Probiotics Prevent Dysbiosis and the Rise in Blood Pressure in Genetic Hypertension: Role of Short-Chain Fatty Acids.

SCOPE: The objective of this study is to determine the cardiovascular effects of the probiotics Bifidobacterium breve CECT7263 (BFM) and Lactobacillus fermentum CECT5716 (LC40), and the short chain fatty acids butyrate, and acetate in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Ten five-week old Wistar Kyoto rats (WKY) and fifty aged-matched SHR are randomly distributed into six groups: control WKY, control SHR, treated SHR-LC40, treated SHR-BMF, treated SHR-butyrate, and treated SHR-acetate. Chronic treatments with LC40 or BFM increase butyrate-producing bacteria and prevent the blood pressure increase in SHR. Oral treatment with butyrate or acetate also prevents the increase in both blood pressure and Firmicutes/Bacteroidetes (F/B) ratio. All treatments restore the Th17/Treg balance in mesenteric lymph nodes, normalized endotoxemia, and prevent the impairment of endothelium-dependent relaxation to acetylcholine, as a result of reduced NADPH oxidase-driven reactive oxygen species production. These protective effects might be mediated by both the reduction in vascular lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) pathway and the increase in Treg infiltration in the vasculature. CONCLUSION: The probiotics LC40 and BFM prevent dysbiosis and the development of endothelial dysfunction and high blood pressure in genetic hypertension. These effects seem to be related to endotoxemia reduction and to increase Treg accumulation in the vasculature.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Effects of Arginase Inhibition in Hypertensive Hyperthyroid Rats.

BACKGROUND: This study analyzed the effects of chronic administration of N[omega]-hydroxy-nor-l-arginine (nor-NOHA), an inhibitor of arginase, on the hemodynamic, oxidative stress, morphologic, metabolic, and renal manifestations of hyperthyroidism in rats. METHODS: Four groups of male Wistar rats were used: control, nor-NOHA-treated (10 mg/kg/day), thyroxine (T4)-treated (75 µg/rat/day), and thyroxine- plus nor-NOHA-treated rats. All treatments were maintained for 4 weeks. Body weight, tail systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, morphologic, metabolic, plasma, and renal variables were measured. Arginase I and II protein abundance and arginase activity were measured in aorta, heart, and kidney. RESULTS: The T4 group showed increased arginase I and II protein abundance, arginase activity, SBP, HR, plasma nitrates/nitrites (NOx), brainstem and urinary isoprostanes, proteinuria and cardiac and renal hypertrophy in comparison to control rats. In hyperthyroid rats, chronic nor-NOHA prevented the increase in SBP and HR and decreased proteinuria in association with an increase in plasma NOx and a decrease in brainstem and urinary isoprostanes. In normal rats, nor-NOHA treatment did not significantly change any hemodynamic, morphologic, or renal variables. Acute nor-NOHA administration did not affect renal or systemic hemodynamic variables in normal or T4-treated rats. CONCLUSION: Hyperthyroidism in rats is associated with the increased expression and activity of arginase in aorta, heart, and kidney. Chronic arginase inhibition with nor-NOHA suppresses the characteristic hemodynamic manifestations of hyperthyroidism in association with a reduced oxidative stress. These results indicate an important role for arginase pathway alterations in the cardiovascular and renal abnormalities of hyperthyroidism.

Epicatechin: endothelial function and blood pressure.

Epidemiological studies indicate an inverse relationship between flavanol intake and the risk of cardiovascular disease. Potential mechanisms include their effects on endothelial function and hypertension. A number of studies have shown that flavanol-rich cocoa reduces blood pressure and endothelial dysfunction, whereas black tea may have opposite effects. These results highlight the importance of the different effects of the multitude of phytochemical constituents in these foods and the need for studying the individual flavanols. Epicatechin seems to be a major bioactive constituent of cocoa and other flavanol-rich foods and beverages. It has been shown to improve endothelial function in animals and humans. In salt-sensitive animal models of hypertension, epicatechin lowers blood pressure and the associated end-organ damage. Nitric oxide (NO) seems to play a key role in the protection of both hypertension and endothelial dysfunction.

Chronic (-)-epicatechin improves vascular oxidative and inflammatory status but not hypertension in chronic nitric oxide-deficient rats.

