Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure

Abstract

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Although the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable, suggesting renin-angiotensin (Ang) pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that Ang II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating Ang II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/mL, n=11) compared with matched healthy controls (27±4 pg/mL, n=10; P=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/mL per hour, respectively; P=0.449). To determine the contribution of Ang II to supine hypertension in these patients, we administered the AT(1) receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mm Hg at 6 hours after administration (P<0.05), decreased nocturnal urinary sodium excretion (P=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of captopril on supine blood pressure in a subset of these patients. These findings suggest that Ang II formation in autonomic failure is independent of plasma renin activity, and perhaps Ang-converting enzyme. Furthermore, these studies suggest that elevations in Ang II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT(1) receptor blockers for treatment of these patients.

Conflict of interest statement

Conflicts of Interest and Disclosures: I.B. is consultant to Chelsea Therapeutics, and receives financial support for an investigator-initiated study from Forest Laboratories through Vanderbilt University.

Figures

Figure 1. Paradoxic Elevations in Angiotensin II in Autonomic Failure

Despite similar renin activity, plasma angiotensin II was significantly higher in autonomic failure patients with supine hypertension relative to matched healthy subjects. ** p = 0.002 versus healthy; AF, autonomic failure; dashed line, detection limit for renin activity.

Figure 2. Effects of Losartan and Captopril on Blood Pressure in Autonomic Failure

Effect of single dose losartan (50 mg, PO; n=11) or captopril (50 mg, PO; n=7) administered at 8:00 PM on overnight systolic blood pressure (SBP) in autonomic failure patients with supine hypertension. Losartan produced significant decreases in SBP compared to placebo as summarized by (A) changes in SBP over time and (B) area under the curve (AUC) for SBP. There was no effect of captopril on overnight SBP in these patients (C, D).

Figure 3. Effect of Losartan on Nocturnal Volume Loss and Sodium Excretion

(A) There was no significant effect of losartan on changes in body weight, a measure of night-time volume loss, in hypertensive autonomic failure patients. (B) Losartan significantly reduced nocturnal urinary sodium (Na+) excretion in these patients. * p = 0.046.