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Aldosterone Antagonist Decreases Blood Pressure and Improves Metabolic Parameters in Obese Patients With the Metabolic Syndrome

2010; Wiley; Volume: 12; Issue: 9 Linguagem: Inglês

10.1111/j.1751-7176.2010.00339.x

1751-7176

Mônica Barros Costa, Danielle Guedes Andrade Ezequiel, Julio Cesar Morais Lovis, Manoel Marques Evangelista Oliveira, Rogério Baumgratz de Paula,

Sodium Intake and Health

To the Editor: The association between obesity and hypertension is well established. Epidemiologic studies have reported that up to 75% of the risk for human essential hypertension is attributable to excess weight.1 Experimental and clinical studies have shown that excess weight raises blood pressure (BP) and that weight loss is the most effective nonpharmacologic strategy for lowering BP in obese hypertensive patients.2, 3 The mechanisms that link excessive weight gain and increased BP are poorly understood, however. Proposed mechanisms include impairment of renal-pressure natriuresis, sympathetic nervous system activation, functional and structural renal abnormalities, and activation of the renin-angiotensin-aldosterone system (RAAS).2, 4, 5 Studies in experimental animals and humans have shown that obesity activates most components of the RAAS.6, 7 It has been established that the treatment of obese patients with an angiotensin-converting enzyme inhibitor attenuates sodium retention and volume expansion as well as high BP. These findings support the hypothesis that angiotensin II plays a significant role in stimulating renal sodium reabsorption and thus contributes to obesity-induced hypertension.7 The involvement of aldosterone (ALDO) in sodium retention and hypertension in obesity has only recently been proposed. In a model of chronic dietary-induced obesity in dogs, ALDO blockade decreased glomerular hyperfiltration and sodium retention and attenuated hypertension, indicating that ALDO plays a role in the pathogenesis of obesity-induced hypertension.8 ALDO has also been implicated in the development of certain deleterious effects on the cardiovascular system. Some studies have demonstrated that ALDO induces endothelial lesions and cardiac and renal fibrosis,9 and that these effects can be attenuated by ALDO antagonism.10 Furthermore, ALDO blockade has been shown to be associated with improved BP control in patients with refractory hypertension, a disorder affecting a population that includes a high percentage of obese individuals.11 To the best of our knowledge, no previous study has been designed to specifically evaluate the BP response to ALDO blockade in obese and hypertensive patients with the metabolic syndrome (MetS). The primary goal of the present study was to determine whether ALDO blockade, achieved through the use of the antagonist spironolactone, attenuates hypertension in obese and hypertensive patients with MetS. The study group consisted of 11 hypertensive individuals, aged 20 to 65 years, who met the Third Report of the Adult Treatment Panel National Cholesterol Education Program (NCEP-ATP III) criteria for MetS. These patients were included in a double-blind observational study that consisted of 3 phases: phase 1, washout (2 weeks); phase 2, spironolactone 25 mg/d to 50 mg/d (8 weeks); and phase 3, placebo (8 weeks). The protocol was revised and approved by the human subjects review committee at the Federal University of Juiz de Fora under approval number 204/2008. All participants provided written informed consent prior to the initiation of any procedure. The study was conducted at the Division of Nephrology and Endocrinology of the Department of Internal Medicine at the Federal University of Juiz de Fora, Brazil. All patients had stage 1 hypertension and were evaluated once every 2 weeks. BP was measured in triplicate in a sitting position after a 10-minute period of rest. The average of the final two measurements was used for the statistical analysis. Endothelium-dependent vasodilatation of the brachial artery was assessed using ultrasound imaging and a 7-MHz linear probe. Imaging was performed by an echocardiographer who was blind to the phases of the study. The images were obtained from the fasting patients in the morning in a temperature-controlled room following a 10-minute period of rest, as described previously.12 Dilatation was quantified as the change from baseline to the peak diameter measured between 45 and 75 seconds after release of the BP cuff (averaged over 3 frames). The following parameters were measured before and after each phase of the study: fasting plasma glucose; total high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; triglycerides; creatinine; potassium; insulin; and ALDO and plasma renin activity. Creatinine clearance was estimated using the Cockcroft-Gault formula corrected for body surface area. All blood samples were collected following a 12-hour overnight period of fasting. Serum creatinine, plasma glucose, total cholesterol, HDL cholesterol, and triglycerides levels were measured using the colorimetric method. Insulin concentration was measured in duplicate using a quimioluminescence assay. LDL cholesterol was calculated using the Friedewald formula. Values were expressed as means and standard deviations. Analysis of variance was used for comparisons between the 3 phases of the study. The level of significance was set at P value ≤.05. All statistical analyses were performed using SPSS 13.0 for Windows (SPSS, Inc, Chicago, IL). Eleven individuals (women=9, men=2) aged 43±11.3 years (range 20–65 years) were eligible for inclusion in the study. Body mass index was 33±4.2 kg/m2 and abdominal circumference was 109±7.5 cm. Following ALDO blockade with spironolactone, a significant decrease in systolic and diastolic BP and creatinine clearance was observed, with no associated changes in glucose metabolism or lipid profile (Table). Brachial artery diameter was obtained in 6 patients, and this significantly increased from 0.343± 0.0406 cm in phase 1 to 0.394±0.0235 cm following treatment with spironolactone. In the present study, it was demonstrated for the first time that spironolactone promoted a significant reduction in BP in obese and hypertensive patients with MetS without changing plasma glucose or lipids levels. We could speculate that, in addition to its natriuretic effect, improvement of endothelial function and renal hemodynamics are potential mechanisms underlying the antihypertensive effect of ALDO blockade in this population. These results indicate a further potential target for the treatment of obese hypertensive patients. Our research findings should be examined within the context of some limitations. BP was not measured by ambulatory BP monitoring and brachial artery diameter could not be obtained in all patients. Finally, we have to acknowledge that our sample size was small and a large-scale prospective study is warranted to confirm our results. Acknowledgments and disclosure: This research was partially supported by CAPES, CNPq, and IMEPEN foundations. The authors would like to thank the research volunteers for their cooperation and compliance with the project.