RESUMO
The prevalence of glucose abnormalities (GAs) and the diagnostic value of fasting plasma glucose and insulin in detecting impaired glucose tolerance (IGT) and diabetes mellitus (DM) were determined in urban Latin Americans. An oral glucose tolerance test was conducted in 592 subjects after administration of 75 g of glucose. Employing American Diabetes Association (ADA) and World Health Organization guidelines, GAs were found in 34% of the subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG + IGT (7.8%), and newly diagnosed type-2-DM (6.5%). All newly diagnosed diabetics had 2-hour glucose levels ≥200 mg/dL, but only 46.1% had fasting glucose ≥126 mg/dL. In addition, nearly half of the subjects with IGT (47%) had fasting glucose levels <100 mg/dL. The sensitivity, specificity, positive and negative predictive values of IFG in predicting IGT was 52.9%, 83%, 36.8%, and 90.4 %, respectively. Fasting insulin levels were not sensitive for differentiating glucose tolerant, from IFG and IGT; only the subjects with combined IFG + IGT had increased fasting insulin levels (22% above IFG) (P < 0.01). Two-hour insulin was increased by 30% in IGT and newly diagnosed diabetics, and by 46% in the subjects with combined IFG + IGT. In summary, the very high prevalence of undetected GA encountered in "healthy" subjects living in Caracas, Venezuela, requires immediate sanitary attention. With 50% of diabetic patients being unaware of their condition, half of IGT and DM not detected by ADA guidelines, and the poor sensitivity/specificity of fasting glucose in predicting 2-hour abnormalities, we recommend that 2-hour postload glucose be included when screening for GAs. Measurements of fasting and/or postload insulin are not cost effective for the diagnosis of GA, because they provide little additional clinical information in this context.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/diagnóstico , Insulina/análise , Guias de Prática Clínica como Assunto , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Jejum , Feminino , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/epidemiologia , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Sensibilidade e Especificidade , População Urbana , Venezuela/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The aim of this study was to evaluate, according to functional response, the neuroendocrine and inflammatory status in patients with chronic heart failure before and after therapy with carvedilol. METHODS AND RESULTS: Serum tumor necrosis factor-α (TNF-α) soluble receptors (sTNF-R1 and sTNF-R2), interleukin (IL)-10 and IL-18, chromogranin A (CgA) and brain natriuretic peptide (pro-BNP) were measured in 37 New York Heart Association class II to IV heart failure patients, at baseline and after 6 months of therapy with carvedilol. Patients were divided in two groups according to whether, following carvedilol, left-ventricular ejection fraction (LVEF) had increased by at least 5% (17 patients) or not (20 patients). Baseline LVEF was higher in nonresponders (38 ± 5 vs. 31 ± 7%, P = 0.002). In responders, LVEF increased from 31 ± 7 to 51 ± 7% (P < 0.0001), whereas in nonresponders it decreased from 38 ± 5 to 33 ± 7%, (P = 0.02). sTNF-R1 (P = 0.019) and sTNF-R2 (P = 0.025) increased in nonresponders, whereas they did not change in responders. After carvedilol, IL-10 was significantly higher in responders (P = 0.03). Conversely, no significant IL-18 and CgA changes were observed in either group. CgA was not significantly different between groups at baseline and after carvedilol in either group, whereas pro-BNP significantly increased in nonresponders (from 438 ± 582 to 1324 ± 1664 pg/ml, P = 0.04) and decreased in responders (from 848 ± 1221 to 420 ± 530 pg/ml, P = 0.08). CONCLUSION: Increased inflammatory activation observed only in heart failure patients not improving left-ventricular function after carvedilol may indicate that inflammation, either as a direct cause or as a consequence, is associated with progressive ventricular dysfunction.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carbazóis/uso terapêutico , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Inflamação/etiologia , Propanolaminas/uso terapêutico , Volume Sistólico/fisiologia , Antagonistas Adrenérgicos beta/efeitos adversos , Idoso , Carbazóis/efeitos adversos , Carvedilol , Estudos de Coortes , Citocinas/sangue , Citocinas/efeitos dos fármacos , Ecocardiografia , Feminino , Insuficiência Cardíaca Sistólica/sangue , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Inflamação/sangue , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/efeitos dos fármacos , Propanolaminas/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Volume Sistólico/efeitos dos fármacos , Resultado do TratamentoRESUMO
