Low-Chloride Diet Prevents the Development of Arterial Hypertension and Protects Kidney Function in Angiotensin II-Infused Mice.

INTRODUCTION: A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl- while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. METHODS: C56BL/6J mice fed with standard Cl- diet or a low-Cl- diet (equimolar substitution of Cl- by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl- diet. RESULTS: The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl- diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl- diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl- diet and infused with AngII presented a similar contractile response. CONCLUSION: We conclude that the reduction in dietary Cl- as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.

Neutrophil gelatinase-associated lipocalin as an immunomodulator in endocrine hypertension.

In recent studies, primary aldosteronism (PA) has been reported as the most common etiology for secondary hypertension of endocrine origin, accounting for approximately 10% of cases. In PA, excess aldosterone production can lead to deleterious effects at the cardiovascular (CV) and renal levels by activating mineralocorticoid receptors, which involves an increase in pro-inflammatory and pro-fibrotic mediators. Among these mediators, neutrophil gelatinase-associated lipocalin (NGAL), a secretion glycoprotein belonging to the lipocalin superfamily, has been closely linked to CV and renal damage in several pathological conditions. Because NGAL can be detected in biofluids such as plasma and urine, it has been proposed as a damage biomarker for target tissues and has also been studied for its role in hypertension and associated with PA. NGAL is produced by many different cell types, can be carried on extracellular vesicles, and is modulated by microRNAs, which would support its use as a biomarker for endocrine hypertension due to PA. Over the last decade, studies have shown that NGAL is necessary for the development of aldosterone-induced hypertension and that is associated with end-organ damage. In addition, it has been proposed that some mechanisms are dependent on the activation of immune cells, such as dendritic cells and macrophages, where the release of specific cytokines (i.e., interleukin [IL]-23) or chemokines (i.e., CCL-5) induced by aldosterone would depend on NGAL. Subsequently, this activates the T helper (Th) lymphocytes, such as Th17 and Th2, resulting in CV and renal fibrosis due to the high aldosterone levels. Although the immune system has been closely associated with essential hypertension, its participation in endocrine hypertension has not been fully elucidated. This review discusses the link between NGAL and endocrine hypertension, particularly in the context of PA, and their possible regulators and mechanisms, with a focus on its role as an immunomodulator.

Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension.

BACKGROUND: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. METHODS: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague-Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. RESULTS: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-ß1 and gene expression of pro-remodeling molecules TGF-ß1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. CONCLUSIONS: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.

[Role of inflammation in hypertension]. / La inflamación en la hipertensión arterial, mecanismos de producción e implicancias terapéuticas.

Even though the mechanisms that mediate essential hypertension (HT) are not fully understood, an immunological-inflammatory mechanism could be the common pathway for diverse pathophysiological mechanisms. We analyze in a simplified way the participation of the immune system in HT. T lymphocytes (TL) and antigen presenting cells (APCs) are components of the immune system capable of generating proinflammatory cytokines. They cause endothelial damage, vasoconstriction, and decreased urinary sodium excretion. CD4+ and CD8+ TL are effector cells, causally implicated in the development of HT, whereas type γδ TL play their pathogenic role in HT enhancing endothelial dysfunction. Additionally, a immunomodulation decrease by regulatory TL, worsens endothelial dysfunction and reduces vasodilation in experimental HT. Results of recent studies indicate that lymphocyte activation would be mediated by antigens captured by antigen APCs for subsequent presentation to "naive" TL. On the other hand, proinflammatory states such as obesity, the change of the intestinal microbiota and the increase in salt intake favors TL and APC activation, contributing to HT development.

α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions.

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.

Oxidized Albumin as a Mediator of Kidney Disease.

Renal diseases are a global health concern, and nearly 24% of kidney disease patients are overweight or obese. Particularly, increased body mass index has been correlated with oxidative stress and urinary albumin excretion in kidney disease patients, also contributing to increased cardiovascular risk. Albumin is the main plasma protein and is able to partially cross the glomerular filtration barrier, being reabsorbed mainly by the proximal tubule through different mechanisms. However, it has been demonstrated that albumin suffers different posttranslational modifications, including oxidation, which appears to be tightly linked to kidney damage progression and is increased in obese patients. Plasma-oxidized albumin levels correlate with a decrease in estimated glomerular filtration rate and an increase in blood urea nitrogen in patients with chronic kidney disease. Moreover, oxidized albumin in kidney disease patients is independently correlated with higher plasma levels of transforming growth factor beta (TGF-ß1), tumor necrosis factor (TNF-α), and interleukin (IL)-1ß and IL-6. In addition, oxidized albumin exerts a direct effect on neutrophils by augmenting the levels of neutrophil gelatinase-associated lipocalin, a well-accepted biomarker for renal damage in patients and in different experimental settings. Moreover, it has been suggested that albumin oxidation occurs at early stages of chronic kidney disease, accelerating the patient requirements for dialytic treatment during disease progression. In this review, we summarize the evidence supporting the role of overweight- and obesity-induced oxidative stress as a critical factor for the progression of renal disease and cardiovascular morbimortality through albumin oxidation.

