- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01996449
The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Texas
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Dallas, Texas, United States, 75390
- UT Southwestern Medical Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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.
|
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 Names:
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 Names:
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 Names:
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
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.
Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip 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.
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.
|
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 Names:
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 Names:
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 Names:
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
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.
Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip 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.
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Muscle Sympathetic Nerve Activity at Rest
Time Frame: 8 weeks post treatment initiation
|
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)
|
8 weeks post treatment initiation
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Muscle Sympathetic Nerve Activity During Exercise
Time Frame: 8 weeks post treatment initiation
|
measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes) during arm cycling exercise
|
8 weeks post treatment initiation
|
Collaborators and Investigators
Publications and helpful links
General Publications
- Fagard R, Staessen J, Amery A. Maximal aerobic power in essential hypertension. J Hypertens. 1988 Nov;6(11):859-65. doi: 10.1097/00004872-198811000-00003.
- Olsen MH, Wachtell K, Hermann KL, Bella JN, Andersen UB, Dige-Petersen H, Rokkedal J, Ibsen H. Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. Am J Hypertens. 2001 Dec;14(12):1205-10. doi: 10.1016/s0895-7061(01)02223-3.
- Filipovsky J, Ducimetiere P, Safar ME. Prognostic significance of exercise blood pressure and heart rate in middle-aged men. Hypertension. 1992 Sep;20(3):333-9. doi: 10.1161/01.hyp.20.3.333.
- Cleroux J, Beaulieu M, Kouame N, Lacourciere Y. Comparative effects of quinapril, atenolol, and verapamil on blood pressure and forearm hemodynamics during handgrip exercise. Am J Hypertens. 1994 Jun;7(6):566-70. doi: 10.1093/ajh/7.6.566.
- Vongpatanasin W, Wang Z, Arbique D, Arbique G, Adams-Huet B, Mitchell JH, Victor RG, Thomas GD. Functional sympatholysis is impaired in hypertensive humans. J Physiol. 2011 Mar 1;589(Pt 5):1209-20. doi: 10.1113/jphysiol.2010.203026. Epub 2011 Jan 4.
- Grassi G, Spaziani D, Seravalle G, Bertinieri G, Dell'Oro R, Cuspidi C, Mancia G. Effects of amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Hypertension. 1999 Feb;33(2):671-5. doi: 10.1161/01.hyp.33.2.671.
- Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF Jr, Montori VM; Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008 Sep;93(9):3266-81. doi: 10.1210/jc.2008-0104. Epub 2008 Jun 13. Erratum In: J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2851.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Hypertension
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Natriuretic Agents
- Membrane Transport Modulators
- Diuretics
- Hormone Antagonists
- Calcium-Regulating Hormones and Agents
- Calcium Channel Blockers
- Mineralocorticoid Receptor Antagonists
- Diuretics, Potassium Sparing
- Amlodipine
- Eplerenone
Other Study ID Numbers
- R01HL113738 (U.S. NIH Grant/Contract)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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