To investigate the role of substance P (sP), nitric oxide (ON) and prostaglandins (PGs) in acrolein (ACR)-induced cystitis, we studied the changes induced by ACR on bladder inducible nitric oxide synthase (iNOS) and mieloperoxidase (MPO) activities, along with PGs and NO metabolites levels. Sprague-Dawley male rats received i.p. ACR (5 mg/Kg) plus one of the following treatments: Group 1: saline 0.10 mL/100g i.p.; Group 2: Win-51.708 (WIN) 25 mg/Kg i.p.; Group 3: S-metilisothiourea (MITU) 35 mg/Kg i.p.; Group 4: Rofecoxib(ROF) 20 mg/Kg o.p.; Group 5: Meloxicam(MEL) 25 mg/Kg i.p.; Group 6: combination MITU+MEL. ACR-induced mortality was partially prevented by WIN (NK1 antagonist) and MITU (iNOS inhibitor). Animals that survived after 24h of ACR exposure, had histological inflammatory changes in bladder along with increased MPO activity. There was augmentation of nitrates+nitrites and of PGs. WIN didn't prevent any of these effects. ROF and MEL (COX-2 inhibitors) partially protected against bladder inflammation; MITU pre-treatment was able to prevent these changes and those of NO metabolites levels. The MITU+MEL combination produced the highest protection against ACR-induced damage. These results suggest that NO produced via iNOS and PGs produced by COX-1/COX-2, have an important role in the pathogenesis of cystitis induced by ACR. ACR could stimulate iNOS and COX-1/COX-2, producing lymphocyte migration and increases of NO and PGs.
Assuntos
Cistite/metabolismo , Óxido Nítrico/análise , Peroxidase/análise , Prostaglandinas/análise , Acroleína/toxicidade , Androstanos/uso terapêutico , Animais , Benzimidazóis/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Dinoprostona/urina , Avaliação Pré-Clínica de Medicamentos , Lactonas/uso terapêutico , Masculino , Meloxicam , Proteínas de Membrana/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sulfonas/uso terapêutico , Tiazinas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinária/química , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/enzimologiaRESUMO
Se estudió el papel de la sustancia P, el óxido nítrico(ON) y las prostaglandinas (PGs) en la cistitis inducida por acroleína(ACR), para lo cual se estudiaron los cambios de las actividades de la óxido nítrico sintasa inducible(iNOS) y de la mieloperoxidasa(MPO) vesicales, así como en los niveles de PGs y de metabolitos del ON. Ratas macho Sprague-Dawley recibieron ACR (5mg/Kg, i.p), más uno de los siguientes tratamientos: Grupo 1: Salina, 0,10mL/100g i.p.; Grupo 2: Win-51.708(WIN), 25mg/Kg i.p.; Grupo 3: S-metilisotiourea(MITU), 35 mg/Kg i.p.; Grupo 4: Rofecoxib(ROF), 20mg/Kg v.o.; Grupo 5: Meloxicam(MEL), 25mg/Kg i.p.; Grupo 6: combinación MITU+ MEL. La mortalidad inducida por ACR fue parcialmente prevenida por WIN (antagonista NK1) y MITU (inhibidor iNOS). En los animales que sobrevivieron a 24 horas de exposición a ACR se encontraron cambios histológicos inflamatorios en vejiga, que se acompañaron de aumentos en la actividad MPO. También se observaron aumentos de nitratos+nitritos y PGs. El WIN no previno ninguno de estos cambios. El ROF y el MEL (inhibidores COX-2) protegieron parcialmente contra la inflamación vesical, mientras que el tratamiento con MITU fue capaz de prevenir estos cambios así como también el aumento de metabolitos del ON. La combinación MITU+MEL produjo una mayor protección contra los efectos inducidos por ACR. Estos resultados indican que el ON producido vía de la iNOS y las PGs producidas por la COX-1/COX-2, desempeñan un papel en la patogénesis de la cistitis por ACR. La ACR podría estimular a la iNOS y a las COX-1/COX-2, induciendo la migración linfocitaria, aumentos de nitratos+nitritos y de PGs.
