Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients.

CONTEXT Previous studies in rats indicated that thiazide-type diuretics reduced blood pressure (BP) and triggered baroreflex-mediated increase in sympathetic nerve activity (SNA), whereas spironolactone exerted central sympathoinhibitory action in addition to diuretic effects. OBJECTIVES The objectives were to determine effects of spironolactone and chlorthalidone on SNA and the role of SNA on diuretic-induced insulin resistance in human hypertension. METHODS We conducted a randomized crossover study in 23 untreated hypertensive patients in which we measured muscle SNA at baseline, after 1 and 3 months of chlorthalidone (12.5-25 mg/d), and after 1 and 3 months of spironolactone (50-75 mg/d). Ambulatory BP, baroreflex sensitivity, and indices of insulin resistance were also assessed at baseline and after 3 months of each drug treatment. RESULTS Chlorthalidone caused a similar reduction in ambulatory BP from baseline when compared with spironolactone (11 +/- 2/4 +/- 2 and 10 +/- 2/4 +/- 2 mm Hg, respectively). However, chlorthalidone increased SNA by 23% (P < 0.01) within 1 month of treatment, whereas spironolactone had no effect in the same subjects. SNA continued to be elevated after 3 months of chlorthalidone when compared with baseline and spironolactone. Baroreflex control of SNA was unaffected by either drug. Chlorthalidone increased indices of insulin resistance, which were significantly correlated with increases in SNA from baseline, whereas spironolactone had no effect in the same subjects. CONCLUSIONS Our data suggest that chlorthalidone, the first-line drug therapy for hypertension, causes persistent activation of sympathetic nervous system and insulin resistance in hypertensive patients. These side effects, however, are avoided by spironolactone despite similar reduction in BP.

[1]  A. Corbould,et al.  Effects of Spironolactone on Glucose Transport and Interleukin-6 Secretion in Adipose Cells of Women , 2007, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[2]  N. Chapman,et al.  Effect of Spironolactone on Blood Pressure in Subjects With Resistant Hypertension , 2007, Hypertension.

[3]  F. Turchi,et al.  Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study , 2007, Journal of hypertension.

[4]  L. Sechi,et al.  Insulin sensitivity in patients with primary aldosteronism: a follow-up study. , 2006, The Journal of clinical endocrinology and metabolism.

[5]  Y. Sharabi,et al.  Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension. , 2006, American journal of hypertension.

[6]  G. Bergus,et al.  Comparative Antihypertensive Effects of Hydrochlorothiazide and Chlorthalidone on Ambulatory and Office Blood Pressure , 2006, Hypertension.

[7]  D. Petitti,et al.  Prescribing patterns for antihypertensive drugs after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: report of experience in a health maintenance organization. , 2005, American journal of hypertension.

[8]  J. Levy,et al.  Use and abuse of HOMA modeling. , 2004, Diabetes care.

[9]  S. Dwivedi,et al.  Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. , 2004, The Journal of clinical endocrinology and metabolism.

[10]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[11]  J. Roos,et al.  Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension , 2004, European Journal of Clinical Pharmacology.

[12]  Jerome D. Cohen,et al.  Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. , 2004, Hypertension.

[13]  D. Calhoun,et al.  Efficacy of low-dose spironolactone in subjects with resistant hypertension. , 2003, American journal of hypertension.

[14]  M. Elam,et al.  Regulation and counterregulation of lipolysis in vivo: different roles of sympathetic activation and insulin. , 2003, The Journal of clinical endocrinology and metabolism.

[15]  G. Mancia,et al.  Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study , 2003, Journal of hypertension.

[16]  B. Davis,et al.  Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). , 2002, JAMA.

[17]  G. Mancia,et al.  Short- and Long-Term Neuroadrenergic Effects of Moderate Dietary Sodium Restriction in Essential Hypertension , 2002, Circulation.

[18]  J. Campión,et al.  Aldosterone impairs insulin responsiveness in U‐937 human promonocytic cells via the downregulation of its own receptor , 2002, Cell biochemistry and function.

[19]  A. Lincoff,et al.  The role of spironolactone in the treatment of patients with refractory hypertension. , 2001, American journal of hypertension.

[20]  R. Weiss,et al.  Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure. , 2001, American journal of physiology. Heart and circulatory physiology.

[21]  K. Rahmouni,et al.  Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats , 2001, Hypertension.

[22]  N. Abate,et al.  Overweight and Sympathetic Overactivity in Black Americans , 2001, Hypertension.

[23]  D A Follmann,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2000 by The Endocrine Society Quantitative Insulin Sensitivity Check Index: A Simple, Accurate Method for Assessing Insulin Sensitivity In Humans , 2022 .

[24]  R S Reneman,et al.  In spontaneously hypertensive rats alterations in aortic wall properties precede development of hypertension. , 2000, American journal of physiology. Heart and circulatory physiology.

[25]  J. Halliwill.  Segregated signal averaging of sympathetic baroreflex responses in humans. , 2000, Journal of applied physiology.

[26]  M. Laakso,et al.  Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[27]  G. Mancia,et al.  Sympathetic and reflex alterations in systo‐diastolic and systolic hypertension of the elderly , 2000, Journal of hypertension.

[28]  C. Sartori,et al.  Effects of sympathectomy and nitric oxide synthase inhibition on vascular actions of insulin in humans. , 1999, Hypertension.

[29]  L. Trueb,et al.  Sympathetic-nerve activity before and after resection of an insulinoma. , 1996, The New England journal of medicine.

[30]  G. Jennings,et al.  Adverse consequences of high sympathetic nervous activity in the failing human heart. , 1995, Journal of the American College of Cardiology.

[31]  S. Haffner,et al.  Glucose and insulin levels during diuretic therapy in hypertensive men. , 1994, Hypertension.

[32]  B. Trimarco,et al.  Acute noradrenergic activation induces insulin resistance in human skeletal muscle. , 1994, The American journal of physiology.

[33]  S. Julius,et al.  Reflex sympathetic activation induces acute insulin resistance in the human forearm. , 1993, Hypertension.

[34]  M. Brody,et al.  Central Nervous System and the Pathogenesis of Hypertension Sites and Mechanisms , 1991, Hypertension.

[35]  E A Anderson,et al.  Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. , 1991, The Journal of clinical investigation.

[36]  A. Mark,et al.  Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. , 1986, Circulation.

[37]  D. Andersen,et al.  Prevention of the Glucose Intolerance of Thiazide Diuretics by Maintenance of Body Potassium , 1983, Diabetes.

[38]  D. Andersen,et al.  Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. , 1983, Diabetes.

[39]  J. Rowe,et al.  Effect of experimental potassium deficiency on glucose and insulin metabolism. , 1980, Metabolism: clinical and experimental.

[40]  A. Vallbo,et al.  Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. , 1979, Physiological reviews.

[41]  Brody Mj,et al.  The effect of thiazide on the sympathetic nervous system of hypertensive rats. , 1969 .

[42]  M. Brody,et al.  The effect of thiazide on the sympathetic nervous system of hypertensive rats. , 1969, Archives internationales de pharmacodynamie et de therapie.