Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients

Prafull Raheja, Angela Price, Zhongyun Wang, Debbie Arbique, Beverley Adams-Huet, Richard J. Auchus, Wanpen Vongpatanasin

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)319-325
Number of pages7
JournalHypertension
Volume60
Issue number2
DOIs
StatePublished - Aug 2012

Fingerprint

Chlorthalidone
Spironolactone
Insulin Resistance
irbesartan
Blood Pressure
Mineralocorticoid Receptor Antagonists
Sympathetic Nervous System
Angiotensins
Aldosterone
Cross-Over Studies
Rodentia
Potassium
Cardiovascular Diseases

Keywords

  • diuretics
  • hypertension
  • insulin resistance
  • sympathetic nervous system

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. / Raheja, Prafull; Price, Angela; Wang, Zhongyun; Arbique, Debbie; Adams-Huet, Beverley; Auchus, Richard J.; Vongpatanasin, Wanpen.

In: Hypertension, Vol. 60, No. 2, 08.2012, p. 319-325.

Research output: Contribution to journalArticle

Raheja, Prafull ; Price, Angela ; Wang, Zhongyun ; Arbique, Debbie ; Adams-Huet, Beverley ; Auchus, Richard J. ; Vongpatanasin, Wanpen. / Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. In: Hypertension. 2012 ; Vol. 60, No. 2. pp. 319-325.
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