The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01996449
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 93
• Patients Per Site Per Month: 0.2

Study Details

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	Phase 2

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

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Apr 1, 2021
• Actual Study Completion Date: Apr 1, 2021

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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. Muscle Sympathetic Nerve Activity at Rest [8 weeks post treatment initiation]

   measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)

Secondary Outcome Measures

1. Muscle Sympathetic Nerve Activity During Exercise [8 weeks post treatment initiation]

   measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes) during arm cycling exercise

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.
• 1. stage I hypertensive subjects with primary aldosteronism
• 1. normotensive controls.

Exclusion Criteria:

• 1. Any evidence of cardiopulmonary disease, left ventricular hypertrophy or systolic dysfunction by echocardiography.
• 1. Blood pressure averaging ≥160/100 mmHg
• 1. Estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2
• 1. Diabetes mellitus or other systemic illness
• 1. Pregnancy
• 1. Hypersensitivity to nitroprusside, phenylephrine, amlodipine or eplerenone
• 1. Any history of substance abuse or current cigarette use
• 1. Any history of psychiatric illness
• 1. History of malignancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Wanpen Vongpatanasin, MD, UT Southwestern Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 12, 2018
• Informed Consent Form - Jun 7, 2019

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Wanpen Vongpatanasin, Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01996449
• Other Study ID Numbers: R01HL113738
• First Posted: Nov 27, 2013
• Last Update Posted: Mar 18, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Wanpen Vongpatanasin, Professor, 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; Amlodipine; Eplerenone

Study Results

Participant Flow

Arm/Group Title	Amlodipine Then Eplerenone	Eplerenone Then Amlodipine
Arm/Group Description	The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 8 weeks. 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.	The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 8 weeks. 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.
Period Title: Period 1: First Drug
STARTED	6	8
COMPLETED	6	8
NOT COMPLETED	0	0
Period Title: Period 1: First Drug
STARTED	6	8
COMPLETED	6	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Amlodipine Then Eplerenone	Eplerenone Then Amlodipine	Total
Arm/Group Description	The subject will be started on Amlodipine 2.5-10 mg daily, which he or she will continue for a period of 8 weeks. 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.	The subject will be started on Eplerenone 50 - 200 mg daily, which he or she will continue for a period of 8 weeks. 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.	Total of all reporting groups
Overall Participants	6	8	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (9)	50 (8)	51 (9)
Sex: Female, Male (Count of Participants)
Female	0 0%	3 37.5%	3 21.4%
Male	6 100%	5 62.5%	11 78.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 16.7%	4 50%	5 35.7%
White	5 83.3%	4 50%	9 64.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	8 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Muscle Sympathetic Nerve Activity at Rest
Description	measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)
Time Frame	8 weeks post treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Eplerenone
Arm/Group Description	Analysis independent of sequence. Amlodipine dosage (2.5 -10mg once daily) was titrated every 2 weeks to target BP of < 140/90 mmHg	Analysis independent of sequence. Eplerenone dosage (50-200 mg once daily) was titrated every 2 weeks to target BP of < 140/90 mmHg.
Measure Participants	14	14
Mean (Standard Deviation) [bursts/minute]	41 (11.7)	43.8 (13)

2. Secondary Outcome

Title	Muscle Sympathetic Nerve Activity During Exercise
Description	measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes) during arm cycling exercise
Time Frame	8 weeks post treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine	Eplerenone
Arm/Group Description	analysis independent of sequence	analysis independent of sequence
Measure Participants	14	14
Mean (Standard Deviation) [bursts/minute]	47 (16)	51 (18)

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Amlodipine		Eplerenone
Arm/Group Description	Analysis independent of sequence. Amlodipine dosage (2.5 -10mg once daily) was titrated every 2 weeks to target BP of < 140/90 mmHg		Analysis independent of sequence. Eplerenone dosage (50 -200mg once daily) was titrated every 2 weeks to target BP of < 140/90 mmHg
All Cause Mortality
	Amlodipine		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Amlodipine		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Amlodipine		Eplerenone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.