Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure
|Hypertension Pure Autonomic Failure Multiple System Atrophy||Drug: Losartan Drug: Captopril Drug: Placebo||Phase 1|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
|Official Title:||Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure|
- Changes in plasma renin activity and subsequent components of the circulating renin-angiotensin system [ Time Frame: 0 - 6 hours post administration ]Changes in supine plasma renin activity and aldosterone following drug administration
- Changes in blood pressure [ Time Frame: 0 - 6 hours post administration ]Changes in supine blood pressure following drug administration
- Changes in heart rate, cardiac output, stroke volume and systemic vascular resistance [ Time Frame: 0 - 6 hours post administration ]Changes in supine systemic hemodynamics following drug administration
|Actual Study Start Date:||March 2011|
|Study Completion Date:||March 2017|
|Primary Completion Date:||March 2017 (Final data collection date for primary outcome measure)|
Angiotensin II AT1 receptor antagonist which blocks the actions of angiotensin II
Oral, single-dose, 50 mg tablet
Other Name: Cozaar
ACE inhibitor which blocks the formation of angiotensin II
Oral, single-dose, 50 mg tablet
Other Name: Capoten
Placebo Comparator: Placebo Tablet
A placebo tablet will be provided by the Vanderbilt Investigational Drug Service for these studies.
Oral, single administration, gelatin capsule filled with microcrystalline cellulose
Primary autonomic failure is a disabling condition characterized by orthostatic hypotension. It is less well appreciated that at least 50% of these patients have high blood pressure when lying down [supine hypertension]. The mechanisms underlying supine hypertension in autonomic failure remain poorly understood. The hypertension in MSA patients may be explained by residual sympathetic tone, possibly acting on hypersensitive adrenoreceptors and unrestrained by the lack of baroreflex modulation. In contrast, the hypertension in PAF is associated with increased vascular resistance in the absence of residual sympathetic tone. However, the factors driving an elevation in either sympathetic or vascular tone in these patients remain unclear.
The investigators hypothesize that angiotensin II, a hormone widely implicated in blood pressure regulation, plays a role in the supine hypertension of autonomic failure. To determine the contribution of angiotensin II to renin and blood pressure regulation in autonomic failure, the investigators will administer the angiotensin II receptor blocker losartan to MSA and PAF patients with supine hypertension. The primary endpoint will be changes in plasma renin activity, and subsequent components of the circulating renin-angiotensin system, in response to angiotensin II blockade. The secondary outcomes will be the decrease in blood pressure and changes in heart rate, cardiac output, stroke volume and systemic vascular resistance during administration of these drugs.
Subjects will be studied on 2 separate days, one with oral administration of placebo and the other with losartan [50 mg]. The order of administration will be randomized in a single-blind manner. The investigators will collect blood samples before and every 2 hours after administration for up to 6 hours to determine if angiotensin II regulates plasma renin activity, and other components of the circulating renin-angiotensin system, in autonomic failure. The investigators will also obtain hemodynamic measurements before and every 1 hour (blood pressure and heart rate) or 2 hours (cardiac output, stroke volume and systemic vascular resistance) after drug administration.
In a subset of patients the investigators will also administer the ACE inhibitor captopril [50 mg] on a separate study day using the same methods. Captopril is less specific for assessing the role of angiotensin II to hypertension. However, it may provide important information on the mechanism for angiotensin II formation in these patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01292694
|United States, Tennessee|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Italo Biaggioni, MD||Vanderbilt University|