The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

The University of Texas System (UT)

Status and phase: Completed; Phase 2

Conditions: Hypertension

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

Study type: Interventional

Funder types: Other

Identifiers

NCT01996449

R01HL113738

Details and patient eligibility

About

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.

Full 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.

Enrollment: 14 patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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14 participants in 2 patient groups

Initial treatment with Amlodipine

Active Comparator group

Description:

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.

Treatment:

Procedure: Arm cycling exercise

Procedure: Cold Pressor test

Procedure: Forearm blood flow

Drug: Eplerenone

Procedure: Microneurography

Drug: Amlodipine

Procedure: Sustained hand grip

Procedure: Rhythmic handgrip exercise

Initial treatment with Eplerenone

Active Comparator group

Description:

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.

Treatment:

Procedure: Arm cycling exercise

Procedure: Cold Pressor test

Procedure: Forearm blood flow

Drug: Eplerenone

Procedure: Microneurography

Drug: Amlodipine

Procedure: Sustained hand grip

Procedure: Rhythmic handgrip exercise