To investigate the role of substance P(sP), nitric oxide (ON) and prostaglandins (PGs) in acrolein(ACR)-induced cystitis, we studied the changes induced by ACR on bladder inducible nitric oxide synthase(iNOS) and mieloperoxidase(MPO) activities, along with PGs and NO metabolites levels. Sprague-Dawley male rats received i.p. ACR (5mg/Kg) plus one of the following treatments: Group 1: saline 0.10 mL/100g i.p.; Group 2: Win-51.708 (WIN) 25mg/Kg i.p.; Group 3: S-metilisothiourea(MITU) 35mg/Kg i.p.; Group 4: Rofecoxib(ROF) 20mg/Kg o.p.; Group 5: Meloxicam(MEL) 25mg/Kg i.p.; Group 6: combination MITU+MEL. ACR-induced mortality was partially prevented by WIN (NK1 antagonist) and MITU (iNOS inhibitor). Animals that survived after 24h of ACR exposure, had histological inflammatory changes in bladder along with increased MPO activity. There was augmentation of nitrates+nitrites and of PGs. WIN didnt prevent any of these effects. ROF and MEL (COX-2 inhibitors) partially protected against bladder inflammation; MITU pre-treatment was able to prevent these changes and those of NO metabolites levels. The MITU+MEL combination produced the highest protection against ACR-induced damage. These results suggest that NO produced via iNOS and PGs produced by COX-1/COX-2, have an important role in the pathogenesis of cystitis induced by ACR. ACR could stimulate iNOS and COX-1/COX-2, producing lymphocyte migration and increases of NO and PGs.
Assuntos
Animais , Ratos , Acroleína , Óxido Nítrico , Oxigenases , Peroxidase , Prostaglandinas , Bexiga UrináriaRESUMO
El óxido nítrico es una molécula neurotransmisora, mediadora de importantes funciones como la vasodilatación, estimulación de la síntesis de músculo liso vascular y antiagregación plaquetaria. El óxido nítrico es continuamente sintetizado y liberado desde el endotelio en condiciones fisiológicas. La inhibición crónica de la producción de óxido nítrico conduce a hipertensión arterial severa; por otra parte la hipertensión arterial se asocia con otros factores de riesgo, como lo es la sensibilidad a la sal. A pesar de que la hipertensión arterial inducida por sodio fue descrita hace medio siglo, aún se desconoce su etiología en humanos, y las implicaciones del óxido nítrico en su aparición. a) La ingesta elevada de sodio inhibe la producción del óxido nítrico; este efecto se revierte con la ingestión de sal. b) en sujetos obesos, la corrección de alteraciones metabólicas asociadas es capaz de corregir la sensibilidad a la sal y por lo tanto, de disminuir la hipertensión arterial en los individuos sal sensibles. También restablece la bioactividad normal del óxido nítrico. Estos hallazgos permiten afirmar que los factores de riesgo adquiridos juegan un papel importante en la patogénesis de la sensibilidad a la sal asociada a la obesidad, y que la corrección de la adiposidad abdominal mejora las anomalías metabólicas asociadas, reduce la reactividad de la presión arterial al sodio y mejora la producción de óxido nítrico.
Nitric oxide, as a neurotransmitter molecule, is a mediator of important functions including vasodilatation, synthesis of vascular smooth muscle and anti-aggregation of platelets. Under physiological conditions nitric oxide is synthesized and released from the endothelium. The chronic inhibition of nitric oxide production leads to severe hypertension; moreover hypertension is associated with other risk factors, such as salt sensitivity. Although hypertension induced by sodium was described half a century ago, its etiology remains unclear as well as the involvement of nitric oxide. A) high sodium intake inhibits the production of nitric oxide; this effect is reversed by reducing salt intake. B) in obese subjects, the reduction of central adiposity and the correction of related metabolic abnormalities can alter the salt sensitivy, and thereby decrease blood pressure in salt-sensitive individuals. It also restores the normal bioactivity of nitric oxide. These findings confirm the important role of risk factors in the pathogenesis of salt sensitivy associated with obesity, and that the correction of abdominal fat improves metabolic abnormalities, leading to the lowering of salt sensitivy and to an improvement in the production of nitric oxide.
