Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet.

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of ß-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with ß-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension.

K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter.

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low-Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Evaluation of thiazide diuretic use as preferred therapy in uncomplicated essential hypertension patients

Thiazide diuretics are effective antihypertensive medications shown to reduce the risk of cardiovascular events and stroke. Despite being the preferred choice for uncomplicated essential hypertension, thiazide diuretics continue to be underutilized. Methods: Uncomplicated essential hypertension patients taking a single antihypertensive medication were evaluated upon enrollment, diagnosis after enrollment or initiation of therapy in treatment naïve patients. Clinician prescribing habits were determined for both pre-existing and newly diagnosed hypertensive patients. For the cost savings analysis, hydrochlorothiazide (HCTZ) 25mg daily was selected as the preferred conversion medication. Results: Four hundred seventy-eight patients were included. ACE inhibitors were the most prescribed at 35.4% (n=169), followed by dihydropyridine calcium channel blockers (DHP CCB) and thiazide diuretics, both at 20.3% (n=97). Only 12.9% (n=33) of patients with hypertension that were taking an antihypertensive medication upon enrollment were either continued or started on thiazide diuretic therapy. Newly diagnosed or treatment naïve patients were prescribed a thiazide diuretic 28.8% (n=64) of the time. DHP CCB accounted for 58.8% of the total medication cost per month with thiazide diuretics responsible for 0.8% of the cost. If all patients had been prescribed HCTZ 25mg daily, 95.8% of the total medication cost per month could have been saved. Conclusions: Thiazide diuretics were underutilized as preferred therapy in patients with pre-existing or newly diagnosed uncomplicated essential hypertension. While cost of therapy should not be the sole reason for medication selection, thiazide diuretics are an attractive option and should be considered as a preferred therapy in this patient population (AU)

Los diuréticos tiazídicos son medicamentos antihipertensivos que demostraron reducir el riesgo de eventos cardiovasculares e infartos. A pesar de ser la elección preferida para hipertensión arterial no complicada, los diuréticos tiazídicos continúan infrautilizados. Métodos: Se evaluó a pacientes con hipertensión esencial no complicada que tomaban un único antihipertensivo después del ingreso, diagnosticados en el ingreso, diagnostico después del inicio del tratamiento en pacientes nuevos. Se determinaron los hábitos de prescripción tanto para pacientes pre-existentes como para nuevos diagnósticos. Para el análisis de ahorros de costes, se seleccionó la hidroclorotiazida (HCTZ) 25mg como medicación de conversión preferida. Resultados: Se incluyó a 478 pacientes. Los IECA fueron los más prescritos con un 35,4% (n=169), seguidos de los bloqueantes de canales de calcio dihidropiridínicos (BCC DHP) y los diuréticos tiazídicos, ambos con un 20,3% (n=97). Sólo el 12,9% (n=33) de los hipertensos que estaban tomando antihipertensivos en el ingreso continuaban o habían iniciado con un diurético tiazídico. Se prescribió un diurético tiazídico a los nuevos diagnósticos o a los nuevos tratamientos sólo en el 28,8% (n=64) de las veces. Los BCC DHP sumaron el 58,8% del coste total por mes, siendo los diuréticos tiazídicos responsables del 0,8%. Si se hubiese prescrito HCTZ 25mg a todos los pacientes, se habría ahorrado el 95,8% del coste total de la medicación por mes. Conclusión: Los diuréticos tiazídicos estaban infrautilizados como tratamiento de elección en pacientes con hipertensión esencial no complicada de nuevo diagnóstico o pre-existentes. Auqnuei el coste no sea la única razón para las elección de la medicación, los diuréticos tiazídicos son una opción atractiva y deberían ser considerados como tratamiento de elección en este tipo de población (AU)

N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension.

BACKGROUND: Salt-sensitive hypertension in humans and experimental animals causes progressive increases in renal damage and dysfunction. The Dahl salt-sensitive (S) rat closely mimics human salt-sensitive hypertension. AIM: Our goal was to test the hypothesis that enhancing the glutathione system with dietary N-acetylcysteine administration in Dahl S rats on a high sodium intake for 5 weeks will attenuate the increases in arterial pressure, the decreases in renal hemodynamics and the increases in renal damage that normally occur in S rats on high sodium. METHODS: Forty-four 7- to 8-week-old Dahl S/Rapp strain rats were maintained on a high sodium (8%), high sodium + N-acetylcysteine (4 g/kg per day), or low sodium (0.3%) diet for 5 weeks. Rats had arterial and venous catheters implanted at day 21. RESULTS: By day 35 in the high-sodium rats, N-acetylcysteine treatment significantly increased the renal reduced-to-oxidized glutathione ratio, glomerular filtration rate, and renal plasma flow, and decreased renal cortical and medullary O2 release, urinary protein excretion, renal tubulointerstitial damage and glomerular necrosis. At this time, mean arterial pressure increased to 183 +/- 1 mmHg, and N-acetylcysteine reduced this arterial pressure to 121 +/- 4 mmHg. By day 35 in S high-sodium rats, N-acetylcysteine had caused a 91% decrease in glomerular necrosis and an 83% decrease in tubulointerstitial damage. CONCLUSIONS: In Dahl S rats on high sodium intake, arterial pressure increases significantly and renal injury is pronounced. Treatment with N-acetylcysteine enhances the renal glutathione system, improves renal dysfunction and markedly decreases arterial pressure and renal injury in Dahl salt-sensitive hypertension.

Marinobufagenin may mediate the adverse impact of salty diets on renal calcium retention by impairing the efficiency of renal tubular sodium-calcium exchange.

