The Role of Aldosterone on Augmented Exercise Pressor Reflex in Hypertension

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.

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