Sexual Dimorphism's impact on adipogenesis: A three-dimensional in vitro model treated with 17ß-estradiol and testosterone.

Using a three-dimensional (3-D) in vitro culture model, we report the dose dependent effect of 17ß-estradiol and testosterone on the adipogenic differentiation and maturation of human adipose derived stem cells (hASCs) obtained from female and male patients. Considering sexual dimorphism, we expected male and female adipocytes to respond differently to the sex steroids. Both male and female hASC spheroids were exposed to 100 nM and 500 nM of 17ß-estradiol and testosterone either at the beginning of the adipogenic maturation (Phase I) to discourage intracellular triglyceride accumulation or exposed after adipogenic maturation (Phase II) to reduce the intracellular triglyceride accumulation. The results show that 17ß-estradiol leads to a dose dependent reduction in intracellular triglyceride accumulation in female hASC spheroids compared to the both untreated and testosterone-treated cells. Affirming our hypothesis, 17ß-estradiol prevented intracellular triglyceride accumulation during Phase I, while it stimulated lipolysis during Phase II. PPAR-γ and adiponectin gene expression also reduced upon 17ß-estradiol treatment in female cells. Interestingly, 17ß-estradiol and testosterone had only a modest effect on the male hASC spheroids. Collectively, our findings suggest that 17ß-estradiol can prevent fat accumulation in adipocytes during early and late stages of maturation in females.

Perfil de riesgo cardiovascular en mujeres de tres entornos de la Provincia de Tucumán - Argentina / Cardiovascular risk profile in women from three different areas of the Province of Tucumán, Argentina

RESUMEN Introducción : El rol del entorno sobre la salud en la población femenina de Tucumán está poco estudiado. El objetivo del presente trabajo fue evaluar el perfil de riesgo cardiovascular de mujeres de los entornos rural, periurbano y urbano de la provincia de Tucumán (Argentina). Material y métodos : Se efectuó un estudio analítico transversal en 3 grupos de mujeres de Tucumán: rural (n=125), periurbano (n= 50) y urbano (n=112). Resultados : La presión arterial (PA) fue menor en el grupo rural; el grupo urbano presentó mayor frecuencia cardíaca y menor circunferencia de cuello. El 29,7% de las mujeres presentaron sobrepeso y el 42,4% obesidad, sin diferencia significativa entre los 3 grupos. La circunferencia de cuello estuvo aumentada en el 62% de las mujeres del grupo rural, 79% del periurbano y 41% del urbano (p<0,001). El grupo urbano presentó más frecuentemente tabaquismo. En los grupos urbano y periurbano fue mayor la proporción de mujeres con estudios superiores (p <0,001). El nivel educativo se correlacionó positivamente con la frecuencia cardíaca. Conclusiones : Independientemente del entorno las mujeres de Tucumán presentan sobrepeso u obesidad asociados a otros factores de riesgo para enfermedad cardiovascular. Ello debe ser tenido en cuenta para la elaboración de políticas y la toma de conductas a fin de mejorar su pronóstico.

ABSTRACT Background : The role of the environment on female population health in Tucumán has been little studied. This study aimed to evaluate the cardiovascular risk profile in women from rural, peri-urban and urban areas in the province of Tucumán (Argentina) and to analyse their differences. Methods : An analytical cross-sectional study was conducted in 3 groups of women from Tucumán: rural (n = 125), peri-urban (n = 50) and urban (n = 112). Results : Blood pressure (BP) was lower in the rural group; the urban group showed higher heart rate and smaller neck cir cumference. Of the studied women, 29.7% were overweight and 42.4% obese, and no significant differences were found in the 3 groups. Increased neck circumference was observed in 62% of women in the rural group, 79% in the peri-urban group and 41% in the urban group (p <0.001). Smoking was more frequent in the urban group. In the urban and peri-urban groups, the proportion of women with higher education level was greater (p <0.001). Education level was positively correlated with heart rate. Conclusion : Regardless of the environment, women from Tucumán are overweight or obese and have other risk factors for cardiovascular disease. This should be considered when planning policies and making decisions in order to improve their prognosis.

Vascular and autonomic function as early predictive biomarkers of the progression to gestational hypertension.

