RESUMEN
In the last decade, clinical studies have investigated the clinical relevance of circulating cell-free-DNA (ccfDNA) as a diagnostic and prognosis tool in various diseases including cancers. However, limited knowledge on ccfDNA biology restrains its full development in the clinical practice. To improve our understanding, we evaluated the impact of the circadian rhythm on ccfDNA release in healthy subjects over a 24-h period. 10 healthy female subjects underwent blood sampling at 8am and 20 healthy male subjects underwent serial blood sampling (8:00 AM, 9:00 AM, 12:00 PM, 4:00 PM, 8:00 PM, 12:00 AM, 4 AM (+ 1 Day) and 8 AM (+ 1 Day)). We performed digital droplet-based PCR (ddPCR) assays to target 2 DNA fragments (69 & 243 bp) located in the KRAS gene to determine the ccfDNA concentration and fragmentation profile. As control, half of the samples were re-analyzed by capillary miniaturized electrophoresis (BIAbooster system). Overall, we did not detect any influence of the circadian rhythm on ccfDNA release. Instead, we observed a decrease in the ccfDNA concentration after meal ingestion, suggesting either a post-prandial effect or a technical detection bias due to a higher plasma load in lipids and triglycerides. We also noticed a potential effect of gender, weight and creatinine levels on ccfDNA concentration.
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Ácidos Nucleicos Libres de Células , Humanos , Masculino , Femenino , Voluntarios Sanos , Pronóstico , Reacción en Cadena de la Polimerasa , ADN , Ritmo CircadianoRESUMEN
BACKGROUND: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. METHODS: We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. RESULTS: Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-ß (transforming growth factor-ß) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. CONCLUSIONS: Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01113268.
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Infarto del Miocardio , Miocardio , Animales , Humanos , Ratones , Cicatriz/patología , Medios de Cultivo Condicionados/farmacología , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Factor 3 de Diferenciación de Crecimiento/metabolismo , Miocardio/metabolismo , Volumen Sistólico , Factor de Crecimiento Transformador beta/metabolismo , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
OBJECTIVES: One-anastomosis gastric bypass (OAGB) is as effective as Roux-en-Y gastric bypass (RYGB) regarding weight loss and diabetes remission. However, there are no data on gut hormone secretions after OAGB. The aim of this study was to compare fasting and postprandial secretions of gut and pancreatic hormones in OAGB versus RYGB patients. DESIGN AND METHODS: Twenty-nine patients, 16 OAGB- and 13 RYGB-operated, underwent a liquid mixed-meal tolerance test at 2 years' post-surgery. Blood was sampled before and 15, 30, 60, 90, and 120 min after meal for plasma measurement of glucose, C-peptide, insulin, glucagon, GLP-1, GIP, GLP-2, PYY, and ghrelin. RESULTS: Percentage of total weight loss 2 years post-surgery were -33.9 ± 1.8% for OAGB and -31.2 ± 1.6% for RYGB (p = 0.6). Four patients with persistent diabetes were excluded for further analysis. Fasting and postprandial glucose levels (peaks and area under curve values) were similar between groups. HOMA index was lower in the OAGB group (0.8 ± 0.1 vs 1.3 ± 0.2 in RYGB, p < 0.05). Levels of C-peptide (or insulin) measured at 30 min were significantly lower in OAGB vs RYGB patients (6.9 ± 0.5 vs 9.7 ± 1.1 µg/l, p < 0.05). No difference was observed between OAGB and RYGB groups for GLP-1, GLP-2, PYY, or ghrelin postprandial secretions, but GIP tended to be lower in OAGB vs RYGB patients (756 ± 155 vs 1100 ± 188 pg/ml for postprandial peak concentrations, p = 0.06). CONCLUSIONS: This is the first clinical study showing that OAGB procedure, like RYGB, results in high postprandial secretions of gut hormones, in particular GLP-1. TRIAL REGISTRATION: Clinical Trials NCT03482895.
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Derivación Gástrica , Obesidad Mórbida , Anastomosis en-Y de Roux/métodos , Glucemia/análisis , Péptido C , Derivación Gástrica/métodos , Ghrelina , Péptido 1 Similar al Glucagón , Glucosa , Humanos , Insulina , Obesidad Mórbida/cirugía , Proyectos Piloto , Pérdida de PesoRESUMEN
BACKGROUND: In rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy. METHODS: Twelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test. RESULTS: The potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin. CONCLUSION: The increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.
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Glándulas Suprarrenales/fisiología , Síndrome de Gitelman/fisiopatología , Potasio/metabolismo , Progesterona/sangre , Adolescente , Adulto , Anciano , Aldosterona/sangre , Animales , Estudios de Casos y Controles , Cromatografía Liquida/métodos , Femenino , Síndrome de Gitelman/sangre , Humanos , Masculino , Ratones , Persona de Mediana Edad , Renina/sangre , Esteroides/sangre , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test. RESULTS: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers. CONCLUSIONS: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.
