Document Detail

Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients.
MedLine Citation:
PMID:  22733474     Owner:  NLM     Status:  MEDLINE    
Recent studies from our laboratory indicate that chlorthalidone triggers persistent activation of the sympathetic nervous system and promotes insulin resistance in hypertensive patients, independent of serum potassium. Mechanisms underlying these adverse effects of chlorthalidone remain unknown, but increasing evidence in rodents suggests the role of angiotensin and aldosterone excess in inducing both sympathetic overactivity and insulin resistance. Accordingly, we conducted studies in 17 subjects with untreated stage 1 hypertension, measuring sympathetic nerve activity at baseline and after 12 weeks of chlorthalidone alone (25 mg/d), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory blood pressure from 135±3/84±2 to 124±2/78±2 mm Hg and significantly increased sympathetic nerve activity from baseline (from 41±3 versus 49±4 bursts per minute; P<0.01). The addition of spironolactone to chlorthalidone returned sympathetic nerve activity value to baseline (42±3 bursts per minute; P>0.05), whereas the addition of irbesartan failed to alter the sympathetic nerve activity response to chlorthalidone in the same subjects (52±2 bursts per minute; P<0.01) despite a similar reduction in ambulatory blood pressure (121±2/75±2 and 121±2/75±2 mm Hg, respectively). Chlorthalidone alone also increased indices of insulin resistance, which was not observed when used in combination with spironolactone. In conclusion, our study demonstrates beneficial effects of spironolactone in attenuating both chlorthalidone-induced sympathetic activation and insulin resistance in humans, independent of blood pressure reduction. Because sympathetic overactivity and insulin resistance contribute to the poor prognosis in patients with cardiovascular disease, combination therapy of chlorthalidone with mineralocorticoid receptor antagonists may constitute a preferable regimen than chlorthalidone alone in hypertensive patients.
Prafull Raheja; Angela Price; Zhongyun Wang; Debbie Arbique; Beverley Adams-Huet; Richard J Auchus; Wanpen Vongpatanasin
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-25
Journal Detail:
Title:  Hypertension     Volume:  60     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-20     Completed Date:  2012-12-13     Revised Date:  2013-08-13    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  319-25     Citation Subset:  IM    
Hypertension Section, Cardiology Division, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8586, USA.
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MeSH Terms
Action Potentials / drug effects,  physiology
Angiotensin II Type 1 Receptor Blockers / pharmacology
Biphenyl Compounds / pharmacology
Chlorthalidone / pharmacology*
Cross-Over Studies
Diuretics / pharmacology
Drug Therapy, Combination
Heart Rate / drug effects,  physiology
Hypertension / classification,  physiopathology*
Insulin Resistance / physiology*
Middle Aged
Spironolactone / pharmacology*
Sympathetic Nervous System / drug effects*,  physiology*
Tetrazoles / pharmacology
Treatment Outcome
Grant Support
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Biphenyl Compounds; 0/Diuretics; 0/Tetrazoles; 138402-11-6/irbesartan; 52-01-7/Spironolactone; 77-36-1/Chlorthalidone
Comment In:
Hypertension. 2012 Dec;60(6):e42   [PMID:  23071128 ]
Hypertension. 2012 Aug;60(2):278-80   [PMID:  22733463 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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