Background: The changes in endothelial function, arterial stiffness, and heart rate variability (HRV) produced in the first trimester of pregnancy in women who develop gestational hypertension (GH) are still being investigated. Objective: to evaluate the HVR, endothelial function, and arterial stiffness changes during the first trimester of pregnancy and their relationship with the development of GH. Methods: A group of women normotensive during the first trimester (n = 43), who later did (GH; n = 11) or did not (no-GH; n = 32) develop GH in that pregnancy, were enrolled. In the first trimester, endothelial function and arterial stiffness were evaluated through photoplethysmography. HRV, parasympathetic (PNS), and sympathetic (SNS) indexes were measured in a 5-minute continuous electrocardiogram record at rest sitting. The Griess reaction measured urinary nitrite excretion (NOx). Results: Systolic blood pressure (SBP) values were higher in GH (no-GH: 105.8 ± 2.0 vs. GH: 112.7 ± 3.0 mmHg; p < 0.05). Endothelial function was decreased, and arterial stiffness was increased in GH. Only in GH the arterial stiffness was correlated with SBP (Pearson's r: 0.5594; 95%CI: 0.06106-0.8681; p < 0.05). In HRV, GH decreased low-frequency power and the ratio SD2/SD1. The inhibition of PNS was lower in GH. The NOx was reduced in GH (no-GH: 3.4 ± 0.4 vs. GH: 0.3 ± 0.1 µM/L; p < 0.001). NOx was correlated negatively with the SNS index only in GH. Conclusions: Developed GH is preceded early in pregnancy by endothelial dysfunction and increased arterial stiffness. In this context, there are SNS-PNS interrelation modifications with less inhibition of PNS.

A novel endothelium-independent effect of insulin on basal vascular tone in cafeteria diet-induced hypertensive rats.

Insulin vasorelaxant effect in metabolic syndrome has been shown on precontracted vessels. However, the insulin effects on basal vascular tone and its interrelationship with nitric oxide (NO) and K-channels are unknown. To test the effect of insulin on the basal vascular tone in isolated aortic rings from the cafeteria diet-induced hypertensive rats and to determine the role of NO and K-channels on this insulin effect. Male Wistar rats were randomized into two groups: one group fed with a cafeteria diet (CafR) and another fed with a standard chow diet (control rats: CR). Then, in isolated aortic rings, the insulin effect on the basal tone and the role of K-channels were evaluated. Also, the endothelial function, NO levels, and resting membrane potential were measured. CafR increased blood pressure (138 ± 6.2 mmHg; n = 9 vs. CR: 109 ± 1.4 mmHg; n = 9; p < 0.001) and vascular basal tone. Insulin 400 mU/ml reduced basal tone in aortic rings (-284 ± 47 mg; n = 9). This effect was unaffected by endothelium removal or NG-nitro-l-arginine methyl ester (L-NAME) treatment. Likewise, CafR showed low NO levels and a hyperpolarized resting membrane potential. Insulin decreased the resting membrane potential and the KCa and Kv channels blockers abolished this effect. In CafR, endothelial dysfunction is accompanied by an increased basal tone. Insulin reduced it by Kv and KCa channels dependent mechanisms, using an endothelium-independent pathway. These results highlight a novel insulin effect on basal tone of aortic rings from animals with metabolic syndrome and endothelial dysfunction, pathophysiological conditions associated with human hypertension.

Changes in vascular function and autonomic balance during the first trimester of pregnancy and its relationship with the new-born weight.

This study aimed to evaluate vascular function changes and autonomic balance during the first trimester of pregnancy and its relationship with the new-born weight. This prospective study performed in pregnant (PG) women and after delivery (not pregnant: NPG) evaluated the endothelial function (EF) and arterial stiffness (AS) by a non-invasive method. We evaluated the heart rate variability (HRV), parasympathetic nervous system (PNS), sympathetic nervous system (SNS) indexes by electrocardiogram (5 min) and the urinary nitrite excretion (NOx). PG increased EF and NOx and decreased AS and HRV. PG decreased the PNS index and augmented the SNS index. The new-born weight positively correlated with the PNS index (Pearson's r: 0.4291; p<.05), NOx, HRV and negatively correlated with AS. In summary, in pregnancy, although haemodynamically, the SNS activation plays a compensatory role, the low rates of PNS inhibition are essential to ensure normal foetal growth.Impact StatementWhat is already known on this subject? In pregnancy, there are adaptive physiological changes in the cardiovascular system that include increases of EF and decreases AS with an SNS activation. The study of HRV lets to predict the SNS and PNS balance and how they affect blood pressure and vascular function.What the results of this study add? Although it is known that SNS activation plays a compensatory role in healthy pregnancy, this study adds the critical role of PNS. Early in pregnancy, the low rates of PNS inhibition are essential to ensure normal foetal growth.What the implications are of these findings for clinical practice and/or further research? The present results show a potential predictive value of SNS and PNS activity early in pregnancy. It will provide valuable information not only on the pregnant woman's vascular function but also on the new-born weight.

Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension.

Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.

Disparate Effect of Antioxidant Supplements on the Basal Tone and Vascular Remodeling of the Aorta in Hypertensive Rats.

BACKGROUND: Oxidative stress plays an essential role in the vascular tone in hypertension; however, the mechanisms remain unclear. AIM: This study aimed to determine the antioxidant effect of tempol and vitamin C (Vit-C) on the basal tone and vascular remodeling of the aorta in nitric oxide (NO) deficiency-induced hypertensive rats. METHOD: Male Sprague-Dawley rats were induced to hypertension by Nω-nitro-L-arginine methyl ester (L-NAME). Animals were randomized as follows: vehicle (Control: CR), CR-tempol, CR-Vit-C, L-NAME, L-NAME-tempol, and L-NAME-Vit-C. After 6 weeks of treatment, the basal aortic tone was evaluated by sodium nitroprusside (SNP) and calcium-free medium. Endothelial function, NO, reduced-to-oxidized glutathione (GSH/GSSG) ratio, resting membrane potential (mP), and vascular remodeling were also measured. RESULTS: L-NAME rats showed an increased basal tone that was blunted by both SNP (-547 ± 69; n = 7 vs. CR: -7.5 ± 6.7 mg; n = 7; p < 0.001) and calcium-free medium. Tempol or Vit-C did not reverse hypertension, and the high basal tone was decreased only with tempol. In L-NAME rats, only tempol partially improved endothelial function, GSH-to-GSSG ratio, mP values, and vascular remodeling. CONCLUSIONS: Tempol decreased calcium-dependent basal aortic tone and improved vascular homeostasis in L-NAME rats. Vit-C did not lead to a similar effect, suggesting that alterations in the superoxide dismutase pathway may play a role in the basal aortic tone.

Sex differences in the structure and function of rat middle cerebral arteries.

Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young Sprague-Dawley (SD) rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared with males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared with males. The MCA of females failed to constrict compared with a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4 and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100 to 180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause.NEW & NOTEWORTHY Using perfusion fixation of the middle cerebral artery (MCA) in calcium-free solution at physiological pressure and systematically randomly sampling the sections prepared from the same M2 segments of MCA, we found that there are structural differences that are associated with altered cerebral blood flow (CBF) autoregulation but not neurovascular coupling and cognition in young, healthy Sprague-Dawley (SD) rats. Understanding the intrinsic differences in cerebrovascular structure and function in males and females is essential to develop new pharmaceutical treatments for cerebrovascular disease (CVD).

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

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

Regulation of blood pressure is influenced by gender: A study in obese Zucker rats.

