The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

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ClinicalTrials.gov Identifier: NCT01996449

Recruitment Status : Recruiting

First Posted : November 27, 2013

Last Update Posted : March 19, 2021

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Sponsor:

Information provided by (Responsible Party):

Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

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 or disease	Intervention/treatment	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	Not Applicable

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	3 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Diagnostic
Official Title:	The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension
Study Start Date :	July 2013
Estimated Primary Completion Date :	December 2021
Estimated Study Completion Date :	December 2021

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Hypertension

MedlinePlus related topics: Exercise and Physical Fitness

Drug Information available for: Aldosterone Amlodipine Eplerenone Amlodipine besylate

U.S. FDA Resources

Arms and Interventions

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.	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.

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.

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

Other Name: Inspra

Drug: Amlodipine

Other Name: Norvasc

Procedure: Microneurography

Other Name: Assessment of sympathetic nerve activity (SNA)

Procedure: Rhythmic handgrip exercise

Procedure: Sustained hand grip

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

Procedure: Cold Pressor test

Outcome Measures

Primary Outcome Measures :

Muscle sympathetic nerve activity during exercise [ Time Frame: 8 weeks after initiation of spironolactone; ]
Muscle sympathetic nerve activity during exercise [ Time Frame: 8 weeks after initiating Amlodipine ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01996449

Contacts

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Contact: Debbie Arbique, DNP	(214)648-3188	debbie.arbique@utsouthwestern.edu
Contact: Poghni Peri-Okonny, MD	2146483180	poghni.peri-okonny@utsouthwestern.edu

Locations

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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

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Principal Investigator:	Wanpen Vongpatanasin, MD	UT Southwestern Medical Center

More Information

Publications:

Fagard R, Staessen J, Amery A. Maximal aerobic power in essential hypertension. J Hypertens. 1988 Nov;6(11):859-65.

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.

Filipovský J, Ducimetière P, Safar ME. Prognostic significance of exercise blood pressure and heart rate in middle-aged men. Hypertension. 1992 Sep;20(3):333-9.

Cléroux J, Beaulieu M, Kouamé N, Lacourcière 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.

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.

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.

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Responsible Party:	Wanpen Vongpatanasin, Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:	NCT01996449
Other Study ID Numbers:	R01HL113738 ( U.S. NIH Grant/Contract )
First Posted:	November 27, 2013 Key Record Dates
Last Update Posted:	March 19, 2021
Last Verified:	March 2021

Keywords provided by Wanpen Vongpatanasin, 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:

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Hypertension Vascular Diseases Cardiovascular Diseases Amlodipine Eplerenone Antihypertensive Agents Calcium Channel Blockers Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action	Calcium-Regulating Hormones and Agents Physiological Effects of Drugs Vasodilator Agents Mineralocorticoid Receptor Antagonists Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Diuretics, Potassium Sparing Diuretics Natriuretic Agents

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