Supine hypertension is a common problem that affects at least 50% of patients with primary autonomic failure. Supine hypertension can be severe, and complicates the treatment of orthostatic hypotension. Drugs used for the treatment of orthostatic hypotension (eg, fludrocortisone and pressor agents), worsen supine hypertension. High blood pressure may also cause target organ damage in this group of patients. The pathophysiologic mechanisms causing supine hypertension in patients with autonomic failure have not been defined.

In a study, we, the investigators at Vanderbilt University, examined 64 patients with AF, 29 with pure autonomic failure (PAF) and 35 with multiple system atrophy (MSA). 66% of patients had supine systolic (systolic blood pressure [SBP] > 150 mmHg) or diastolic (diastolic blood pressure [DBP] > 90 mmHg) hypertension (average blood pressure [BP]: 179 ± 5/89 ± 3 mmHg in 21 PAF and 175 ± 5/92 ± 3 mmHg in 21 MSA patients). Plasma norepinephrine (92 ± 15 pg/mL) and plasma renin activity (0.3 ± 0.05 ng/mL per hour) were very low in a subset of patients with AF and supine hypertension. (Shannon et al., 1997).

Our group has showed that a residual sympathetic function contributes to supine hypertension in patients with severe autonomic failure and that this effect is more prominent in patients with MSA than in those with PAF (Shannon et al., 2000). MSA patients had a marked depressor response to low infusion rates of trimethaphan, a ganglionic blocker; the response in PAF patients was more variable. At 1 mg/min, trimethaphan decreased supine SBP by 67 +/- 8 and 12 +/- 6 mmHg in MSA and PAF patients, respectively (P < 0.0001). MSA patients with supine hypertension also had greater SBP response to oral yohimbine, a central alpha2 receptor blocker, than PAF patients. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. This result suggests that residual sympathetic activity drives supine hypertension in MSA; in contrast, supine hypertension in PAF.

It is hoped that from this study will emerge a complete picture of the supine hypertension of autonomic failure. Understanding the mechanism of this paradoxical hypertension in the setting of profound loss of sympathetic function will improve our approach to the treatment of hypertension in autonomic failure, and it could also contribute to our understanding of hypertension in general.

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 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. 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 in order to learn more about the mechanisms responsible for BP reduction in supine hypertension.

The duration of this study 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.

• Drug: Clonidine
• Drug: Nitroglycerin transdermal
• Drug: Dipyridamole/ Aspirin (Aggrenox)
• Drug: Desmopressin (DDAVP)
• Drug: Sildenafil
• Drug: Nifedipine
• Drug: Hydralazine
• Drug: Hydrochlorothiazide
• Drug: Placebo
• Drug: Bosentan
• Drug: Diltiazem
• Drug: Eplerenone
• Drug: guanfacine
• Dietary Supplement: L-arginine
• Drug: captopril
• Drug: carbidopa
• Drug: losartan
• Drug: metoprolol tartrate
• Drug: nebivolol hydrochloride
• Drug: prazosin hydrochloride
• Drug: tamsulosin hydrochloride
• Other: Head-up tilt.

• Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic dysfunction. Curr Treat Options Cardiovasc Med. 2006 Apr;8(2):105-9.
• Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, Robertson D, Biaggioni I. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. 2006 Mar;47(3):522-6. Epub 2006 Jan 3.
• Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. 2005 Apr;45(4):469-76. Epub 2005 Feb 28.
• Diedrich A, Jordan J, Tank J, Shannon JR, Robertson R, Luft FC, Robertson D, Biaggioni I. The sympathetic nervous system in hypertension: assessment by blood pressure variability and ganglionic blockade. J Hypertens. 2003 Sep;21(9):1677-86. Erratum in: J Hypertens. 2003 Nov;21(11):2204-5.
• Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002 May;20(2):291-301, vii. Review.
• Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens (Greenwich). 2002 Mar-Apr;4(2):139-45.
• Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, Biaggioni I. Sympathetically mediated hypertension in autonomic failure. Circulation. 2000 Jun 13;101(23):2710-5.
• Jordan J, Shannon JR, Pohar B, Paranjape SY, Robertson D, Robertson RM, Biaggioni I. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999 Jan;10(1):35-42.
• Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997 Nov;30(5):1062-7.
• Okamoto LE, Gamboa A, Shibao C, Black BK, Diedrich A, Raj SR, Robertson D, Biaggioni I. Nocturnal blood pressure dipping in the hypertension of autonomic failure. Hypertension. 2009 Feb;53(2):363-9. Epub 2008 Dec 1.
• Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008 Jun;51(6):1531-6. Epub 2008 Apr 21.

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.