AIM: The present study determined the role of renin-angiotensin system (RAS), endothelin system, and eicosanoid system in the blood pressure (BP) regulation in male and female Zucker rats, and whether the pressor response change similarly in lean and obese animals. MATERIAL AND METHODS: In female (f) and male (m), lean (L) and obese (O) Zucker rats (ZR) at 22 weeks old, we evaluated the role of the 3 mentioned systems using the following treatments: 1) enalapril (angiotensin I converting enzyme inhibitor), 2) the ABT-627 (endothelin receptor A (ETA) antagonist), and 3) the 1-aminobenzotriazol (1-ABT: eicosanoid synthesis inhibitor). KEY FINDINGS: MAP by radiotelemetry was similar and significantly higher in mOZR (120 ±â€¯2 mm Hg) and fOZR (116 ±â€¯4 mm Hg) (p < 0.05 vs. m-, fLZR), than mLZR (105 ±â€¯3 mm Hg) and fLZR (106 ±â€¯1 mm Hg), that were also similar. Enalapril reduced MAP more in mOZR (23%) and mLZR (26%), than fLZR (20%, p < 0.905 vs. mLZR) or fOZR (9%; p < 0.05 vs. other groups). After 10 days of drug-free and recovery period, ABT-627 reduced MAP in fLZR and mLZR by similar amounts (102 ±â€¯4 to 92 ±â€¯3 mm Hg, n = 6; p < 0.05 and 105 ±â€¯2 vs. 92 ±â€¯3 mm Hg, n = 6; p < 0.05, respectively), but did not affect either fOZR or mOZR. After another 10 days of drug-free and recovery period, 1-ABT reduced MAP in fOZR (116 ±â€¯4 to 95 ±â€¯2, n = 6; p < 0.05), and did not affect all other groups. SIGNIFICANCE: We show that the mechanisms responsible for elevated BP in male and female OZR and LZR are different, and suggest that obesity may cause an increase in BP via different mechanisms in men and women as well.

Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects.

Rodent vertical sleeve gastrectomy alters maternal immune health and fetoplacental development.

Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism, and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 19 had reduced circulating T-cell (CD3+ and CD8+) populations compared with lean or obese controls. Further, local interleukin (IL) 1ß and IL 1 receptor antagonist (il1rn) cmRNA were increased in placenta of VSG dams. Placental barrier function was also affected, with increased transplacental permeability to small molecules, increased matrix metalloproteinase 9 expression, and increased apoptosis in VSG. Furthermore, we identified increased placental mTOR signaling that may contribute to preserving the body weight of the fetuses during gestation. These changes occurred in the absence of a macronutrient deficit or gestational hypertension in the VSG dams. In summary, previous VSG in dams may contribute to fetal demise by affecting maternal immune system activity and compromise placental integrity.

Cardiovascular and Metabolic Consequences of Testosterone Supplements in Young and Old Male Spontaneously Hypertensive Rats: Implications for Testosterone Supplements in Men.

BACKGROUND: The safety of testosterone supplements in men remains unclear. In the present study, we tested the hypothesis that in young and old male spontaneously hypertensive rats (SHR), long-term testosterone supplements increase blood pressure and that the mechanism is mediated in part by activation of the renin-angiotensin system. METHODS AND RESULTS: In untreated males, serum testosterone exhibited a sustained decrease after 5 months of age, reaching a nadir by 18 to 22 months of age. The reductions in serum testosterone were accompanied by an increase in body weight until very old age (18 months). Testosterone supplements were given for 6 weeks to young (12 weeks-YMSHR) and old (21-22 months-OMSHR) male SHR that increased serum testosterone by 2-fold in young males and by 4-fold in old males. Testosterone supplements decreased body weight, fat mass, lean mass, and plasma leptin, and increased plasma estradiol in YMSHR but had no effect in OMSHR. Mean arterial pressure (MAP) was significantly higher in OMSHR than in YMSHR and testosterone supplements decreased MAP in OMSHR, but significantly increased MAP in YMSHR. Enalapril, the angiotensin-converting enzyme inhibitor, reduced MAP in both control and testosterone-supplemented YMSHR, but had a greater effect on MAP in testosterone-treated rats, suggesting the mechanism responsible for the increase in MAP in YMSHR is mediated at least in part by activation of the renin-angiotensin system. CONCLUSIONS: Taken together with previous studies, these data suggest that testosterone supplements may have differential effects on men depending on age, cardiovascular and metabolic status, and dose and whether given long-term or short-term.

Role and Regulation of MicroRNAs in Aldosterone-Mediated Cardiac Injury and Dysfunction in Male Rats.