The present study analysed the effects of the flavanol (-)-epicatechin in rats after chronic inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME), at doses equivalent to those achieved in the studies involving human subjects. Wistar rats were randomly divided into four groups: (1) control-vehicle, (2) L-NAME, (3) L-NAME-epicatechin 2 (L-NAME-Epi 2) and (4) L-NAME-epicatechin 10 (L-NAME-Epi 10). Rats were daily given by oral administration for 4 weeks: vehicle, (-)-epicatechin 2 or 10 mg/kg. Animals in the L-NAME groups daily received L-NAME 75 mg/100 ml in drinking-water. The evolution in systolic blood pressure and heart rate, and morphological and plasma variables, proteinuria, vascular superoxide, reactivity and protein expression at the end of the experiment were analysed. Chronic (-)-epicatechin treatment did not modify the development of hypertension and only weakly affected the endothelial dysfunction induced by L-NAME but prevented the cardiac hypertrophy, the renal parenchyma and vascular lesions and proteinuria, and blunted the prostanoid-mediated enhanced endothelium-dependent vasoconstrictor responses and the cyclo-oxygenase-2 and endothelial NO synthase (eNOS) up-regulation. Furthermore, (-)-epicatechin also increased Akt and eNOS phosphorylation and prevented the L-NAME-induced increase in systemic (plasma malonyldialdehyde and urinary 8-iso-PGF2α) and vascular (dihydroethidium staining, NADPH oxidase activity and p22phox up-regulation) oxidative stress, proinflammatory status (intercellular adhesion molecule-1, IL-1ß and TNFα up-regulation) and extracellular-signal-regulated kinase 1/2 phosphorylation. The present study shows for the first time that chronic oral administration of (-)-epicatechin does not improve hypertension but reduced pro-atherogenic pathways such as oxidative stress and proinflammatory status of the vascular wall induced by blockade of NO production.

Glucuronidated metabolites of the flavonoid quercetin do not auto-oxidise, do not generate free radicals and do not decrease nitric oxide bioavailability.

Quercetin, the most abundant flavonoid in the diet, reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (as the aglycone) is usually not present in plasma, but it is rapidly metabolised during absorption by methylation, glucuronidation and sulfation. Depending on the experimental conditions, quercetin can show anti-oxidant or pro-oxidant effects. We have analysed the pro-oxidant effects of quercetin and its methylated (3-methylquercetin or isorhamnetin), sulfated (quercetin 3'-sulfate), glucuronidated (quercetin 3-glucuronide) and methylated plus glucuronidated (isorhamnetin 3-glucuronide) metabolites. Auto-oxidation, O(2)(-) release and NO scavenging were analysed by means of absorption spectra, lucigenin chemiluminescence or superoxide dismutase inhibitable cytochrome C reduction and an amperometric electrode, respectively. The biological activity of NO was tested in rat aortic rings. Quercetin, isorhamnetin and quercetin 3'-sulfate auto-oxidized in aqueous buffer and generated superoxide radical. Quercetin but not the glucuronide scavenged NO. In contrast, the glucuronides were without effect. Quercetin, but not quercetin 3-glucuronide, inhibited the biological activity of NO. These data indicate that, in contrast to quercetin, its main circulating forms, i. e., the glucuronides, do not exert pro-oxidant effects.

Genistein restores caveolin-1 and AT-1 receptor expression and vascular function in large vessels of ovariectomized hypertensive rats.

OBJECTIVE: The soy-derived phytoestrogen genistein improves endothelial function in postmenopausal women and ovariectomized (OVX) normotensive rats. We hypothesized that genistein would improve vascular reactivity involving changes in endothelial nitric oxide synthase (NOS) expression and its regulatory proteins (caveolin and calmodulin), angiotensin II receptor, and/or oxidative status in OVX spontaneously hypertensive rats (SHRs). DESIGN: After ovariectomy or sham operation, 23-week-old female SHRs received either 17beta-estradiol (2 mg/kg/wk SC), genistein (10 mg/kg/d by gavage), or placebo. RESULTS: In OVX rats, final body weight was increased and uterus weight was decreased, and these values were reduced and increased, respectively, by 17beta-estradiol but unaffected by genistein. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from OVX placebo SHRs. The contractions induced by the NOS inhibitor L-NAME and angiotensin II in OVX placebo were lower and higher, respectively, than in sham rats. Estradiol and genistein restored these functional changes. Aortic endothelial NOS and calmodulin-1 expression were unchanged, whereas caveolin-1 and angiotensin II receptor expression was increased in OVX rats. Estradiol and genistein treatment did not modify endothelial NOS, but normalized caveolin-1 and angiotensin II receptor and increased calmodulin-1 expression. Vascular superoxide production was increased in OVX placebo and normalized by both estradiol and genistein. CONCLUSIONS: Genistein prevented all cardiovascular changes induced by estrogen depletion in SHRs to a similar extent as estradiol but had no uterotrophic effect. The present findings may help to explain the potential benefits of genistein as a therapeutic agent for preventing menopausal vascular complications, especially in hypertensive women.