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Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/genética , Heterocigoto , Resistencia a la Insulina/genética , Adolescente , Adulto , Anciano , Remodelación Ósea , Estudios Transversales , Diabetes Mellitus Tipo 2/prevención & control , Electrólitos , Femenino , Prueba de Tolerancia a la Glucosa , Hemodinámica , Humanos , Hipopotasemia/complicaciones , Insulina/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estado Prediabético/complicaciones , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Adulto JovenRESUMEN
OBJECTIVES: P-glycoprotein (P-gp), the product of the ABCB1 gene, is involved in the transport of aldosterone and cortisol in adrenal cells in vitro but its physiological role in humans remains controversial. Our objective was to test the influence of P-gp polymorphisms on aldosterone. METHODS: We evaluated plasma aldosterone concentration (PAC), urinary aldosterone, and blood pressure in a cohort of white normotensive men at baseline on diets unrestricted for sodium and potassium and after a 5-day treatment with 500âmg b.i.d. clarithromycin, a P-gp inhibitor. Included were 20 homozygous wild-type (P-gp0), 20 heterozygous (P-gp1), and 20 individuals with combined 2677G>T/A-3435C>T loss-of-function polymorphism of the ABCB1 gene (P-gp2). RESULTS: At baseline, PAC, urinary aldosterone, urinary free cortisol to urine creatinine ratios, and blood pressure did not differ in the three genotypes. After clarithromycin administration, the urinary aldosterone to creatinine ratio increased by an average of 30% in the entire cohort (Pâ<â0.001, nâ=â60). Increases were pronounced in P-gp1 (+40%; Pâ=â0.014) and P-gp2 individuals (+50%; Pâ=â0.020) but lesser and were NS in P-gp0 individuals (+10%; Pâ=â0.259). PAC also increased from baseline after clarithromycin treatment in all individuals (+19%, Pâ=â0.050); however, the increase in PAC was NS when the three genotypes were analyzed separately. CONCLUSION: In our experimental conditions, the interaction between P-gp inhibition and the ABCB1 genotype, suggests that aldosterone is indeed a physiological endogenous substrate of P-gp in humans and that P-gp interferes with the net equilibrium between aldosterone secretion and elimination processes in humans.Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01627665.
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Aldosterona/orina , Hidrocortisona/orina , Renina/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Adulto , Aldosterona/sangre , Claritromicina , Genotipo , Voluntarios Sanos , Heterocigoto , Homocigoto , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Potasio , Sodio , Adulto JovenRESUMEN
OBJECTIVES: The participation of vasopressin in the mechanisms of resistant hypertension is unclear. We compared plasma copeptin concentration, a surrogate marker for vasopressin secretion, between patients with resistant hypertension and those with controlled blood pressure (CBP), in a post hoc analysis of the Prise en charge de l'Hypertension Artérielle RESistante au traitement trial. METHODS: After 4-week treatment with irbesartan 300âmg/day, hydrochlorothiazide 12.5âmg/day, and amlodipine 5âmg/day (baseline), 166 patients were classified as having resistant hypertension (nâ=â140) or CBP (nâ=â26) by ambulatory BP monitoring. Patients with resistant hypertension were then randomized for 12 weeks of sequential nephron blockade (nâ=â74) or sequential renin-angiotensin system blockade (nâ=â66). Plasma copeptin concentration was measured at baseline and week 12 by immunoassay. RESULTS: Baseline plasma copeptin concentration was positively associated with male sex, plasma osmolality, BP, and negatively with glomerular filtration rate. It was higher in the resistant hypertension than in the CBP group [geometric mean 5.7 (confidence interval 95% 5.1-6.4) vs. 2.9 (2.3-3.9) fmol/ml, adjusted Pâ<â0.0001). The relationship between plasma copeptin concentration and urinary osmolality was similar in the two groups. At 12 weeks, plasma copeptin concentration in patients whose BP was controlled by sequential nephron blockade or sequential renin-angiotensin system blockade [6.8 (5.6-8.2) and 4.3 (3.0-5.9) fmol/ml, respectively) remained significantly higher than in patients with CBP at baseline (Pâ<â0.0001 vs. both). CONCLUSION: In patients with resistant hypertension, plasma copeptin concentrations were approximately two-fold higher than those of patients with CBP, after adjustment for plasma osmolality. This difference was not accounted for by renal resistance to vasopressin, suggesting a primary reset of osmostat.