Primary aldosteronism is characterized by excess aldosterone (ALDO) secretion independent of the renin-angiotensin system and accounts for approximately 10% of hypertension cases. Excess ALDO that is inappropriate for salt intake status causes cardiac hypertrophy, inflammation, fibrosis, and hypertension. The molecular mechanisms that trigger the onset and progression of ALDO-mediated cardiac injury are poorly understood. MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that have been implicated in diverse cardiac abnormalities, yet very little is known about their regulation and role in ALDO-mediated cardiac injury. To elucidate the regulation of miRNAs in ALDO-mediated cardiac injury, we performed a time-series analysis of left ventricle (LV) miRNA expression. Uninephrectomized male Sprague-Dawley rats were treated with ALDO (0.75 µg/h) infusion and SALT (1.0% NaCl/0.3% KCl) in the drinking water for up to 8 weeks. ALDO/SALT time dependently modulated the expression of multiple miRNAs in the LV. miR-21 was the most upregulated miRNA after 2 weeks of treatment and remained elevated until the end of the study. To elucidate the role of miR-21 in ALDO/SALT-mediated cardiac injury, miR-21 was downregulated by using antagomirs in ALDO/SALT-treated rats. miR-21 downregulation exacerbated ALDO/SALT-mediated cardiac hypertrophy, expression of fibrosis marker genes, interstitial and perivascular fibrosis, OH-proline content, and cardiac dysfunction. These results suggest that ALDO/SALT-mediated cardiac miR-21 upregulation may be a compensatory mechanism that mitigates ALDO/SALT-mediated cardiac deleterious effects. We speculate that miR-21 supplementation would have beneficial effects in reverting or mitigating cardiac injury and dysfunction in patients with primary aldosteronism.

Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system.

Hypertension in postmenopausal women is less well controlled than in age-matched men. The aging female SHR is a model of postmenopausal hypertension that is mediated in part by activation of the renin-angiotensin system (RAS) and by the renal sympathetic nervous system. In this study, the hypothesis was tested that renal denervation would lower the blood pressure in old female SHR and would attenuate the antihypertensive effects of AT1 receptor antagonism. Retired breeder female SHR were subjected to right uninephrectomy (UNX) and left renal denervation (RD) or UNX and sham, and 2 weeks later, baseline mean arterial pressure (MAP; radiotelemetry) was measured for 4 days, and then rats were treated with angiotensin (AT1) receptor antagonist, losartan (40 mg/kg/day po) for 6 days. Renal denervation reduced MAP in old females compared to sham (172 ± 6 vs. 193 ± 6 mm Hg; P < 0.05). Losartan reduced MAP in both sham and RD rats similarly (numerically and by percentage) (142 ± 10 vs. 161 ± 6 mm Hg; P < 0.05 vs. RD, P < 0.05 vs. baseline). However, female SHR rats remained significantly hypertensive despite both pharmacological intervention and RD. The data suggest that both the renal sympathetic nervous system and the RAS have independent effects to control the blood pressure in old female SHR. Since the denervated rats treated with losartan remained hypertensive, the data also suggest that other mechanisms than the RAS and renal sympathetic nervous system contribute to the hypertension in old female SHR. The data also suggest that multiple mechanisms may mediate the elevated blood pressure in postmenopausal women.

Gestión en salud y su articulación con el sector científico en la atención primaria de la salud / Health management and its articulation with the scientific sector in the primary health care

Objetivos: Determinar los programas y proyectos de investigación e intervención, incluyendo diagnósticos de salud, entre Abril de 2001 a Diciembre del 2007, en la Provincia de Tucumán, Argentina. Materiales y Métodos: Para los proyectos de investigación científica en salud se utilizó la base de datos del Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) y la Universidad Nacional de Tucumán (UNT). Para las investigaciones socio-sanitarias se realizaron entrevistas a actores claves involucrados en la gestión del conocimiento, funcionarios del gobierno del Ministerio de Salud y de la Secretaría de Ciencia y Técnica de Innovación Productiva de la Provincia, Ministerio de Desarrollo Social y a autoridades del Sistema Provincial de Salud. Resultados: Medicina representó el 4,9% del total de Proyectos financiados por la Universidad y el 1,9% del total de Programas aprobados por la Secretaría de Ciencia y Técnica de la UNT. Una situación similar se describe para nuestra provincia en relación a los subsidios otorgados por CONICET con el 2% del total de financiamiento. La Investigación Clínica y Epidemiológica fueron los temas más investigados de acuerdo a la clasificación presentada. De acuerdo con la encuesta, el 32% de los entrevistados opinó que “articula bastante” la investigación científica con los programas de la Atención Primaria de la Salud. Conclusiones: Hay escaso conocimiento sobre los proyectos de investigación en salud financiados por entidades públicas en las diferentes áreas geográficas estudiadas (Metropolitana, Agroindustrial y SILOS). Se observó que a nivel institucional universitario el área de Ciencias de la Salud y especialmente Medicina, es un área de vacancia.

