The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

Study ID
R01HL113738

Cancer Related
No

Healthy Volunteers
Yes

Study Sites

  • UT Southwestern-Other
  • UT Southwestern-Clinical Translational Research Center (CTRC)

Contact
Debbie Arbique
214/648-2968
debbie.arbique@utsouthwestern.edu

Principal Investigator
Wanpen Vongpatanasin

Official Title

The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

Brief Overview


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.

Summary


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.

Participant Eligibility


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