La inflamación en la hipertensión arterial, mecanismos de producción e implicancias terapéuticas / Role of inflammation in hypertension

Even though the mechanisms that mediate essential hypertension (HT) are not fully understood, an immunological-inflammatory mechanism could be the common pathway for diverse pathophysiological mechanisms. We analyze in a simplified way the participation of the immune system in HT. T lymphocytes (TL) and antigen presenting cells (APCs) are components of the immune system capable of generating proinflammatory cytokines. They cause endothelial damage, vasoconstriction, and decreased urinary sodium excretion. CD4+ and CD8+ TL are effector cells, causally implicated in the development of HT, whereas type γδ TL play their pathogenic role in HT enhancing endothelial dysfunction. Additionally, a immunomodulation decrease by regulatory TL, worsens endothelial dysfunction and reduces vasodilation in experimental HT. Results of recent studies indicate that lymphocyte activation would be mediated by antigens captured by antigen APCs for subsequent presentation to "naive" TL. On the other hand, proinflammatory states such as obesity, the change of the intestinal microbiota and the increase in salt intake favors TL and APC activation, contributing to HT development.

The Role of Neutrophils in Hypertension.

It is well accepted that the immune system and some cells from adaptive and innate immunity are necessary for the initiation/perpetuation of arterial hypertension (AH). However, whether neutrophils are part of this group remains debatable. There is evidence showing that the neutrophil/lymphocyte ratio correlates with AH and is higher in non-dipper patients. On the other hand, the experimental neutrophil depletion in mice reduces basal blood pressure. Nevertheless, their participation in AH is still controversial. Apparently, neutrophils may modulate the microenvironment in blood vessels by increasing oxidative stress, favoring endothelial disfunction. In addition, neutrophils may contribute to the tissue infiltration of immune cells, secreting chemoattractant chemokines/cytokines and promoting the proinflammatory phenotype, leading to AH development. In this work, we discuss the potential role of neutrophils in AH by analyzing different mechanisms proposed from clinical and basic studies, with a perspective on cardiovascular and renal damages relating to the hypertensive phenotype.

Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase-associated lipocalin expression upon mineralocorticoid receptor activation.

BACKGROUND: Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown. OBJECTIVE: We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation. METHODS: Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment. RESULTS: The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively. CONCLUSION: NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess.

Myeloid CD11c+ Antigen-Presenting Cells Ablation Prevents Hypertension in Response to Angiotensin II Plus High-Salt Diet.

Increasing evidence shows that antigen-presenting cells (APCs) are involved in the development of inflammation associated to hypertension. However, the potential role of APCs in the modulation of renal sodium transport has not been addressed. We hypothesized that APCs participate in renal sodium transport and, thus, development of high blood pressure in response to angiotensin II plus a high-salt diet. Using transgenic mice that allow the ablation of CD11chigh APCs, we studied renal sodium transport, the intrarenal renin-angiotensin system components, blood pressure, and cardiac/renal tissue damage in response to angiotensin II plus a high-salt diet. Strikingly, we found that APCs are required for the development of hypertension and that the ablation/restitution of APCs produces rapid changes in the blood pressure in mice with angiotensin II plus a high-salt diet. Moreover, APCs were necessary for the induction of intrarenal renin-angiotensin system components and affected the modulation of natriuresis and tubular sodium transporters. Consistent with the prevention of hypertension, the ablation of APCs also prevented cardiac hypertrophy and the induction of several indicators of renal and cardiac damage. Thus, our findings indicate a prominent role of APCs as modulators of blood pressure by mechanisms including renal sodium handling, with kinetics that suggest the involvement of tubular cell functions in addition to the modulation of inflammation and adaptive immune response.

