The Role of Endothelin in the Supine Hypertension of Autonomic Failure

The pathophysiologic mechanisms causing supine hypertension in patients with autonomic
failure are not completely understood.In MSA patients, supine hypertension may be explained
by residual sympathetic tone, possibly acting on hypersensitive adrenoreceptors and
unstrained by the lack of baroreflex modulation. In contrast, the pathogenesis of
hypertension in PAF remains unknown. Hypertension in these patients is not related to
intravascular volume, residual sympathetic tone, or renin mechanisms. Increased vascular
resistance is the underlying hemodynamic mechanism. The driving force of this increased
vascular tone, however, is not known.

We hypothesize that endothelin (ET)-l contributes to the increased vascular resistance in
pure autonomic failure patients with supine hypertension. To gauge its contribution to blood
pressure regulation, we will induce endothelin blockade with acute systemic administration of
BQ123 in an ascending dose regimen (25, 50, 100 and 300 nmol/min) and we will compare the
hemodynamic effects between PAF and MSA patients.

Subjects will be studied on 3 different days, one with saline (placebo) and two with BQ123: a
'low dose' day (25 and 50 nmol/min infusions separated by 75 min) and a 'high dose' day (100
and 300 nmol/min infusions separated by 75 min). The order of the placebo day will be
randomized in a single-blinded manner so that each subject receives it on a different visit.
The order of the BQ123 study days will be always the same, starting with the low dose. If SBP
drops by >40 mm Hg or SBP < 130 mm Hg during the monitoring period after the first or second
infusion, the following dose(s) of BQ123 will not be given and patients will receive normal
saline until the study ends.

Ganglionic Blockade with Trimethaphan (optional study day):

The purpose of this study day is to determine the level of residual sympathetic tone that
contributes to supine hypertension in each autonomic failure patient by inducing transient
withdrawal of the autonomic nervous system. This approach would allow us to identify patients
in whom supine hypertension is not driven by sympathetic tone and thus, better characterize
the role of endothelin in the hypertension of these patients.

Inclusion Criteria:

- Patients with autonomic failure and supine hypertension from all races, who are in the
hospital participating in the study "The Evaluation and Treatment of Autonomic
Failure" (IRB# 000814).

- Supine hypertension, defined as a systolic blood pressure >150 mm Hg or diastolic
blood pressure > 90 mm Hg.

- Males and females, between 18-85yr.

- Provide written informed consent to participate in the study and understand that they
may withdraw their consent at any time without prejudice to their future medical care.

Exclusion Criteria:

- Pregnant women.

- High-risk patients (e.g. heart failure, symptomatic coronary artery disease, liver
impairment, history of stroke or myocardial infarction).

- History of serious allergies or asthma.

- In the investigator's opinion, have clinically significant abnormalities on clinical,
mental examination or laboratory testing.

- All medical students.