The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by University of Texas Southwestern Medical Center
Sponsor:
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:
NCT01996449
First received: November 21, 2013
Last updated: November 26, 2013
Last verified: November 2013
  Purpose

Hypertensive patients often show an exaggerated rise in blood pressure during exercise through overactivity of the exercise pressor reflex. An increasing body of evidence suggests a role for aldosterone in augmenting the exercise pressor reflex in hypertensive humans. We hypothesize that this effect of aldosterone is mediated by its direct action on the central nervous system and that administration of mineralocorticoid receptor antagonists constitute an effective treatment for EPR overactivity in hypertension, independent of reductions in resting BP.


Condition Intervention Phase
Hypertension
Drug: Eplerenone
Drug: Amlodipine
Procedure: Microneurography
Procedure: Rhythmic handgrip exercise
Procedure: Sustained hand grip
Procedure: Forearm blood flow
Procedure: Arm cycling exercise
Procedure: Cold Pressor test
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Muscle sympathetic nerve activity during exercise [ Time Frame: 8 weeks after initiation of spironolactone ] [ Designated as safety issue: No ]
  • Muscle sympathetic nerve activity during exercise [ Time Frame: 8 weeks after initiating Amlodipine ] [ Designated as safety issue: No ]

Estimated Enrollment: 3
Study Start Date: July 2013
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Initial treatment with Amlodipine
The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Drug: Eplerenone
The subject will be started on Eplerenone (Inspra) 50-200mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued
Other Name: Inspra
Drug: Amlodipine
The subject will be started on Amlodipine (Norvasc) 2.5 -10mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Other Name: Norvasc
Procedure: Microneurography
Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.
Other Name: Assessment of sympathetic nerve activity (SNA)
Procedure: Rhythmic handgrip exercise
Subjects will perform a rhythmic handgrip exercise at 30% or 45% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise
Procedure: Sustained hand grip
Subjects will perform a sustained handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.
Procedure: Forearm blood flow
Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip exercise
Procedure: Arm cycling exercise
Subjects will perform a cycling arm exercise with a stationary cycling device. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this exercise.
Procedure: Cold Pressor test
Subjects will place hand in cold water with ice for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline, during and 2 minutes after the test.
Active Comparator: Initial treatment with Eplerenone
The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 12 weeks. Following the 12-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued. The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 8 weeks. Following the 8 week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Drug: Eplerenone
The subject will be started on Eplerenone (Inspra) 50-200mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued
Other Name: Inspra
Drug: Amlodipine
The subject will be started on Amlodipine (Norvasc) 2.5 -10mg daily, which he or she will continue for a period of 8 weeks. Following the 8-week treatment period, the procedures listed below will be performed. After completion of the study procedures, the medication will be discontinued.
Other Name: Norvasc
Procedure: Microneurography
Investigators will measure sympathetic nerve activity from the peroneal nerve by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. With this stimulation, subject will notice either involuntary twitching or a tingling sensation, which may be annoying but not painful. Investigators will then introduce a tiny, sterile wire needle (an electrode) through the skin at the same location. When the tip of the needle enters the nerve, subjects may again notice involuntary muscle twitches or tingling in the leg. Investigators will then turn the electrical stimulator off and make minor adjustments in the position of the needle until investigators begin to record the nerve signals. The recording needle will remain in position throughout the study.
Other Name: Assessment of sympathetic nerve activity (SNA)
Procedure: Rhythmic handgrip exercise
Subjects will perform a rhythmic handgrip exercise at 30% or 45% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise
Procedure: Sustained hand grip
Subjects will perform a sustained handgrip exercise at 30% of maximal voluntary contraction for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this handgrip exercise.
Procedure: Forearm blood flow
Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip exercise
Procedure: Arm cycling exercise
Subjects will perform a cycling arm exercise with a stationary cycling device. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline and following this exercise.
Procedure: Cold Pressor test
Subjects will place hand in cold water with ice for 3 minutes. Investigators will measure cardiac output (non-invasive impedance plethysmography), blood pressure, and sympathetic nerve activity (SNA) at baseline, during and 2 minutes after the test.

Detailed Description:

Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but the underlying mechanisms are poorly understood.

Traditionally, muscle afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of their receptive fields. The increase in sympathetic nerve activity and BP caused by activation of these receptors, known as exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to operate at higher BP range but at the same level of sensitivity. Mechanisms responsible for overactive exercise pressor reflex in hypertension remain unknown, but an increasing body of evidence suggested a role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and humans.

Experiments will be performed on 3 groups of subjects 1) stage I (140-159/90-99 mmHg) subjects with essential hypertension, 2) stage I hypertensive subjects with Primary Aldosteronism (PA), and 3) normotensive controls. All participants will attend a baseline study visit, which will include a physical examination, a medical history review, vital sign measurements, and blood and urine collection. Small electrodes will be used to measure muscle nerve activity while the subjects perform a series of exercises that include passive arm cycling, active arm cycling, rhythmic hand grip, sustained hand grip and cold pressor test. Muscle blood flow will be measured before and after hand grip exercises.

A subgroup of subjects with essential hypertension and PA will be assigned to receive Eplerenone or Amlodipine on a randomized, double-blinded design. Participants will attend two weeks visits over a period of 16 weeks. Study visits include measurement of vital signs and blood samples collection. After completing 8 weeks on each medication, muscle nerve activity will be measured while performing the same exercises described in the baseline study visit.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Experiments will be performed on 3 groups of nondiabetic human subjects:
  • 1) stage I (140-159/90-99 mmHg) subjects with essential hypertension.
  • 2) stage I hypertensive subjects with primary aldosteronism
  • 3) normotensive controls.

Exclusion Criteria:

  • 1) Any evidence of cardiopulmonary disease, left ventricular hypertrophy or systolic dysfunction by echocardiography.
  • 2) Blood pressure averaging ≥160/100 mmHg
  • 3) Estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2
  • 4) Diabetes mellitus or other systemic illness
  • 5) Pregnancy
  • 6) Hypersensitivity to nitroprusside, phenylephrine, amlodipine or eplerenone
  • 7) Any history of substance abuse or current cigarette use
  • 8) Any history of psychiatric illness
  • 9) History of malignancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01996449

Contacts
Contact: Debbie Arbique, DNP (214)648-3188 debbie.arbique@utsouthwestern.edu
Contact: Alejandro Velasco, MD 2146483180 alejandro.velasco@utsouthwestern.edu

Locations
United States, Texas
UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Debbie Arbique, DNP    214-648-3188    debbie.arbique@utsouthwestern.edu   
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: Wanpen Vongpatanasin, MD UT Southwestern Medical Center
  More Information

Publications:
Responsible Party: Wanpen Vongpatanasin, Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT01996449     History of Changes
Other Study ID Numbers: R01HL113738
Study First Received: November 21, 2013
Last Updated: November 26, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Texas Southwestern Medical Center:
Hypertension
blood pressure
Aldosterone
Eplerenone
Amlodipine
Primary aldosteronism
Exercise pressor reflex
handgrip exercise
passive arm cycling
active arm cycling

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Amlodipine
Eplerenone
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Vasodilator Agents
Antihypertensive Agents
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 22, 2014