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Presión Sanguínea , Vasoespasmo Coronario/sangre , Glicopéptidos/sangre , Hipertensión/sangre , Adulto , Anciano , Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Biomarcadores/sangre , Compuestos de Bifenilo/uso terapéutico , Vasoespasmo Coronario/tratamiento farmacológico , Diuréticos/uso terapéutico , Femenino , Tasa de Filtración Glomerular , Humanos , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Irbesartán , Masculino , Persona de Mediana Edad , Nefronas/fisiopatología , Concentración Osmolar , Sistema Renina-Angiotensina/efectos de los fármacos , Factores Sexuales , Tetrazoles/uso terapéutico , VasopresinasRESUMEN
BACKGROUND: We describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure. METHODS: This randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements. RESULTS: There were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3-82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9-106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects. CONCLUSIONS: Administration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.
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Hiponatremia/sangre , Hiponatremia/orina , Oligopéptidos/sangre , Oligopéptidos/orina , Perindopril/farmacología , Adolescente , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Sodio en la Dieta/administración & dosificación , Sodio en la Dieta/antagonistas & inhibidores , Adulto JovenRESUMEN
CONTEXT: The role of vasopressin (AVP) in the pathophysiology of primary aldosteronism (PA) remains unclear. OBJECTIVES: The primary aim of this study was to investigate AVP secretion in PA by measuring the plasma concentration of copeptin (PCop), the C-terminal portion of provasopressin. The secondary aim was to assess renal sensitivity to AVP. DESIGN AND SETTING: This was a cross-sectional study in a tertiary-care hospital. PROTOCOL: We recruited 115 patients with PA, 48 patients with essential hypertension (EH), and 108 normotensive healthy subjects (HS). Blood was sampled for biochemical and hormonal evaluations in fasting condition after 1-h rest in supine position. Osmolality was determined in 24-h urine. PCop was determined by immunoassay. MAIN OUTCOME MEASURE: The main outcome measure was adjusted difference in PCop between groups. RESULTS: After adjustment for sex, body mass index, systolic blood pressure, natremia, and kalemia, PCop was significantly higher in patients with PA than in HS (geometric mean ratio, 1.61; 95% confidence interval [CI], 1.26-2.06; P < .0001) and patients with EH (1.40; 95% CI, 1.08-1.82; P = .0070) PCop was positively correlated with natremia (P = .0094). Urine osmolality was significantly lower in patients with PA than in HS (0.82; 95% CI, 0.74-0.92; P = .0002) and 24-h urinary output was significantly higher in patients with PA than in HS (1.32; 95% CI, 1.11-1.56; P = .0005). The relationship between urine osmolality and PCop was shifted downward in patients with PA but was similar in patients with EH and HS, indicating peripheral resistance to AVP. CONCLUSION: PCop increases in patients with PA in response to an increase in natremia and a renal resistance phenomenon, indicating that AVP release is chronically stimulated in PA.
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Arginina Vasopresina/sangre , Glicopéptidos/sangre , Hiperaldosteronismo/sangre , Adulto , Anciano , Estudios Transversales , Hipertensión Esencial , Femenino , Humanos , Hipertensión/sangre , Masculino , Persona de Mediana Edad , Concentración OsmolarRESUMEN
Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.
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Amilorida/uso terapéutico , Síndrome de Gitelman/complicaciones , Hipopotasemia/tratamiento farmacológico , Hipopotasemia/etiología , Indometacina/uso terapéutico , Espironolactona/análogos & derivados , Adolescente , Adulto , Amilorida/efectos adversos , Amilorida/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Eplerenona , Femenino , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/fisiopatología , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Hipopotasemia/fisiopatología , Indometacina/efectos adversos , Indometacina/farmacología , Masculino , Persona de Mediana Edad , Potasio/sangre , Renina/sangre , Espironolactona/efectos adversos , Espironolactona/farmacología , Espironolactona/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Individuals with metabolic syndrome (MetS) are prone to develop heart failure (HF). However, the deleterious effects of MetS on the continuum of events leading to cardiac remodeling and subsequently to HF are not fully understood. This study characterized simultaneously MetS and cardiac, vascular and renal phenotypes in aging Spontaneously Hypertensive Heart Failure lean (SHHF(+/?) regrouping (+/+) and (+/cp) rats) and obese (SHHF(cp/cp), "cp" defective mutant allele of the leptin receptor gene) rats. We aimed to refine the milestones and their onset during the progression from MetS to HF in this experimental model. We found that SHHF(cp/cp )but not SHHF(+/?) rats developed dyslipidemia, as early as 1.5 months of age. This early alteration in the lipidic profile was detectable concomitantly to impaired renal function (polyuria, proteinuria but no glycosuria) and reduced carotid distensibility as compared to SHHF(+/?) rats. By 3 months of age SHHFcp/cp animals developed severe obesity associated with dislipidemia and hypertension defining the onset of MetS. From 6 months of age, SHHF(+/?) rats developed concentric left ventricular hypertrophy (LVH) while SHHF(cp/cp) rats developed eccentric LVH apparent from progressive dilation of the LV dimensions. By 14 months of age only SHHF(cp/cp) rats showed significantly higher central systolic blood pressure and a reduced ejection fraction resulting in systolic dysfunction as compared to SHHF(+/?). In summary, the metabolic and hemodynamic mechanisms participating in the faster decline of cardiac functions in SHHF(cp/cp) rats are established long before their physiological consequences are detectable. Our results suggest that the molecular mechanisms triggered within the first three months after birth of SHHF(cp/cp) rats should be targeted preferentially by therapeutic interventions in order to mitigate the later HF development.