Tiroidectomía en régimen de cirugía mayor ambulatoria. Estudio prospectivo / Thyroidectomy in the ambulatory setting. A prospective study

Introducción. La reciente reintroducción de la anestesia locorregional para la tiroidectomía ha facilitado esta cirugía en régimen de cirugía mayor ambulatoria (CMA). El objeto de este estudio fue evaluar los resultados de este tratamiento comparando 2 regímenes anestésicos. Pacientes y métodos. Se seleccionó a 125 pacientes que precisaban tiroidectomía y cumplían requisitos de CMA. A los pacientes se les ofreció anestesia locorregional más sedación (ALS); si no aceptaron, se les propuso un método de anestesia locorregional combinada con intubación orotraqueal (ALC). Cincuenta y ocho pacientes aceptaron ALS y 67 ALC. Ambos grupos fueron comparables en edad, sexo, riesgo anestésico, índice de masa corporal y función tiroidea. Se evaluaron los vómitos postoperatorios, el dolor al alta, la necesidad de ingreso, la morbilidad postoperatoria y los problemas surgidos en el domicilio. Resultados. Se realizaron 61 tiroidectomías bilaterales y 64 unilaterales, sin diferencia entre grupos. Tampoco hubo diferencias respecto al tiempo quirúrgico, la conversión a anestesia general, las incidencias operatorias, el diagnóstico anatomopatológico, el tamaño y el peso de las piezas de exéresis. La única diferencia entre grupos fue la hora del alta (ALS: 6,5 ± 1,2 h; ALC: 7,76 ± 2,07 h, p = 0,0003). Aunque la tasa de ingreso fue superior en ALC (22,4%), no alcanzó diferencia estadísticamente significativa respecto a ALS (8,62%) (p = 0,06), cuya causa principal era la preferencia del paciente en el grupo ALC. No hubo diferencias respecto a vómitos (7,2%) o náuseas (6,4%), dolor (2,47 ± 1,85 en escala visual analógica), o necesidad de analgésicos. A las 36 h del alta se observó un hematoma asintomático no compresivo en el grupo ALS, que ingresó en observación y no requirió cirugía. Los problemas en domicilio fueron todos menores. El grado de satisfacción fue muy alto o alto en el 95% de los casos, sin diferencias entre grupos. Conclusiones. En casos seleccionados la tiroidectomía en régimen de CMA es segura y satisfactoria para los pacientes. Ambos regímenes anestésicos se mostraron válidos, pero la ALS mostró una recuperación más rápida que la ALC (AU)

Introduction. The recent reintroduction of local/regional anesthesia (LRA) for thyroidectomy has enabled this intervention to be performed in the outpatient setting. The aim of this study was to compare the results of thyroidectomy using two anesthesia methods. Patients and methods. One hundred twenty-five patients requiring thyroidectomy and who met the criteria for outpatient surgery were prospectively selected. The patients were offered LRA plus sedation; patients who did not accept this option were offered LRA combined with orotracheal intubation (CLRA). LRA was accepted by 58 patients and CLRA by 67. Age, sex, anesthesia risk, body mass index, and thyroid function were similar in both groups. Postoperative vomiting, pain at discharge, need for admission, postoperative morbidity, and complaints occurring at home were evaluated. Results. Sixty-one bilateral and 64 unilateral thyroidectomies were performed, with no statistically significant difference between the two groups. There were no differences in surgical time, conversion to general anesthesia, intraoperative events, pathological diagnosis, or size and weight of the surgical specimen. The only difference between the two groups was the hour of discharge (LRA: 6.5 ± 1.2 hours; CLRA: 7.76 ± 2.07 hours; p = 0.0003). The admission rate was higher in the CLRA group (22.4%) than in the LRA group (8.62%); this difference was not statistically significant (p = 0.06) and the main cause was personal preference in patients in the CLRA group. Rates of postoperative morbidity, vomiting (7.2%) and nausea (6.4%), postoperative pain (2.47 ± 1.85 on a visual analog scale), and analgesic requirements showed no differences between the two groups. One patient in the LRA group developed a noncompressive asymptomatic neck hematoma 36 hours after discharge. The patient was admitted for observation but did not require reoperation. Complaints occurring at home were minor. Satisfaction with the procedure was high or very high in 95% of the patients, with no differences between the two groups. Conclusions. In selected patients, outpatient thyroidectomy is safe and produces good patient satisfaction. Both anesthesia methods were valid, but postoperative recovery was faster with LRA than with CLRA (AU)

