Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic

The investigators will study male and female subjects, age 40-80 years with possible or
probable Multiple System Atrophy, as defined by Consensus Criteria who suffer from supine
hypertension defined as SBP≥150, and neurogenic orthostatic hypotension, defined as a
≥30-mmHg decrease in systolic BP within 3 minutes of standing associated with impaired
autonomic reflexes determined by autonomic testing in the absence of other identifiable
causes. All participants will be able and willing to provide informed consent.

Screening Procedures. Potential participants will be studied in the Vanderbilt Autonomic
Dysfunction Center (ADC). Medications affecting BP, blood volume and the autonomic nervous
system such as antihypertensives, pressor medications and fludrocortisone will be withdrawn
for at least 5 half-lives before studies. Screening procedures can be performed in one or
more days depending on the patient's and investigator's availability.

- Patients will undergo a complete history and physical examination, ECG, routine clinical
laboratory analysis and a blood pregnancy test for women with childbearing potential.

- Autonomic testing including sinus arrhythmia, Valsalva maneuver and a posture study with
plasma catecholamines is then performed to determine if they meet the
inclusion/exclusion criteria. During these tests, blood pressure (BP) and heart rate
(HR) will be obtained using an automated oscillometric sphygmomanometer, finger
photoplethysmography, and continuous ECG. During the orthostatic test, blood samples
will be obtained for hormones that regulate BP, such as catecholamines, while patients
are supine and upright.

Medical history information and results from any of the screening procedures obtained within
the previous 6 months for other studies within this research group may be utilized.

Study Procedures: Study Day 1 and 2

Eligible Multiple System Atrophy patients with supine hypertension will be studied twice in a
randomized, single blind, crossover design, once with trimethaphan and once with placebo. The
order of administration is randomized. The placebo day will have identical interventions, but
saline will be infused instead of trimethaphan to provide a time control. Studies will be
conducted in a postvoid state and ≥2 hours after meals. Each study day will last 2-3 hours.
The following procedures will be conducted:

Patients will be instrumented to measure blood pressure continuously with
photoplethysmography, and intermittently with an automated oscillometric device. Heart rate
will be monitored continuously with ECG. Electrodes will be placed on thorax and abdomen to
measure segmental impedance. Skin blood flow will be measured in the forearm with a laser
Doppler. Cardiac output will be measured by the inert gas rebreathing technique and/or by
impedance cardiography. An IV will be placed in one arm for drug administration.

After instrumentation baseline measurements will be recorded, including cardiac output and
splanchnic venous capacitance. Venous capacitance will be estimated using an adaptation of
the method of Schmitt et al. In this technique, segmental impedance is monitored, while
continuous positive airway pressure (CPAP) is applied sequentially at 0, 4, 8, 12 and 16 cm
water (H20) for 1-2 minute each.

Patients will then receive either placebo (time control) or trimethaphan, to induce complete
withdrawal of residual sympathetic tone. Intravenous infusion of trimethaphan camsylate
(Cambridge Labs) will be started at 0.5-1 mg/min and increased by 1.0 mg/min in 2-6 minute
intervals to one of the following endpoints: presyncopal symptoms, no further decrease in
blood pressure with increased infusion rates, or an infusion rate of 4 mg/min. Once a stable
decrease in blood pressure is obtained, outcome measurements will be repeated.

Abdominal compression will be applied to a sustained 40 mm Hg pressure while supine with an
inflatable binder. Outcome measurements will be repeated 5-15 minutes later. The investigator
may decide not to perform this procedure (due to a longer than anticipated study day duration
/ drug infusion). In this case, the study will include only the outcome measurements during
the drug infusion.

The infusion of trimethaphan is then stopped and patient monitored until blood pressure is
restored to baseline values.

Inclusion Criteria:

- Male and female subjects, age 40-80 years, with possible or probable Multiple System
Atrophy, as defined by Consensus Criteria.

- Neurogenic orthostatic hypotension defined as a ≥30-mmHg decrease in systolic blood
pressure within 3 minutes of standing associated with impaired autonomic reflexes
determined by autonomic testing in the absence of other identifiable causes.

- Supine hypertension, defined as systolic blood pressure ≥150 mmHg measured on two
separate occasions.

- Subjects able and willing to provide informed consent.

Exclusion Criteria:

- Pregnancy.

- Systemic illnesses known to produce autonomic neuropathy, including but not limited to
diabetes mellitus, amyloidosis, monoclonal gammopathies, and autoimmune neuropathies

- History of known aortic aneurysms, thoracic, abdominal or pelvic surgery in the past 6
months

- Symptomatic abdominal or inguinal hernias

- Severe gastroesophageal reflux

- Recent fractures or fissures of ribs, thoracic or lumbar spine

- Medical devices implanted on the abdominal wall or abdomen that would interfere with
the abdominal compression

- Intolerance to any increase in intra-abdominal pressure

- Clinically unstable coronary artery disease or major cardiovascular or neurological
event in the past 6 months, and other factors which in the investigator's opinion
would prevent the subject from completing the protocol including clinically
significant abnormalities in clinical, mental or laboratory testing.