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Modelos Animales de Enfermedad , Síndrome Metabólico/patología , Animales , Presión Sanguínea , Progresión de la Enfermedad , Ecocardiografía , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Hipertensión/fisiopatología , Resistencia a la Insulina , Riñón/patología , Masculino , Fenotipo , Ratas , SístoleRESUMEN
A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity.
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Aldosterona/sangre , Nefropatías Diabéticas/etnología , Hipertensión Renal/etnología , Receptores de Superficie Celular/sangre , Renina/sangre , ATPasas de Translocación de Protón Vacuolares/sangre , Adolescente , Adulto , Anciano , Población Negra/estadística & datos numéricos , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/etnología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etnología , Nefropatías Diabéticas/sangre , Femenino , Síndrome de Gitelman/sangre , Síndrome de Gitelman/etnología , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/etnología , Hipertensión Renal/sangre , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sistema Renina-Angiotensina/fisiología , Solubilidad , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Inhibition of brain aminopeptidase A (APA), which converts angiotensin II into angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin-angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans. DESIGN AND METHODS: Fifty-six healthy male volunteers were randomly assigned to receive in double-blind and fasted conditions single oral doses of 10, 50, 125, 250, 500, 750, 1,000 and 1,250 mg of QGC001 (n = 6/dose) or placebo (n = 2/dose). We measured plasma and urine concentrations of both QGC001 and EC33 by liquid chromatography-tandem mass spectrometry, plasma renin concentrations (PRC), plasma and free urine aldosterone (PAldo and UAldo), plasma copeptine (PCop), and plasma and urine cortisol (PCort and UCort) concentrations, and supine systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) at various time points. RESULTS: All doses of QGC001 were clinically and biologically well-tolerated. Peak plasma concentrations (Cmax) of QGC001 and EC33 increased linearly with the dose, with a median time to reach Cmax (tmax) of 1.5 h for QGC001 and 3.0 h for EC33. The median plasma elimination half-life of QGC001 was 1.6 h consistently throughout doses. Urinary excretion of QGC001 and EC33 was below 2% of the administered dose. When compared with placebo, QGC001 did not significantly change PRC, PAldo, UAldo, PCop, PCort or UCort. No significant change was observed for supine HR, SBP and DBP in any treatment group. CONCLUSION: Single oral administration of QGC001 up to 1,250 mg in healthy volunteers was well-tolerated. Following oral administration, QGC001 is absorbed via the gastrointestinal tract and converted partially into its active metabolite EC33 in plasma. As in animal experiments, in normotensive subjects QGC001 had no effect on the systemic renin-angiotensin-aldosterone parameters and on PCop concentrations, a marker of vasopressin release. In normotensive subjects, a single dose of QCG001 had no effect on SBP, DBP or HR. These data support further evaluation of multiple oral doses of QGC001 in human volunteers and its clinical efficacy in hypertensive patients.
Asunto(s)
Antihipertensivos/farmacología , Antihipertensivos/farmacocinética , Disulfuros/farmacología , Glutamil Aminopeptidasa/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/farmacocinética , Ácidos Sulfónicos/farmacología , Adolescente , Adulto , Antihipertensivos/administración & dosificación , Arginina Vasopresina/metabolismo , Disulfuros/administración & dosificación , Disulfuros/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Profármacos , Inhibidores de Proteasas/administración & dosificación , Sistema Renina-Angiotensina/efectos de los fármacos , Ácidos Sulfónicos/administración & dosificación , Ácidos Sulfónicos/farmacocinética , Adulto JovenRESUMEN
Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and region-specific changes in glutamatergic transmission, which likely lead to the reduced synaptic efficacy in the mPFC and DH and augmented activity in the amygdala and VH. In addition, these findings suggest that modifications of glutamate receptor phosphorylation could mediate the disruptive effects of stress on cognition. They also provide a means to reconcile the contrasting effects that stress has on synaptic plasticity in these regions. Taken together, the results provide support for a brain region-oriented approach to therapeutics.