Effects of quercetin treatment on vascular function in deoxycorticosterone acetate-salt hypertensive rats. Comparative study with verapamil.

This study analysed and compared the effects of chronic oral treatment with quercetin or verapamil on systolic blood pressure and vascular function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Quercetin and verapamil inhibited the development of DOCA-salt-induced hypertension in a similar manner. DOCA-salt-hypertensive rats showed potassium depletion and oxidative stress, prevented only by concomitant quercetin administration. Quercetin and verapamil treatments reduced the endothelium-independent hyper-reactivity to KCl observed in the aorta of DOCA-salt-hypertensive rats, but only quercetin increased the contractile responses to angiotensin II, improved endothelial dysfunction and restored basal aortic Cu/Zn SOD expression, altered in DOCA-salt-treated rats. In conclusion, quercetin and verapamil show similar antihypertensive effects in mineralocorticoid hypertension, but quercetin was superior to verapamil in improving endothelial-dependent aortic dilatation, suggesting a better vascular protection in this volume expansion hypertension model.

Effects of chronic chrysin treatment in spontaneously hypertensive rats.

The effects of an oral daily dose (20 mg kg(-1)) of the flavonoid chrysin for 6 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. Chrysin reduces SHR elevated blood pressure, cardiac hypertrophy and functional vascular changes, but is without effect in WKY. These protective effects were associated with a reduced oxidative status due to the antioxidant properties of the drug.

Involvement of protein kinase C and Na+/K+-ATPase in the contractile response induced by myricetin in rat isolated aorta.

The role of PKC and Na+/K+-ATPase in the vascular smooth muscle responses induced by the bioflavonoid myricetin was investigated. KCl induced a concentration-dependent relaxation in arteries exposed to K+-free solution that was mainly mediated by an activation of Na+/K+-ATPase. Myricetin (50 microM) partially inhibited this vasorelaxant effect induced by KCl in intact rings, being unaffected in the endothelium-denuded rings. This inhibitory effect induced by myricetin was suppressed by the PGH2-TXA2 receptor antagonist, SQ 29,548, and the PKC inhibitor, staurosporine. Myricetin also induced an endothelium-dependent contractile response which was increased in the presence of PMA and reduced by staurosporine. In conclusion, myricetin both modulates Na+/K+-ATPase-induced vasodilatation acting as a functional inhibitor of Na+/K+-ATPase activity and activates protein kinases, including PKC, to induce contraction. These effects appear to be related to the activation of PGH2-TXA2 receptors on vascular smooth muscle by the TXA2 released from endothelium.NA:noradrenalineNA+/K+-ATPase pump:sodium-potassium-activated ATPasePKC:protein kinase CPMA:phorbol 12-myristate 13-acetateTXA2:thromboxane A2The role of PKC and Na+/K+-ATPase in the vascular smooth muscle responses induced by the bioflavonoid myricetin was investigated. KCl induced a concentration-dependent relaxation in arteries exposed to K+-free solution that was mainly mediated by an activation of Na+/K+-ATPase. Myricetin (50 microM) partially inhibited this vasorelaxant effect induced by KCl in intact rings, being unaffected in the endothelium-denuded rings. This inhibitory effect induced by myricetin was suppressed by the PGH2-TXA2 receptor antagonist, SQ 29,548, and the PKC inhibitor, staurosporine. Myricetin also induced an endothelium-dependent contractile response which was increased in the presence of PMA and reduced by staurosporine. In conclusion, myricetin both modulates Na+/K+-ATPase-induced vasodilatation acting as a functional inhibitor of Na+/K+-ATPase activity and activates protein kinases, including PKC, to induce contraction. These effects appear to be related to the activation of PGH2-TXA2 receptors on vascular smooth muscle by the TXA2 released from endothelium.