Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients.
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.
Hypertension Section, Cardiology Division, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8586, USA.
Prafull
P
Raheja
Angela
A
Price
Zhongyun
Z
Wang
Debbie
D
Arbique
Beverley
B
Adams-Huet
Richard J
RJ
Auchus
Wanpen
W
Vongpatanasin
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002752:Chlorthalidone / Q000494:pharmacology*; D018592:Cross-Over Studies; D004232:Diuretics / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000145:classification / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology*; D000077405:Irbesartan; D008297:Male; D008839:Microelectrodes; D008875:Middle Aged; D013148:Spironolactone / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D004232:Diuretics; D013777:Tetrazoles; D013148:Spironolactone; D000077405:Irbesartan; D002752:Chlorthalidone