Treatment of Supine Hypertension in Autonomic Failure

1. Overnight Medication Trials:

Patients will be studied on the GCRC while in 150 mEq/day sodium balance and on a diet
free of substances which interfere with catecholamine determination. Subjects will be
asked to use the bathroom to empty their bladder at 8:00 PM. They will be given a
randomly chosen medication aliskiren (Tekturna) 150-300mg po, bosentan (Tracleer) 62.5
-125 mg po, captopril 25-50mg po, carbidopa 25-200mg po, clonidine 0.1-0.2mg po,
desmopressin 0.2 - 0.6mg po (DDAVP), -diltiazem 30-60 mg po, dipyridamole 200 mg and
aspirin 25 mg po (Aggrenox), eplerenone (Inspra) 50-100 mg po, guanfacine (Tenex) 1-3 mg
po, hydralazine 10-50 mg po, hydrochlorothiazide 12.5-100 mg po, L- arginine 6-17 g po,
losartan 25-100mg po, metoprolol tartrate (Lopressor) 25-100 mg po, nebivolol
hydrochloride (Bystolic) 2.5-40 mg po, nitroglycerin-transdermal 0.05-0.2 mg patch,
nifedipine (adalat) doses 10-30 mg, prazosin hydrochloride 0.5-1 mg po, sildenafil
(Viagra) 25- 100 mg po, tamsulosin hydrochloride (Flomax) 0.4-0.8 mg po. The combination
desmopressin 0.2 mg po (DDAVP) and nitroglycerin-transdermal 0.05-0.2 mg. The
combinations desmopressin 0.2 mg po and nifedipine (10-30 mg). A placebo pill or skin
patch will be done as a control to measure their supine blood pressure without
medication intervention. They will then be asked to lie down with the head of the bed
elevated 10 degrees. An automated blood pressure cuff (Dinamap) will be wrapped around
an upper arm and blood pressure will be measured automatically 2 times in a row every 2
hours. At 8 AM the following morning the study ends. The subjects will then stand at the
bedside as motionless as possible for 30 minutes for blood pressure and heart rate
determination.

Urine will be collected for 24 hours for determination of volume and sodium, potassium
and catecholamines (for some medication trials) in 12 hour segments, from 8 a.m. to 8
p.m. and 8 p.m. to 8 a.m. to ascertain how the medications affect urine production.

For medication trials affecting renal Na and/or water regulation (e.g. desmopressin,
carbidopa), blood samples will be collected (5 mL, 1 teaspoon) at 8 PM and 8 AM for
determination of a basic metabolic panel.

Raising the head of the bed during the night is a non-pharmacologic measure that may
reduce supine blood pressure, nocturnal natriuresis and improve orthostatic hypotension
the following morning in autonomic failure patients with supine hypertension. However,
it is not known if tilting the bed with the head up is better than raising only the head
of the bed. To compare the effect of these two ways of raising the head of the bed on
nighttime blood pressure and nocturnal natriuresis, some patients will undergo two
additional tests. On two separate nights (either consecutive or not), patients will
receive the placebo and will be assigned by simple randomization to lie down in one of
two different bed positions:

1. The head of the bed elevated 10 degrees (~ 7 inches); or

2. The whole bed tilted head-up 5 degrees in reverse trendelenburg (head of the bed
elevated ~7 inches).

Blood pressure, orthostatic tolerance at 8 AM and urine collections will be performed as
described above.

2. Blood Pressure Lowering Effect of Local Heat Stress in Supine Hypertension:

Heat stress due to high environmental temperatures lowers blood pressure in autonomic
failure patients. The mechanisms underlying this phenomenon are not fully understood but
it could be associated with 2 factors: First, heart stress is more likely to increase
core temperature in this patient population because heat dissipation is impaired due to
inability to sweat. Second, autonomic failure patients lack the compensatory sympathetic
splanchnic vasoconstriction and tachycardia that normally maintain blood pressure in
response to heat stress in healthy subjects. We hypothesize, therefore, that even
moderate levels of local heat stress will lower blood pressure in patients with
autonomic failure and supine hypertension. We propose a pilot study to evaluate the
effect of local (abdominal) heat stress on blood pressure in autonomic failure patients,
something that has not been previously done, and to assess its potential use in the
treatment of supine hypertension

This pilot study is optional and will be conducted in patients already enrolled in the
"Evaluation and Treatment of Autonomic Failure" and the medication trial part of this
protocol. Subjects will be studied in the supine position on two study days (with and
without heat stress). Each study day will last ~3 hours. Core body and skin temperature
will be monitored throughout the study using an ingestible telemetry pill and dermal
patches. Blood pressure and heart rate will be measured intermittently with an automated
blood pressure sphygmomanometer wrapped around an upper arm. Segmental body fluid shifts
will be estimated using bioelectrical Impedance and hemodynamic parameters using body
impedance and the rebreathing test (Innocor). After obtaining normothermic baseline
measurements, we apply passive heat-stress with a commercial heating pad that covers all
the abdomen and part of the torso to provide local heating at ~44ºC continuously for 2
hr. Outcome measurements are obtained at 1 and 2 hours after passive heat-stress, or
when the CBT increases ~1ºC above baseline, whichever occurs first. For the control
(non-heating) study day, the heating pad will be applied on patients but we will not
turn it on, and data collection will be performed at the one-hour intervals for 2 hours,
to provide a time control.

3. Circadian Hemodynamic Changes in Autonomic Failure Patients with Supine Hypertension:

This study is optional and will be conducted in patients already enrolled in the "Evaluation
and Treatment of Autonomic Failure" and the medication trial part of this protocol. A
separate consent form (addendum) will be provided. In the present study, we propose the
following:

1. Monitor BP and HR in patients with AF and supine hypertension during a 24-hour period,
which includes fixed periods of supine rest during the day, with strict control of
physical activities, meals, water ingestion and other confounding factors. This will
allow us to learn more about the intrinsic circadian variation of BP in our patients
without the influence of "external factors".

2. Characterize the hemodynamic changes underlying the dipping phenomenon and the morning
BP surge, and

3. Assess changes in plasma volume (measured by changes in hematocrit), calculated plasma
osmolality and hormones that regulate blood pressure and blood volume, in order to learn
more about the mechanisms responsible for the dipping phenomenon and morning BP surge in
autonomic failure patients with supine hypertension.

These parameters will be compared with the circadian rhythm of body temperature, a marker of
the central circadian rhythm, to determine whether these diurnal changes are synchronized to
the circadian pacemaker.

The duration of the study day will be 24 hours and can start any time during the day.
Typically, the study will start ~ 8AM. Therapeutic trials for orthostatic hypotension and/or
supine hypertension as well as other study procedures related to the above mentioned
protocols may be performed while participating in this study. If an overnight medication
trial is performed during the study, patients may be offered to participate in a second study
day without any medication.

Inclusion Criteria:

- Patients with autonomic failure and with supine hypertension from all races

Exclusion Criteria:

- All medical students

- 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.