Espironolactona aumenta los niveles circulantes de angiotensina-(1-9) y revierte el remodelado cardíaco en la hipertensión arterial experimental / Spironolactone increases circulating levels of angiotensin-(1-9) and reverts cardiac remodeling in experimental hypertension

Previamente hemos demostrado que la eficacia de enalapril, candesartán y de fasudil -inhibidor de la vía RhoA/ROCK,- en el tratamiento del remodelado cardíaco en la hipertensión (HTA) e infarto al miocardio está mediada por aumento en los niveles circulantes del péptido vasoactivo angiotensina [Ang]-(1-9). Sin embargo, no hay información disponible si el antagonista del receptor de mineralocorticoide, espironolactona (espiro) disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9). El objetivo de este trabajo fue determinar si espironolac-tona disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9) en la hipertensión arterial experimental. Métodos. Estudio comparativo de 3 grupos experimentales. Se utilizaron ratas Sprague Dawley macho (150 ± 10 grs) unifrectomizadas tratadas con desoxi-corticosterona (DOCA, 60mg/Kg 2 veces sem, im) por 6 semanas. Como controles (Sham) se usaron ratas unifrectomizadas. A partir de la 3° semana las ratas DOCA con HTA> 140 mmHg fueron randomizadas a recibir vehículo o espiro (100 mg/kg día, gavage) por 3 sem. Al finalizar el tratamiento se determinó la presión arterial sistólica (PAS), masa corporal, peso del corazón (PC) y masa cardíaca relativa al largo de la tibia (MCR, mg ventrículos/LT*100). El grado de hipertrofia car-diomiocitaria se determinó midiendo el área y perímetro de los cardiomiocitos y la fibrosis por el contenido de colágeno en cortes teñidos con rojo picrosirio. Resultados (promedio ± ES): Conclusión: Espironolactona disminuye la PAS y aumenta los niveles circulantes de Ang-(1-9). Este aumento en los niveles circulantes de Ang-(1-9) se asocia con una disminución significativa de la hipertrofia y la fibrosis cardiaca hipertensiva. Este nuevo efecto de espironolactona en los niveles circulantes de Ang-(1-9), - péptido vasoactivo de la vía paralela del sistema renina-angiotensina-aldosterona,- podría contribuir al efecto antihipertensivo y disminución del daño cardiaco en la hipertensión y remodelamiento cardiovascular y renal patológico. Estos hallazgos pueden tener relevancia terapéutica en términos que Ang-(1-9) podría disminuir el daño cardiovascular patológico.

We have previously demonstrated that the efficacy of enalapril, candesartan and fasudil,- RhoA / ROCK inhibitor-, in the treatment of cardiac remodeling in hypertension (HT) and myocardial infarction is mediated by an increase in circulating levels of the vasoactive peptide angiotensin (Ang) -(1-9). However, it is not known whether the mineralocorticoid receptor antagonist, spironolactone (spiro) decreases cardiac remodeling by increasing the circulating levels of Ang- (1-9). The aim of this study was to determine whether spironolactone decreases cardiac remodeling by increasing circulating levels of Ang-(1-9) in experimental hypertension. Methods. Comparative study of 3 experimental groups. Unifirectomized male Sprague Dawley rats (150 ± 10 grams) were treated with deoxycorticos-terone (DOCA, 60 mg / kg 2 times a week, im) for 6 weeks. Unifirectomized rats were used as controls (Sham). At 3rd week after surgery, DOCA rats with HTA> 140 mmHg were randomized to receive vehicle or spironolactone (Spiro, 100 mg / kg day, gavage) for 3 weeks. At the end of treatment, systolic blood pressure (SBP), body mass (BM), heart weight (HW) and relative cardiac mass to the tibia length (MCR, mg ventricles / LT * 100) were determined. The degree of cardiomyocyte hypertrophy was determined by measuring the area and perimeter of cardiomyocytes and fibrosis by collagen content in sections stained with picrosirius red. Results (mean ± ES): Conclusion: Spironolactone decreases systolic blood pressure and increases circulating levels of Ang-(1-9). This increase in circulating levels of Ang- (1-9) was associated with a significant decrease in hypertrophy and hypertensive cardiac fibrosis. This new effect of spironolactone on the circulating levels of Ang- (1-9) - vasoactive peptide of the parallel pathway of the re-nin-angiotensin-aldosterone system - could contribute to the antihypertensive effect and decrease of cardiac damage in HT and cardiovascular remodeling and renal disease. These findings may have therapeutic relevance supporting that Ang-(1-9) may decreases pathologic cardiovascular damage.

Diuretics prevent Rho-kinase activation and expression of profibrotic/oxidative genes in the hypertensive aortic wall.

