Abstract P644: Mineralocorticoid receptor activation may contribute to supine hypertension in patients with primary autonomic failure

Abstract

Primary autonomic failure is characterized by disabling orthostatic hypotension; but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin (Ang) mechanisms were not initially thought to contribute to this hypertension as autonomic failure patients often have undetectable plasma renin activity. Despite suppressed renin, plasma aldosterone levels are normal and we recently showed that plasma Ang II is elevated and acts at AT 1 receptors to contribute to supine hypertension in these patients. Since aldosterone and Ang II also bind mineralocorticoid receptors (MR) to elevate blood pressure, we tested the hypothesis that MR activation plays a role in the hypertension of autonomic failure. To test this, we determined the acute effects of the MR antagonist eplerenone (50 mg, PO) versus placebo on supine blood pressure in a randomized, double blind, crossover study. Medications were given at 8:00 PM and blood pressure was recorded q2 hours for 12 hours. Seven autonomic failure patients with supine hypertension completed this study (5 pure autonomic failure, 1 Parkinson’s, 1 multiple system atrophy; 5 male; 68±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 34±6 mmHg at 8 hours after administration (vs. 6±12 mmHg for placebo, p=0.047), with no effect on volume measures (12-hour urine volume: 927±205 placebo vs. 1247±151 ml eplerenone, p=0.438; nocturnal weight loss: -1.1±0.2 placebo vs. -1.2±0.2 kg eplerenone, p=0.813). These findings suggest that inappropriate MR activation may contribute to hypertension in autonomic failure, and provide rationale for use of eplerenone in treatment of these patients. While still under investigation, the lack of effect on volume measures combined with the rapid time course for blood pressure lowering following eplerenone may suggest extra-renal mechanisms are involved in MR antagonism in autonomic failure.