Assuntos
Humanos , Fármacos Cardiovasculares , Endotélio/fisiologia , Hipertensão/fisiopatologia , Óxido Nítrico , Obesidade/fisiopatologia , Sódio/efeitos adversos , Fenômenos Fisiológicos Cardiovasculares , Fatores de RiscoRESUMO
Neuroendocrine/inflammatory and endothelial functions have been indicated as crucial for heart failure (HF) patients. We evaluated relation in HF patients among cytokines and asymmetric dimethylarginine (ADMA) and left ventricular ejection fraction (LVEF) at baseline and after long-term administration of carvedilol. Interleukin 10 (IL-10), interleukin 18 (IL-18), and ADMA were measured in 22 NYHA class II to IV HF patients at baseline and after 40 +/- 14 months of carvedilol treatment. Patients were divided into 2 groups according to whether, after treatment with carvedilol, LVEF had increased at least 5% (responders) or less than 5% (non-responders). In responders (11 of 22 patients), LVEF increased from 38 +/- 6% to 50 +/- 7%, (P < 0.001); in non-responders, it decreased from 36 +/- 9% to 31 +/- 6%, (P = 0.02); NYHA class significantly decreased in both groups. IL-18 decreased in responders (from 586.4 +/- 128 to 183.13 +/- 64.4 pg/mL; P < 0.001) and in non-responders (from 529.3 +/- 116.25 to 142.4 +/- 58.9 pg/mL; P < 0.001). IL-10 increased in responders (from 0.49 +/- 0.25 to 2.01 +/- 1.01 pg/mL; P < 0.001) and in non-responders (from 0.64 +/- 0.31 to 1.33 +/- 0.59 pg/mL; P < 0.001). Conversely, ADMA levels decreased only in responders (from 0.67 +/- 0.16 to 0.44 +/- 0.15 micromol/L; P < 0.001), and an inverse correlation was observed between basal ADMA levels and changes in LVEF after treatment. In HF patients, carvedilol appears to reduce symptoms and the expression of inflammation, regardless of the LV functional response. In those patients showing improvement of LVEF, the reduction of inflammation is paralleled by a reduction of ADMA. We surmise that carvedilol could be effective at various independent levels as a result of possible pleiotropic effects of this agent.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Arginina/análogos & derivados , Carbazóis/farmacologia , Citocinas/sangue , Insuficiência Cardíaca/sangue , Propanolaminas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Arginina/sangue , Carbazóis/uso terapêutico , Carvedilol , Esquema de Medicação , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Interleucina-10/sangue , Interleucina-18/sangue , Masculino , Propanolaminas/uso terapêutico , Estudos ProspectivosRESUMO
High blood pressure (BP) is extremely common in persons with obesity. However, not all obese individuals have high BP, nor does weight loss lower BP in all persons. In this study, the authors investigated whether the salt-sensitive (SS) or salt-resistant (SR) phenotype determines the degree of BP lowering induced by weight loss in a group of middle-aged individuals of whom 80% are of Hispanic descent. Overweight/obese participants classified as SS or SR (N=45; body mass index, 27-35 kg/m(2)) entered a 1-year program of dietary restriction, aerobic exercise, and metformin therapy. Comparable reductions in obesity (8%-10%), triglycerides (25%), and fasting insulin concentrations (40%) were observed in SR and SS individuals. In SS patients, the intervention lowered systolic BP/diastolic BP by 8.8/6.1 mm Hg, decreased albuminuria by 63%, and decreased the patient's salt sensitivity. Neither BP nor albuminuria was modified in SR persons by the intervention. In obese SS individuals, salt restriction induced comparable BP lowering as weight reduction. In summary, BP lowering induced by the lifestyle/metformin intervention appears to be determined by the SR/SS phenotype. Weight loss and correction of metabolic abnormalities lowers BP in obese SS persons but not in obese SR persons. Correcting adiposity in SS patients lowers BP by making the BP insensitive to dietary salt. The SR phenotype protects from obesity-induced increases in BP.
