Treatment of Supine Hypertension in Autonomic Failure

Condition(s) targeted: Hypertension

Intervention: BQ123 (Drug); Trimethaphan (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 (Drug); L-arginine (Dietary Supplement)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Vanderbilt University

Official(s) and/or principal investigator(s):
Italo Biaggioni, MD, Principal Investigator, Affiliation: Vanderbilt University

Overall contact:
Bonnie Black, RN, Email: adcresearch@vanderbilt.edu

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.

Official title: Pathophysiology and Treatment of Supine Hypertension

Study design: Treatment, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Efficacy Study

Primary outcome: Decrease in supine systolic blood pressure

Secondary outcome: Decrease in pressure natriuresis

Detailed description: Overnight Medication Trials:

Patients will be studied at 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

antihypertensive medication bosentan (Tracleer) (62. 5 - 125 mg po, clonidine 0. 1-0. 2 mg po),

desmopressin 0. 2 - 0. 6 mg 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, nitroglycerin-transdermal 0. 05-0. 2 mg patch, nifedipine (adalat) doses 10-30 mg, sildenafil (Viagra) (25- 100 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 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.

Trimethaphan study (for research purpose only):

On a different day, to determine the level of residual sympathetic tone that contributes to supine hypertension in each patient, continuous infusion of trimethaphan will be used. Patients will be studied in the supine position. Heart rate will be determined with continuous ECG. Blood pressure will be monitored beat-to-beat by photoplethysmography but determined manually with a brachial cuff for subsequent analysis. After the subject is rested quietly for > 20 minutes, sympathetic and parasympathetic ganglia will be blocked by continuous infusion of the NN-cholinergic antagonist trimethaphan. The infusion will be initiated at 0. 5 or 1 mg/min and increased by 1. 0 mg/minute in 6-minute intervals to one of the following end points: presyncopal symptoms, no further decrease in blood pressure with increased infusion rates, or an infusion rate of 12 mg/min. Blood will be obtained before and after the infusion for catecholamine determinations. A total of 25 ml of blood is drawn during this study.

BQ123 study (for research purpose only):

On a different day, to determine the contribution of endothelin to supine hypertension in each patient, continuous infusion of BQ123, an endothelin antagonist, will be used. All patients will be studied in the supine position, in a fasting state. Overnight medication trials won't be scheduled the night before the administration of BQ123 to avoid any carry over effect. If the patient required any intervention to control his/her blood pressure non-pharmacologic measurements will be used. Heart rate will be determined with continuous ECG. Blood pressure will be monitored continuously by the finger volume clamp method (Finometer) and intermittently with an automated brachial blood pressure cuff (Dinamap). Forearm blood flow will be measured by venous occlusion plethysmography using a mercury-in-silastic gauge. Changes in cardiac output will be determined by impedance technique and by acetylene rebreathing technique.

BQ123: BQ123 (Clinalfa, Merck Biosciences AG, Weidenmattweg 4448 Läufelfingen molecular weight 632. 7) at doses ranging from 10-3000 nmol min-1 will be used as a selective endothelin receptor antagonist. An ascending dose regimen will be followed, allowing safety and tolerability of lower doses to be assessed before proceeding. Previous studies that

investigated the local effect of BQ123, suggested that 100 nmol min - 1 is the threshold

around which systemic effect might be observed (Haynes and Webb, 1994; Spratt et al., 2001). Because the hemodynamic effect of BQ123 has not been tested in patients with autonomic failure we will start with a dose 10-times less used in normal volunteers (10 nmol min-1). BQ123 will be dissolved in physiological saline and infused intravenously at rate of 1 ml min-1 for 15 minutes via an intravenous catheter placed in the Antecubital fossa.

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

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.

Bonnie Black, RN, Email: adcresearch@vanderbilt.edu

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
Bonnie Black, RN, Email: adcresearch@vanderbilt.edu
Italo Biaggioni, MD, Principal Investigator
David Robertson, MD, Sub-Investigator
Satish Raj, MD, Sub-Investigator
Alfredo Gamboa, MD, Sub-Investigator
Cyndya Shibao, MD, Sub-Investigator
Andre Diedrich, MD, Sub-Investigator
Luis E Okamoto, MD, Sub-Investigator

Autonomic Dysfunction Center Website

Starting date: June 2001
Ending date: April 2010
Last updated: August 8, 2008