For reasons yet to be clarified, salt loading and plasma volume expansion decrease renal calcium retention; consequently, high-salt diets are thought to increase risk for osteoporosis and renal stones. These measures also can evoke increased adrenal production of the natriuretic factor marinobufagenin (MBG), recently implicated in the genesis of essential hypertension. MBG achieves natriuresis via potent selective inhibition of the alpha-1-type sodium pump, expressed throughout the nephron. In as much as renal calcium retention is largely dependent on efficient activity of calcium-sodium exchangers situated in the basolateral membranes of tubular epithelium, it is evident that an increased intracellular sodium concentration consequent to sodium pump inhibition could blunt the activity of these exchangers. Thus, it is postulated that MBG mediates the impact of salt loading on renal calcium retention.

Efecto de la ingesta de sal sobre la función endotelial y su relación con el fenómeno de la sensibilidad a la sal en la hipertensión arterial esencial / Effect of salt intake upon endothelial function and its relationship with the salt sensitivity phenomenon in essential hypertension

El objetivo del presente trabajo ha sido el de evaluar las alteraciones en la función de la célula endotelial inducidas por el consumo de sal en pacientes hipertensos esenciales caracterizados en funcion de la presencia de sensibilidad o resistencia a la sal. Para ello hemos incluido a 60 pacientes hipertensos esenciales de ambos sexos, con una media de 42 años, sometidos a ingesta de baja (50 mmol/día) y elevada (250 mmol/día) cantidad de sal, evaluando los cambios en los productos derivados del endotelio. La evaluación funcional de la función endotelial se ha realizado mediante pletismografía de oclusión venosa frente a infusiones intraarteriales de acetilcolina, nitroprusiato sódico y el inhibidor de la síntesis de óxido nítrico, L-NMMA. Los resultados muestran que en el conjunto de los pacientes estudiados, una elevada ingesta de sal induce un descenso estadísticamente significativo en la concentración plasmática de nitratos (p < 0,001) de endotelina (p = 0,005). Además los pacientes sensibles a la sal mostraron un descenso estadísticamente significativo de la excreción urinaria de nitratos (p = 0,045), inducidos por la ingesta de sal. Finalmente, el estudio mediante pletismografía mostró que los pacientes sensibles a la sal presentaban una menor vasodilatación dependiente del endotelio inducida por acetilcolina (p = 0,008) en comparación con los resistentes a la sal. Además, la infusión de L-NMMA indujo a un menor descenso en la respuesta vasodilatadora a acetilcolina en los pacientes sensibles a la sal (p = 0,013). En conclusión, la ingesta de una dieta rica en sal ejerce en los pacientes hipertensos un efecto inhibitorio sobre la secreción de la célula endotelial. Hay que añadir que los pacientes sensibles a la sal presentan mayores alteraciones en la función de la célula endotelial. Estos resultados apoyan la existencia de una relación entre la disfunción endotelial y el desarrollo de la hipertensión sensible a la sal (AU)

Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area

In this study we investigated the effects of the injection into the supraoptic nucleus (SON) of non-peptide AT1- and AT2-angiotensin II (ANG II) receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP) receptor antagonist d(CH2)5-Tyr(Me)-AVP, on water and 3 percent NaCl intake induced by the injection of ANG II into the medial septal area (MSA). The effects on water or 3 percent NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 µl over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65 percent, N = 10, P<0.01) and sodium intake (81 percent, N = 8, P<0.01) induced by the injection of ANG II (10 nmol) into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45 percent, N = 9, P<0.01), ANG II-induced sodium intake was significantly increased (70 percent, N = 8, P<0.01) following injection of the V1-type vasopressin antagonist d(CH2)5-Tyr(Me)-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses

Area postrema, lateral parabrachial nucleus, and the antinatriorexic effect of bombesin.

Bombesin (BN) injected to sodium depleted rats either centrally, particularly into the paraventricular nucleus (PVN) or peripherally by intraperitoneal (IP) route, exerts a potent inhibitory effect on the intake of 2% sodium chloride. To determine whether the area postrema (AP) and the lateral parabrachial nucleus (LPBN), which are known to be involved in the control of ingestive behavior, could be sites for the antinatiorexic activity of BN, we studied the effects of injections of this peptide into the LPBN or, by IP or fourth ventricular route, to surgically AP-lesioned rats. We observed that in sodium depleted rats: 1) injected into the LPBN at a dose of 50, but not of 25, ng per nucleus, BN significantly reduced the intake of 2% sodium chloride; 2) administered either intraperitoneally or into the fourth brain ventricle, BN induced a potent antinatriorexic effect in AP-sham lesioned animals; and 3) in the same experimental conditions, surgical ablation of the AP did not reduce the antinatriorexic effect of the peptide. These data indicate that the LPBN may be, with the PVN, a site for the BN-ergic inhibitory control of salt appetite and that the AP, which has been implicated in BN-induced anorexia, does not play a role in the antinatriorexic effect of this peptide.

Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area.

In this study we investigated the effects of the injection into the supraoptic nucleus (SON) of non-peptide AT1- and AT2-angiotensin II (ANG II) receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP) receptor antagonist d(CH2)5-Tyr(Me)-AVP, on water and 3% NaCl intake induced by the injection of ANG II into the medial septal area (MSA). The effects on water or 3% NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 microliter over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65%, N = 10, P < 0.01) and sodium intake (81%, N = 8, P < 0.01) induced by the injection of ANG II (10 nmol) into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45%, N = 9, P < 0.01), ANG II-induced sodium intake was significantly increased (70%, N = 8, P < 0.01) following injection of the V1-type vasopressin antagonist d(CH2)5-Tyr(Me)-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses.

Effects of enalapril and hydrochlorothiazide on the salt-induced cardiac and renal hypertrophy in normotensive rats.

Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide-type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration. In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide.