Primary autonomic failure is characterized by disabling
orthostatic hypotension, but at least half of these patients have paradoxical supine
hypertension.
Renin-
angiotensin mechanisms were not initially thought to contribute to this
hypertension because plasma
renin activity is often undetectable in autonomic failure. Plasma
aldosterone levels are normal, however, and we recently showed that plasma
angiotensin II is elevated and acts at AT1 (
angiotensin type 1) receptors to contribute to
hypertension in these patients. Because
aldosterone and
angiotensin II can also bind
mineralocorticoid receptors to elevate blood pressure, we hypothesized that
mineralocorticoid receptor activation plays a role in the
hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the
mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine
hypertension completed this study (7
pure autonomic failure, 2
multiple system atrophy, 1
parkinson's disease; 7 male; 70±2 years of age).
Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on
nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL
eplerenone, P=0.492; nocturnal
weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg
eplerenone, P=0.766). These findings suggest that inappropriate
mineralocorticoid receptor activation contributes to the
hypertension of autonomic failure, likely independent of canonical
mineralocorticoid effects, and provides rationale for use of
eplerenone in these patients.