RESUMEN
Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-ß, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17ß-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.
Asunto(s)
Estrógenos/sangre , Resistencia a la Insulina/fisiología , Obesidad/sangre , Obesidad/tratamiento farmacológico , Ovariectomía , Espironolactona/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Mediadores de Inflamación/sangre , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Ovariectomía/efectos adversos , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC)-induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9-10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway.
Asunto(s)
Inhibidores de la Adenosina Desaminasa/farmacología , Anticonceptivos Orales Combinados/efectos adversos , Hipertensión/tratamiento farmacológico , Ácido Valproico/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Adenosina Desaminasa/sangre , Adenosina Desaminasa/metabolismo , Inhibidores de la Adenosina Desaminasa/uso terapéutico , Aldosterona/sangre , Animales , Anticonceptivos Orales Combinados/administración & dosificación , Corticosterona/sangre , Modelos Animales de Enfermedad , Estrógenos/administración & dosificación , Estrógenos/efectos adversos , Femenino , Glucosa/metabolismo , Humanos , Hipertensión/sangre , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Progestinas/administración & dosificación , Progestinas/efectos adversos , Ratas , Ratas Wistar , Triglicéridos/metabolismo , Ácido Úrico/sangre , Ácido Valproico/uso terapéutico , Xantina Oxidasa/metabolismoRESUMEN
The presence of cardiometabolic syndrome (CMS) confers an increased risk for cardiovascular disease (CVD) and mortality and is associated with reduced health-related quality of life (HRQoL). Although the effects of exercise on biomarkers, HRQoL, and future risk have been studied, no study has measured the effects on all three components. The present study compared the effects of steady-state, moderate-intensity treadmill training (TM) and high-velocity circuit resistance training (HVCRT) on biological markers, HRQoL, and overall CVD risk in adults with CMS and CVD risk factors. Thirty participants (22 females, 8 males) were randomly assigned to 1 of 3 groups: HVCRT, TM, or control. Participants in the exercise groups attended training 3 days/week for a total of 12 weeks. Of the 30 participants who began the study, 24 (19 females, 5 males) were included in the final analysis. Primary outcome measures included CMS criteria, hemodynamic measures, Framingham Risk Score (FRS), and HRQoL. All variables were measured pre- and post-intervention. CMS z score significantly decreased for HVCRT (p = 0.03), while there were no significant changes for TM or control. FRS significantly decreased for HVCRT compared with TM (p = 0.03) and control (p = 0.03). Significant decreases in systolic (p < 0.01) and diastolic blood pressures (p < 0.01) for HVCRT accompanied significant increases from baseline in stroke volume (p = 0.03) and end-diastolic volume (p < 0.01). Systemic vascular resistance significantly decreased (p = 0.05) for HVCRT compared with control. Emotional well-being significantly improved following HVCRT and TM compared with control (p = 0.04; p = 0.03). HVCRT represents a novel training modality that improved factors in each of the 3 components assessed.
Asunto(s)
Envejecimiento , Hemodinámica , Síndrome Metabólico/prevención & control , Calidad de Vida , Entrenamiento de Fuerza/métodos , Caminata , Factores de Edad , Anciano , Envejecimiento/sangre , Envejecimiento/psicología , Biomarcadores/sangre , Presión Sanguínea , Emociones , Tolerancia al Ejercicio , Femenino , Florida , Humanos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/psicología , Persona de Mediana Edad , Volumen Sistólico , Factores de Tiempo , Resultado del Tratamiento , Resistencia VascularRESUMEN
Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen-progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol-levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-ß, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic ß-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats.
Asunto(s)
Estrógenos/deficiencia , Etinilestradiol/administración & dosificación , Etinilestradiol/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Resistencia a la Insulina , Levonorgestrel/administración & dosificación , Levonorgestrel/farmacología , Mineralocorticoides/sangre , Obesidad/tratamiento farmacológico , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Combinación de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Estradiol/metabolismo , Etinilestradiol/uso terapéutico , Ayuno/sangre , Femenino , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , Grasa Intraabdominal/citología , Grasa Intraabdominal/efectos de los fármacos , Levonorgestrel/uso terapéutico , Obesidad/metabolismo , Obesidad/patología , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
An open-label, randomized, exploratory study of 44 healthy overweight subjects with cardio-metabolic syndrome (CMS) risk factors was conducted to assess the safety, tolerability, and efficacy of a proprietary lifestyle modification program without (DIET) and with (PROG) targeted nutraceutical supplementation, including phytosterols, antioxidants, probiotics, fish oil, berberine, and soy, pea, and whey proteins over 13 weeks. Key metrics were recorded at baseline and weeks 9 and 13. For the DIET and PROG groups, compliance was 85% and 86%, respectively, with no adverse events related to the diet or supplements. Twelve subjects discontinued participation before week 9 for reasons unrelated to the study. PROG subjects experienced greater decreases (p < 0.05) than DIET in body mass, fat mass, total cholesterol, LDL cholesterol, TG, cholesterol / HDL ratio, TG/HDL ratio, apolipoprotein B / apolipoprotein A1 ratio, and hs-CRP. The Framingham 10-year cardiovascular disease risk score decreased by 40% (p < 0.01) in the PROG arm versus no change for the DIET arm. As a pilot study, it was not possible to state whether the observed effects were the result of nutraceutical supplementation alone or the result of additive or synergistic interactions among diet, lifestyle modifications, and nutraceutical supplementation. Moreover, individuals with CMS risk factors following a lifestyle modification program received additional health benefits from targeted nutraceutical supplementation.