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 I hypertension, measuring sympathetic nerve activity (SNA) at baseline, after 12 weeks of chlorthalidone alone (25 mg/day), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory BP (ABP) from 135±3/84±2 to 124±2/78±2 mm Hg and significantly increased SNA from baseline (from 41±3 vs 49±4 bursts/min, p < 0.01). Addition of spironolactone to chlorthalidone returned SNA value to baseline (42±3 bursts/min, p = NS) while addition of irbesartan failed to alter the SNA response to chlorthalidone in the same subjects (52±2 bursts/min, p < 0.01) despite similar reduction in ABP (121±2/75±2 and 121±2/75±2 mmHg, 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 BP reduction. Because sympathetic overactivity and insulin resistance contributes 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.

Mineralocorticoid Receptor Antagonists for the Treatment of Hypertension and the Metabolic Syndrome

“…angiotensin-converting enzyme inhibitor and the thiazide diuretic chlorthalidone have an increase in directly measured sympathetic nerve traffic and that the addition of an MRA but not a angiotensin receptor blocker significantly reduces sympathetic nerve traffic 13 would also support consideration of an MRA in patients with hypertension. At the moment, MRAs are not widely used early in the therapy of hypertension and are often considered fourth line drugs in the treatment of patients with resistant hypertension already treated with a thiazide diuretic, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocking agent at target or maximally tolerated doses.…”

Aldosterone and Blood Pressure Regulation

“…26 Furthermore, aldosterone antagonism has been shown to block the diuretic-induced increase in sympathetic activity, an effect that may underlie the synergistic antihypertensive actions of this drug combination. 27 In animal models, the central administration of aldosterone has been shown to sensitize forebrain nuclei involved in cardiovascular control to the hypertensive effects of angiotensin II. 28 In related studies, the same group demonstrated that the expression and function of both angiotensin II type I receptors and MR in the central nervous system were required for the development of hypertension in response to either aldosterone or angiotensin II.…”

Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade

“…Although both studies had the merit of administering doses applied generally in clinical practice, the conclusion, by Krum et al, 6 that "reversal of sympathetic activation in hypertension cannot be expected with renin-angiotensin antagonism" should be considered premature. In contrast, Raheja et al 4 considered the possibility that, in their study, central AT 1 receptors may not have been inhibited, and their results might have differed had a higher dose of irbesartan been given.…”

“…For example, with respect to irbesartan, the AT 1 receptor blocker selected by Raheja et al 4 in their study of hypertensive patients, we have shown previously in Dahl S rats consuming a high-salt diet that the degree of central but not peripheral AT 1 receptor blockade parallels the antihypertensive effects of its systemic administration. These findings indicate that inhibition of the brain renin-angiotensin system can contribute importantly to the therapeutic effectiveness Neither study showed a change in resting sympathetic tone, whether assessed by MSNA or whole body norepinephrine spillover.…”

“…With respect to hypertension, this question is addressed in the well-designed study by Raheja et al 4 reported in the present issue of Hypertension. These authors enrolled 17 stage I subjects into a randomized crossover comparison of the effect on ambulatory blood pressure and MSNA of 12 weeks of therapy with chlorthalidone (25 mg/d) alone, chlorthalidone plus spironolactone (25 mg/d), and chlorthalidone plus irbesartan (150 mg/d).…”