The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

NCT01996449 | Completed Phase 2 Results DMC

• 1 other identifier: R01HL113738
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension

Keywords

Hypertension; blood pressure; Aldosterone; Eplerenone; Amlodipine; Primary aldosteronism; Exercise pressor reflex; handgrip exercise; passive arm cycling; active arm cycling

Outcome Measures

Primary Outcomes (1)

• Muscle Sympathetic Nerve Activity at Rest

  measurement of sympathetic nerve activity by microneurography (intraneural microelectrodes)

  8 weeks post treatment initiation

Secondary Outcomes (1)

• Muscle Sympathetic Nerve Activity During Exercise

  8 weeks post treatment initiation

Study Arms (2)

Initial treatment with Amlodipine

ACTIVE COMPARATOR

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; Drug: Amlodipine; Procedure: Microneurography; Procedure: Rhythmic handgrip exercise; Procedure: Sustained hand grip; Procedure: Forearm blood flow; Procedure: Arm cycling exercise; Procedure: Cold Pressor test

Initial treatment with Eplerenone

ACTIVE COMPARATOR

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; Drug: Amlodipine; Procedure: Microneurography; Procedure: Rhythmic handgrip exercise; Procedure: Sustained hand grip; Procedure: Forearm blood flow; Procedure: Arm cycling exercise; Procedure: Cold Pressor test

Interventions

Eplerenone DRUG

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

Also known as: Inspra

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Amlodipine DRUG

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.

Also known as: Norvasc

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Microneurography PROCEDURE

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.

Also known as: Assessment of sympathetic nerve activity (SNA)

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Rhythmic handgrip exercise PROCEDURE

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

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Sustained hand grip PROCEDURE

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.

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Forearm blood flow PROCEDURE

Using high-resolution ultrasound, investigators will measure skeletal muscle blood flow in the forearm at rest, following sustained handgrip exercise

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Arm cycling exercise PROCEDURE

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.

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Cold Pressor test PROCEDURE

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.

Initial treatment with Amlodipine; Initial treatment with Eplerenone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Publications (7)

• 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.

  PMID: 3235835 BACKGROUND

• 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.

  PMID: 11775128 BACKGROUND

• 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.

  PMID: 1387630 BACKGROUND

• 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.

  PMID: 7917158 BACKGROUND

• 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.

  PMID: 21224235 BACKGROUND

• 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.

  PMID: 10024325 BACKGROUND

• 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.

  PMID: 18552288 BACKGROUND

MeSH Terms

Conditions

Hypertension; Hyperaldosteronism

Interventions

Eplerenone; Amlodipine

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Wanpen Vongpatanasin
• Organization: UT Southwestern Medical Center

Wanpen.Vongpatanasin@UTSouthwestern.edu

2146458000

Study Officials

• Wanpen Vongpatanasin, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 21, 2013
• First Posted: November 27, 2013
• Study Start: July 1, 2013
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: March 18, 2022
• Results First Posted: February 23, 2022

Record last verified: 2022-02

Locations

US (1)