the natriuretic peptide type A receptor. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity. The objective of the present work was to investigate the intracellular signals involved in urodilatin effects on dopamine uptake in renal cortex of kidney rats. We show that urodilatin-elicited increase in 3H-dopamine was blunted by methylene (..) (AU)

Urodilatin increases renal dopamine uptake: intracellular network involved.

Dopamine and urodilatin promote natriuresis and diuresis through a common pathway that involves reversible deactivation of renal Na+, K+-ATPase. We have reported that urodilatin enhances dopamine uptake in outer renal cortex through the natriuretic peptide type A receptor. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity. The objective of the present work was to investigate the intracellular signals involved in urodilatin effects on dopamine uptake in renal cortex of kidney rats. We show that urodilatin-elicited increase in ³H-dopamine was blunted by methylene blue (10 µM), a non-specific guanylate cyclase inhibitor, and by phorbol-12-myristate-13-acetate (1 µM), a particulate guanylate cyclase inhibitor, but not by 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (10 µM), a specific soluble guanylate cyclase inhibitor; therefore the involvement of particulate guanylate cyclase on urodilatin mediated dopamine uptake was confirmed. Cyclic guanosine monophosphate and proteinkinase G were also implicated in the signaling pathway, since urodilatin effects were mimicked by the analog 125 µM 8-Br-cGMP and blocked by the proteinkinase G-specific inhibitor, KT-5823 (1 µM). In conclusion, urodilatin increases dopamine uptake in renal cortex stimulating natriuretic peptide type A receptor, which signals through particulate guanylate cyclase activation, cyclic guanosine monophosphate generation, and proteinkinase G activation. Dopamine and urodilatin may achieve their effects through a common pathway that involves deactivation of renal Na+, K+-ATPase, reinforcing their natriuretic and diuretic properties.

High-sodium diet promotes a profibrogenic reaction in normal rat kidneys: effects of Tempol administration.

BACKGROUND: Studies carried out in vitro have recently shown that salt loading induces an increasing mechanical stretch and a flow-induced superoxide production in the thick ascending limb of Henle's loop. In this regard, we hypothesized that the oxidative stress induced by salt overload could stimulate inflammatory and fibrogenic signaling pathways in normal rats. METHODS: Sprague Dawley rats were fed with an 8% NaCl high- (HS) or 0.4% NaCl normal-salt (NS) diet for 3 weeks, with or without Tempol (T) administration (1 mM, administered in drinking water). Mean arterial pressure (MAP), glomerular filtration rate (GFR) and urinary sodium excretion (UVNa) were measured. NAD(P)H oxidase p47phox, angiotensin II (Ang II), transforming growth factor ß1 (TGF-ß1), a-smooth muscle actin (a-SMA) and nuclear factor-kappa B (NF-kB) expression were evaluated in renal tissues by immunohistochemistry. RESULTS: A high NaCl diet produced a slight but significant increase in MAP and enhanced UVNa and oxidative stress. Administration of a high NaCl diet induced the overexpression of TGF-ß1, a-SMA and NF-?B in cortex and medulla, while Ang II increased in proximal convoluted tubules, and decreased in cortical collecting ducts. Tempol administration prevented these changes and simultaneously normalized MAP accompanied by an enhancement in GFR and UVNa. CONCLUSION: The results showed that a high NaCl diet is able to produce a renal profibrotic response also in normal rats, which could be associated with oxidative stress rather than intrarenal Ang II expression.

Participación de los péptidos natriuréticos en la hipertensión renovascular y su correlación con la evolución de la hipertrofia de miocardio / The Role of Natriuretic Peptides in Renovascular Hypertension and Its Correlation with the Evolution of Myocardial Hypertrophy

Durante la hipertensión arterial, las interacciones entre las sobrecargas de presión y volumen conducen a diferentes patrones de hipertrofia cardíaca y a un aumento de los péptidos natriuréticos (PN). Los perfiles de síntesis y secreción de ANP y BNP se han investigado en modelos de hipertensión arterial. Sin embargo, aún no se ha estudiado su evolución diferencial durante períodos agudos y crónicos de la hipertrofia cardíaca producida por sobrecarga de presión. Por este motivo estudiamos ratas Sprague-Dawley con el modelo 1 riñón-1 clip a las 2, 4, 6 y 12 semanas, correlacionando la evolución de dichos perfiles con la hipertrofia cardíaca y la hipertensión arterial. Observamos una correlación positiva entre la elevación de la presión arterial y el grado de hipertrofia cardíaca, presentando ambos parámetros un incremento dependiente del tiempo a partir de las 2 semanas. La expresión del BNP mostró un aumento precoz a las 2 semanas de tratamiento, mientras que el ANP se incrementó significativamente a las 6 semanas. No obstante, la expresión del ANP aumentó en forma gradual, lo que permitió su correlación con la hipertrofia y la hipertensión. En estadios tempranos del desarrollo de la hipertrofia producida por el modelo renovascular, la expresión de los PN respondería en forma diferencial, incrementándose en forma precoz el BNP. Con la evolución de la hipertrofia, la expresión del BNP deja de ser específica y el aumento de ambos PN pasa a depender y a correlacionarse con el grado de evolución de la hipertrofia cardíaca.