BACKGROUND: Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats. METHODS: Deoxycorticosterone acetate (DOCA)-salt hypertensive rats (male, Sprague-Dawley) were randomized to the specific ROCK inhibitor FAS, HCTZ, spiro or the combinations of FAS/HCTZ or FAS/spiro for 3 weeks. At the end of the study, ROCK activation (by western blot), gene expression of proremodeling markers (by reverse transcription polymerase chain reaction, RT-PCR) and vascular hypertrophy (by morphometry) were determined in the aortic wall. RESULTS: All treatments significantly reduced blood pressure. In the DOCA rats the p-myosin phosphatase target protein-1 (MYPT1)/t-MYPT1 ratio, index of ROCK activation was higher by 2.8 fold (p < 0.05) compared with control rats. All treatments reduced ROCK activation in the aortic wall to control levels (p < 0.05). Besides, significantly increased protein levels of transforming growth factor ß1 (TGF-ß1), gene expression of TGF-ß1, connective tissue growth factor (CTGF), p22 phox and gp91 phox subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as well as increased media thickness and aortic media area/lumen area (AM/LA) in the untreated hypertensive rats were significantly reduced (p < 0.05) to control levels by all treatments. Similar effects were observed using both diuretics alone or in combination with FAS. CONCLUSIONS: In the aortic wall, both HCTZ and spiro in antihypertensive doses reduce ROCK activation, subsequent expression of genes that promote vascular remodeling and hypertrophy in this experimental model of hypertension. These effects could explain some of their clinical benefits in hypertensive patients.

p-Coumaric acid reduces high glucose-mediated impairment of endothelium-dependent relaxation in rat aorta / Ácido p-cumárico reduce el deterioro mediado por alta glucosa de la relajación dependiente de endotelio en aorta de rata

p-Coumaric acid (p-CA) is an ubiquitous plant metabolite with antioxidant, anti-inflammatory, and anticancer properties. The present study was designed to evaluate the preventive effects of p-CA on endothelium-dependent impairment produced by high glucose (HG) (D-Glucose 25 mM) in isolated rat thoracic aorta. Aortic rings obtained from male Sprague-Dawley rats were mounted in an organ bath and pretreated for 3 h with D-Glucose 5 mM, HG and HG plus p-CA (1, 10 and 100 uM). After this period of time endothelium-dependent relaxation was tested by cumulative addition of acetylcholine (ACh) in pre-contracted rings with phenylephrine (PE) (0.1 μM). p-CA elicited a moderate endothelium-dependent vasodilatory effect (Emax= 29.28 +/- 1.89 percent, N=6; pD2= 6.075 +/- 0.184, N=6). When aortic rings were pre-incubated for 3 h with HG, Emax for ACh decreased dramatically from 87.69 +/- 2.59 percent (N=6) to 40.54 +/- 1.78 percent (N=6). The negative effect of HG was partially reverted in rings co-incubated with p-CA in a concentration-dependent manner as shown for Emax values to each p-CA concentration: 1 uM (48.57 +/- 1.82 percent), 10 uM (60.81 +/- 1.80 percent) and 100 uM (64.51 +/- 1.80 percent). The action of p-CA was associated with a significant change in Emax. No statistical difference in pD2 was observed. Our results clearly show that p-CA protect ACh-induced endothelial-dependent relaxation affected by HG in isolated rat aortic rings.

El ácido p-cumárico (p-CA) es un metabolito ubicuo en plantas, con propiedades antioxidantes, anti-inflamatoria, y anticancerígenas. El presente estudio fue diseñado para evaluar los efectos preventivos de p-CA sobre la relajación dependiente de endotelio, deteriorada por niveles altos de glucosa (HG) (D-glucosa 25 mM) en aorta torácica aislada de rata. Los anillos aórticos obtenidos de ratas macho Sprague-Dawley se montaron en un baño de órganos y fueron pre-tratados durante 3 h con D-glucosa 5 mM, HG, y HG más de p-CA (1, 10 y 100 uM). Después de este período de tiempo se evaluó la relajación dependiente de endotelio mediante la adición acumulativa de acetilcolina (ACh) en anillos pre-contraídos con fenilefrina (PE) (0,1 uM). p-CA mostró un moderado efecto vasodilatador dependiente de endotelio (Emax = 29,28 +/- 1,89 por ciento, N = 6; pD2 = 6,075 +/- 0,184, N = 6). Cuando los anillos aórticos se pre-incubaron durante 3 h con HG, la Emax para ACh se redujo drásticamente desde 87,69 +/- 2,59 por ciento (N = 6) a 40,54 +/- 1,78 por ciento (N = 6). El efecto negativo de HG se revirtió parcialmente, de manera dependiente de concentración, en los anillos co-incubados con p-CA tal como lo muestra el valor de Emax para cada concentración de p-CA: 1 u M (48,57 +/- 1,82 por ciento), 10 uM (60,81 +/- 1,80 por ciento) y 100 uM (64,51 +/- 1,80 por ciento). La acción de p-CA se asoció con un cambio significativo en la Emax. No se observó diferencia estadísticamente significativa en el pD2. Nuestros resultados muestran claramente que p-CA protege la relajación dependiente de endotelio inducida por ACh, la cual es afectada por HG en anillos aislados de aorta de rata.

Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction.

Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N-dimethyl-thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N-dimethyl-thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N-dimethyl- thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N-dimethyl-thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects.

Hidroclorotiazida y espironolactona reducen la hipertrofia de la pared aórtica en la hipertensión arterial experimental / Diuretics are important and effective antihypertensive agents: however, there are a few studies assessing its role on the arterial wall remodelling in hypertension

Introducción: Los diuréticos forman parte del tratamiento antihipertensivo actual con efectividad e impacto clínico demostrados. Sin embargo, los efectos de estos fármacos sobre el remodelado de la pared arterial en la hipertensión arterial (HTA) han sido poco evaluados. Objetivos: Determinar y comparar el efecto de Hidroclorotiazida (HCTZ) y de Espironolactona (ESP) en la hipertrofia de la pared aórtica en la HTA experimental. Metodología: Estudio comparativo en 4 grupos experimentales. Se utilizaron ratas Sprague Dawley macho de 150 +/- 10 grs. unifrectomizadas tratadas con desoxicorticosterona Acetato (DOCA, 100 mg/Kg/sem sbc) por 6 semanas. Como controles (Sham) se usaron ratas unifrectomizadas. A partir de la tercera semana con DOCA se administró diuréticos en dos grupos adicionales durante 3 semanas. Uno recibió HCTZ (6 mg/ kg/día) y otro ESP (100 mg/Kg/dia), vía gavage. Al finalizar los tratamientos se determinó la presión arterial sistólica (PAS), masa corporal (MC), peso del corazón (PC) y masa cardiaca relativa (MCR). El grado de hipertrofia de la pared aórtica se determinó midiendo el grosor de la túnica media (GTM), área de la túnica media (ATM), área luminal (AL) y la relación ATM/AL en cortes teñidos con hematoxilina-eosina. Resultados: En las ratas DOCA no tratadas hubo un aumento significativo de PAS (51 por ciento), MCR (79 por ciento), ATM (44 por ciento), GTM (57 por ciento), y de la razón ATM/AL (43 por ciento) respecto al grupo Sham. Ambos tratamientos (Hctz y Esp) redujeron en forma muy importante y significativamente la PAS, MCR, ATM, GTM y la razón ATM/AL en magnitudes similares y también por cada mm de Hg de descenso de la PAS logrado. Conclusión: Además del efecto antihipertensivo, tanto hidroclorotiazida como espironolactona previenen y/o revierten en magnitud similar el desarrollo de hipertrofia de la pared aórtica en este modelo de HTA experimental.

Aims: To determine and compare the effects of hydrochlorotiazide (Hctz) and spironolactone (Esp) on hypertrophy of the aortic wall in experimental hypertension. Methods: This was a comparative study with 4 experimental groups. We used male. uninephrectomized Sprague Dawley rats (150 +/- 10 grs) treated with des-oxycorticosterone acetate (DOCA, 100 mg/Kg/week sbc) during 6 weeks. As controls uninephrectomized rats (Sham) were used. Starting from the third week with DOCA, two groups recived diuretics by gavage during 3 weeks. One group received Hctz (6 mg/kg/ day) and other group received Sp (100 mg/kg/day). At the end of the study, systolic blood pressure (SBP), body weight, heart weight and relative cardiac weight were measured. Hypertrohy in the aortic wall was assessed by measuring the media thickness (MT), media area (MA), lumen area (LA) and by the AM/LA ratio on hematoxyline-eosine stained cross sections. Results: Compared to the Sham group, in the untreated hypertensive DOCA group, SBP and relative cardiac weight increased significantly (by 51 percent and 79 percent, respectively), MA increased by 44 percent, as well as MT (57 percent) and the AM/LA ratio (43 percent). Both treatments (Hctz and Sp) reduced importantly and significantly SBP, relative cardiac mass as well as MT, MA and the AM/LA ratio at a similar extent and by mm Hg. Conclusion: Besides the antihypertensive effect, both hydrochlorotiazide and spironolactone prevent and/or regress aortic wall hypertrophy in this experimental model of hypertension.