Assuntos
Pressão Sanguínea/fisiologia , Dieta Hipossódica , Hipertensão/prevenção & controle , Sobrepeso/dietoterapia , Redução de Peso , Adulto , Índice de Massa Corporal , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/fisiopatologia , Fenótipo , PrognósticoRESUMO
BACKGROUND: We investigated whether levels of albuminuria (urinary albumin excretion (UAE)) below those conventionally accepted as microalbuminuria (<30 mg/day) are sensitive to correction of obesity and obesity-related risk factors. METHODS: The effects of a 12-month lifestyle modification-metformin program were evaluated in otherwise healthy overweight/obese "normoalbuminuric" subjects: group I with UAE of <10 mg/day (n = 23) and group II with UAE of 10-29 mg/day (n = 18). RESULTS: The subjects of group II were older and heavier, and had higher blood pressure (BP) and lower high-density lipoprotein (HDL) levels, than those of group I. Creatinine clearances were also higher in group II (148 +/- 14 ml/min) than in group I (108 +/- 9 ml/min). Although the intervention induced comparable reductions in obesity, BP, lipids and insulin levels in both groups, UAE was significantly reduced in group II (9.1 +/- 1.8 mg/24 h; 60% reduction; P < 0.001), and non-significantly in group I (0.75 +/- 0.5 mg/day; 12% reduction; P > 0.1). Additionally, greater reduction in creatinine clearance was observed in subjects with higher UAE rates. After the intervention, both groups achieved similar UAE rates (5.7 +/- 0.9 and 5.2 +/- 1.0 mg/day; P > 0.10). Basal UAE was related to the subjects' creatinine clearance (r = 0.38; P = 0.04). For both groups together, intervention-induced changes in UAE rates were not significantly related to BP, age, or body weight. However, for group II subjects, BP and UAE reduction were positively associated (r = 0.44; P = 0.03). CONCLUSIONS: UAE of 10-29 mg/day (hyperalbuminuria), below the conventionally used limit to define microalbuminuria, is already associated with a more adverse cardiovascular risk profile, and is exquisitely sensitive to interventions that reduce obesity, BP, and insulin resistance.
Assuntos
Albuminúria/prevenção & controle , Restrição Calórica , Doenças Cardiovasculares/prevenção & controle , Exercício Físico , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Metformina/uso terapêutico , Obesidade/terapia , Adulto , Albuminúria/sangue , Albuminúria/classificação , Albuminúria/etiologia , Albuminúria/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Creatinina/sangue , Feminino , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Redução de PesoRESUMO
PURPOSE: The role of substance P, inducible nitric oxide synthase, and cyclooxygenase-1 and 2 on the pathogenesis of cyclophosphamide induced cystitis was investigated in rats. MATERIALS AND METHODS: Sprague-Dawley male rats received 1 of certain treatments, including 1) 0.9 weight per volume saline (0.10 ml/100 gm intraperitoneally), 2) cyclophosphamide (75 mg/kg intraperitoneally), 3) cyclophosphamide plus the NK(1) receptor antagonist Win-51.708 (20 mg/kg intraperitoneally), 4) cyclophosphamide plus the inducible nitric oxide synthase inhibitor S-methylthiourea (20 mg/kg intraperitoneally), 5) cyclophosphamide plus the highly selective cyclooxygenase-2 inhibitor rofecoxib (15 mg/kg intraperitoneally), 6) cyclophosphamide plus the selective cyclooxygenase-2 inhibitor meloxicam (15 mg/kg intraperitoneally), 7) cyclophosphamide plus the nonselective cyclooxygenase inhibitor ketoprofen (20 mg/kg intraperitoneally) or 8) cyclophosphamide plus methylthiourea plus meloxicam. Parameters were evaluated 6 hours after cyclophosphamide administration, including plasma protein extravasation, histological changes, myeloperoxidase and inducible nitric oxide synthase activities in the bladder, plasmatic nitric oxide metabolites and urinary nitric oxide metabolites, and prostaglandin E(2) levels. RESULTS: Cyclophosphamide produced inflammatory and cytotoxic changes in the bladder, accompanied by increased nitric oxide metabolites, urinary prostaglandins, myeloperoxidase and inducible nitric oxide synthase activity. Pretreatment with Win-51.708 and with methylthiourea prevented all of these effects except myeloperoxidase activity, which was only prevented by Win-51.708. All inducible cyclooxygenases were able to prevent prostaglandin synthesis and increases in myeloperoxidase activity. Combined inhibition of inducible nitric oxide synthase and cyclooxygenase-2/cyclooxygenase-1 (methylthiourea plus meloxicam) did not provide any additional protection against bladder damage, increased inducible nitric oxide synthase activity or prostaglandin E(2) synthesis. Additionally, this combination was unable to prevent increased myeloperoxidase activity. CONCLUSIONS: The results of this study suggest that there is crosstalk between nitric oxide and the cyclooxygenase enzyme with cyclooxygenase-1/cyclooxygenase-2 isoforms having an important role in this relationship. Augmented myeloperoxidase activity seems to be associated with NK(1) receptor activation and low levels of nitric oxide with cyclooxygenase-1 having an important role.