The interactions between pressure and volume overload that occur in hypertension lead to different patterns of cardiac hypertrophy and to increase natriuretic peptides (NPs) levels. The profiles of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) synthesis and secretion have been investigated in models of hypertension. However, the different evolution of these profiles during the acute and chronic periods of pressure overload-induced cardiac hypertrophy is still unknown. For this reason, we studied one-kidney, one clip model using Sprague-Dawley rats at weeks 2, 4, 6 and 12 and correlated the evolution of these profiles with cardiac hypertrophy and hypertension. We observed a positive correlation between blood pressure elevation and the degree of cardiac hypertrophy, with a time-dependent increase in both parameters from week 2. Levels of BNP expression showed an early increase after 2 weeks of treatment while ANP increased significantly after 6 weeks. Neverless, the increase in ANP expression was gradual, allowing its correlation with hypertrophy and hypertension. The NP expression has a differential response in the early stages of the development of hypertrophy induced by the renovascular model, with an early increase in BNP expression. Once hypertrophy develops, BNP expression is no longer specific and the increase of both NPs depends on and correlates with the degree of cardiac hypertrophy.

Centrally administered insulin potentiates the pressor response to angiotensin II.

The aim of the present study was to determine if insulin can modulate the pressor response to angiotensin II at brain level in normotensive rats. Anaesthetized male rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2 h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In other subset of animals, PD98059 (MAPK inhibitor) or vehicle were intracerebroventricularly administered previously to insulin perfusion for 2 h and changes in MAP in response to intracerebroventricular angiotensin II (5 pmol) injection were evaluated for 10 min (n=6 for each group). Angiotensin II did not modify MAP in vehicle pre-treated rats, but increased MAP in insulin pre-treated animals. Insulin significantly increased Akt phosphorylation, but no changes were observed after angiotensin II injection in vehicle-pretreated animals. Angiotensin II or insulin infusion increased in more than two fold phospho-ERK 1/2 hypothalamic levels. Animals that received insulin infusion followed by Ang II injection presented 4.5 higher values than those which received vehicle, and nearly twice than those who received Ang II without insulin pre-treatment. PD98059 administration abolished the blood pressure response exerted by angiotensin II in insulin pre-treated rats. In conclusion, centrally administered insulin potentiates the pressor effects to angiotensin II, suggesting a novel mechanism, possibly involving MAPK activation, by which insulin influences blood pressure control at central level.

Effects of angiotensin II on renal dopamine metabolism: synthesis, release, catabolism and turnover.

BACKGROUND/AIMS: Dopamine (DA) uptake inhibition in the renal cortex, elicited by angiotensin II (ANG II), is mediated by AT(1) receptors and signals through the phospholipase C pathway and activation of protein kinase C and CaM-kinase II. By this indirect way, ANG II stimulates renal Na(+),K(+)-ATPase activity through DA intracellular reduction. In the present work, we continued to study different aspects of renal DA metabolism in DA-ANG II interaction, such as DA synthesis, release, catabolism and turnover. METHODS: ANG II effects on DA synthesis, release, catabolism and turnover were measured in samples from the outer renal cortex of Sprague-Dawley rats. RESULTS: ANG II reduced renal aromatic acid decarboxylate activity without affecting basal secretion of DA or its KCl-induced release. Moreover, ANG II enhanced monoamine oxidase activity without altering catechol-o-methyl transferase activity and increased DA turnover. CONCLUSION: Current results as well as previous findings show that ANG II modifies DA metabolism in rat renal cortex by reducing DA uptake, decreasing DA synthesis enzyme activity and increasing monoamine oxidase activity, and DA turnover. Together, all these effects may reduce DA accumulation into renal cells and decrease its endogenous content and availability. This would prevent D1 receptor recruitment and stimulation, while diminishing DA inhibition of Na(+),K(+)-ATPase activity and stimulating sodium reabsorption.