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J Clin Endocrinol Metab. 2009 Apr;94(4):1361-6. doi: 10.1210/jc.2008-2660. Epub 2009 Jan 21.

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

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Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8586, USA.



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.


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.


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.


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.


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.

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