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

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.

Trial registration: ClinicalTrials.gov NCT00353652.

Figures

Figure 1

Original recordings of SNA at baseline, after 12 weeks of chlorthalidone alone, after 12 weeks of chlorthalidone plus spironolactone, and after 12 weeks of chlorthalidone plus irbesartan in one hypertensive subject. In this subject, SNA increased from 40 to 55 bursts/min with chlorthalidone alone but returned to baseline (39 bursts/min) with combination of chlorthalidone plus spironolactone. In contrast, addition of irbesartan failed to alter SNA response to chlorthalidone (59 bursts/min) despite similar reduction in BP.

Figure 2

Summary data showing changes in SNA (top left) and SNA per 100 RR intervals (top right), baroreflex control of SNA (bottom left) and baroreflex control of HR (bottom right) in all subjects after 12 weeks of chlorthalidone (Chlor) alone (solid bars), chlorthalidone plus spironolactone (Spiro, hatched bars), and chlorthalidone plus irbesartan (gray bars) compared with baseline (white bars). Data are mean ± SE. * p

Figure 3

Summary data showing changes in fasting plasma glucose (left), HOMA-IR (middle), and serum potassium (K), after 12 weeks of chlorthalidone (Chlor) alone (solid bars), chlorthalidone plus spironolactone (Spiro, hatched bars), and chlorthalidone plus irbesartan (gray bars) compared with baseline (white bars). Data are mean ± SE. * p