Aim: To determine programs and projects of research and intervention, including diagnosis of health, during April 2001 to December 2007, in the Province of Tucuman, Argentina. Material and Methods: Data were obtained from public organisms of the Province of Tucuman. For research in health were used the data base of the National Scientific and Technical Research Council - Argentina (CONICET) and the National University of Tucuman (UNT). For research in Health and social care were realized interviews to key actors directly involved in knowledge management, Government officials of the Ministry of Health and the Secretary of Science and Technology of Productive Innovation of the Province of Tucuman, and Ministry of Social Development and the officials of the Health System of Tucuman. Results: Medicine accounted 4.9% of all projects funded by the University and 1.9% of total approved by the Ministry of Science and Technology of UNT. A similar situation is described for our province in relation to grants from CONICET with the 2% of total funding. Clinical and Epidemiological Research were the most investigated according to the classification presented. According to the survey, 32% of respondents felt that “articulates quite” the scientific research programs with Primary Health Care. Conclusions: There is little knowledge about health research projects funded by public entities in different geographical areas studied (Metropolitan, Agroindustrial and SILOS). It was noted that in a university institutional area, Health Sciences, and Medicine in particular, is an area of vacancy.

Postmenopausal hypertension: role of the sympathetic nervous system in an animal model.

In postmenopausal women the mechanisms responsible for hypertension have not been completely elucidated, and there are no gender-specific guidelines for women despite studies showing that blood pressure is not as well controlled to goal in women as in men. In the present study we tested the hypotheses that the sympathetic nervous system and the renal sympathetic nerves contribute to hypertension in aging female rats, that sympathetic activation may be mediated by the melanocortin 3/4 receptor (MC3/4R), and that MC3/4R activation may be due to increases in leptin. α-1, ß-1,2-Adrenergic blockade reduced blood pressure in both young (3-4 mo) and old (18-19 mo) female spontaneously hypertensive rats (SHR). Renal denervation attenuated the hypertension more in old females than young females. MC3/4R antagonism with SHU-9119 given intracerebroventricularly had no effect on blood pressure in either young or old females but significantly reduced blood pressure in old males. Plasma leptin levels were similar in old male and female SHR and in old versus young females. These data suggest that the hypertension in old female SHR is in part due to activation of the sympathetic nervous system, that the renal nerves contribute to the hypertension, and that the mechanism responsible for sympathetic activation in old females is independent of the MC3/4R.

Tempol blunts afferent arteriolar remodeling in chronic nitric oxide-deficient hypertension without normalizing blood pressure.

BACKGROUND/AIM: Renal preglomerular vessels play a central role in modulating renal function and injury, especially during conditions of renal hemodynamic stress such as hypertension. We evaluated whether improving the balance between nitric oxide (NO) and oxidative stress improves the morphological alterations of renal afferent arterioles that occur in NO deficiency-induced hypertension. METHODS: We measured indices of NO and oxidative stress and evaluated renal morphology and afferent arteriolar remodeling in rats treated with vehicle, L-NAME or L-NAME plus tempol (a superoxide dismutase mimetic) for 6 weeks. RESULTS: L-NAME-treated rats had hypertension, lower urinary and renal NO indices, higher renal cortical levels of TBARS, GSSG and GSSG/GSH. This was associated with significant eutrophic inward remodeling of the afferent arterioles; they had a marked decrease in arteriolar lumen area and a striking increase in arteriolar wall thickness and media to lumen ratio. Tempol did not significantly reduce blood pressure, but increased NO levels, decreased oxidative stress and partially blunted L-NAME-induced remodeling of afferent arterioles. CONCLUSION: L-NAME-induced remodeling of afferent arterioles is blunted by tempol. This beneficial effect on remodeling is associated with increases in NO indices, decreases in oxidative stress, without significant decreases in blood pressure. Thus, the balance between these components may contribute to the altered renal hemodynamics and function in this model.