Assuntos
Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Ciclofosfamida/administração & dosagem , Cistite/induzido quimicamente , Cistite/enzimologia , Óxido Nítrico Sintase/fisiologia , Receptores da Neurocinina-1/fisiologia , Substância P/fisiologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Substância P/antagonistas & inibidoresRESUMO
BACKGROUND: Genetic and environmental factors determine the blood pressure (BP) response to changes in salt intake. Mutations in the alpha-adducin gene may be associated with hypertension and salt-sensitive hypertension. We investigated whether one alpha-adducin polymorphism, the Gly460Trp (G/T) variant, was associated with salt sensitivity, nitric oxide (NO) production; and cardiovascular risk factors in healthy adult normotensive Venezuelans. METHODS AND RESULTS: Subjects (n = 126) were screened for salt sensitivity. The alpha-Adducin polymorphism was tested in salt-sensitive (SS) and salt-resistant (SR) subjects. The G/T and G/G (wild gene) groups had similar BP levels. The G/T subjects had higher LDL-cholesterol (P =.01) and postload glucose AUC (P =.03) than G/G individuals. Genotype frequencies were not associated with BP or salt sensitivity (G/G, 38.1% SS and 61.9% SR vs G/T, 40.7% SS and 59.3% SR). Shifting from high salt to low salt diet produced comparable reductions in systolic BP and diastolic BP in G/T and G/G groups. The G/G and G/T groups excreted similar amounts of sodium on high and low salt diets. The SR subjects carrying the wild or the mutated gene showed no changes in NO metabolite excretion at different levels of salt intake. In SS subjects, the level of NO metabolite excretion was highly dependent on salt intake. A combination of SS and 460Trp mutation enhanced the sodium-dependent modulation of NO production. CONCLUSIONS: In normotensive Venezuelans, the alpha-adducin G/T polymorphism was not associated with BP, salt sensitivity, or with sodium excretion during sodium loading or restriction. G/T was associated with increased LDL-cholesterol and postload glucose levels. In SS, G/T was associated with greater salt-dependent modulation of NO excretion. However, this larger increase in NO excretion was not associated with a larger decrease in BP.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ligação a Calmodulina/genética , Doenças Cardiovasculares/etiologia , Hispânico ou Latino/genética , Óxido Nítrico/biossíntese , Cloreto de Sódio na Dieta/farmacologia , Adulto , Pressão Sanguínea/genética , Doenças Cardiovasculares/etnologia , Humanos , Óxido Nítrico/genética , Polimorfismo Genético , Fatores de Risco , VenezuelaRESUMO
Type 1 diabetes mellitus (IDDM) is associated with coronary artery disease and microvascular damage. Long-term glycemic control reduces but not fully prevents such complications. Recent evidence suggests that microvascular disease associated to IDDM begins with endothelial dysfunction. In this study, we evaluated changes in levels of nitric oxide (NO) and von Willebrand Factor (vWF) to detect early endothelial dysfunction in IDDM patients recently diagnosed. Subjects were included in one of the following groups: Group 1 (n=14): healthy subjects; Group 2 (n=14): IDDM patients recently diagnosed (<1 year), with no clinical evidence of microvascular disease; Group 3 (n=14): IDDM patients with microvascular disease (retinopathy and nephropathy). Urinary NO metabolites were similar in Group 1 (1.45+/-0.13) and Group 2 (1.6+/-0.2 micromol/mg creatinine) (P>.05), as well as vWF (99.6+/-5.7% and 84.3+/-5.1%, Groups 1 and 2, respectively, P>.05). Plasmatic NO metabolites were lower in Groups 2 and 3 (54.6+/-5.1 and 50.02+/-13.65 nmol/ml, respectively) compared with Group 1 (91.1+/-6.6 nmol/ml) (P=.0005). Also, in Group 3, urinary NO metabolites were lower (0.27+/-0.03 micromol/mg creatinine) and vWF was higher (184+/-25%) than Groups 1 and 2. There is evidence of early endothelial dysfunction even in IDDM patients recently diagnosed, with good glycemic control and without systemic hypertension, dyslipidemia or microvascular disease; this endothelial damage was detected as a decrease in plasmatic NO metabolite levels, before appearance of any clinical evidence of microvascular disease.