Understanding the Exercise-Hypertension Paradox

Nearly 37% of all Veterans are clinically hypertensive, making hypertension the most common
medical condition in the VA Health Care System. Importantly, of the 67 million Americans
diagnosed with hypertension less than half are being effectively treated for their condition.
Hypertension constitutes a major risk factor for cardiovascular disease and when left
untreated leads to the development of heart failure, coronary heart disease, peripheral
artery disease, stroke, and renal disease. Exercise and regular physical activity are
considered the cornerstones of prevention and management of hypertension. However,
individuals with hypertension exhibit exercise intolerance characterized by impaired skeletal
muscle blood flow and heightened afferent fiber sensitivity leading to an exaggerated or
greater than normal physiologic increase in blood pressure during exercise (i.e. exercise
pressor reflex or EPR). This imbalance between the beneficial effects of exercise and
exercise intolerance creates an interesting paradox, the causes and consequences of which are
poorly understood. The etiology of hypertension is undoubtedly complex, however a common
denominator in this condition, elevated oxidative stress, may contribute to impaired muscle
blood flow and heightened skeletal muscle afferent feedback leading to the exaggerated EPR.
Previous work from the investigators' laboratory and others suggests that elevated oxidative
stress associated with aging impairs muscle blood flow. Additionally, free radicals, the
initiators of oxidative stress, can directly stimulate skeletal muscle afferent fibers
leading to the exaggerated EPR. Importantly, the role of oxidative stress in regulating
muscle blood flow and afferent fiber function in human hypertension has not been determined.
Preliminary studies support a significant role of oxidative stress in impairing muscle blood
flow and contributing to the exaggerated EPR in hypertension. With this information as
context two aims are proposed that will systematically identify the consequences of elevated
oxidative stress in hypertension. Specific Aim 1 will determine the consequences of oxidative
stress by examining how elevated free radicals contribute to heightened skeletal muscle
afferent feedback and impaired muscle blood flow during exercise in hypertension leading to
the exaggerated EPR. Additionally, vascular endothelial cells collected from an antecubital
vein will provide novel insight regarding the endothelium as potential source of elevated
oxidative stress in hypertension. Specific Aim 2 will determine the effectiveness of combined
antioxidant therapy and exercise rehabilitation in the treatment of hypertension. The overall
goal of this proposal is to provide novel information regarding the role of oxidative stress
as a critical regulator of cardiovascular and hemodynamic responses to exercise in
hypertension. By identifying potential causes and consequences of oxidative stress, important
insight will be gained facilitating the development of novel approaches and therapeutic
strategies for the treatment of hypertension. Importantly, the practical applications tested
in these studies (i.e. antioxidant treatment and combined exercise rehabilitation) are
designed to identify and document effective countermeasures to aid in the treatment and
management of hypertension allowing for the safe performance of exercise in a large number of
Veterans.

Inclusion Criteria:

- A total of 72 middle-aged (40 - 60 years of age) healthy and hypertensive men and
women will participate in these protocols after providing written informed consent.

- The investigators aim to include a 1 to 1 ratio of females and males in each group.

- Individuals diagnosed or presenting with stage 1 and stage 2 hypertension (range
140/90 to 179/109 mmHg, according to the seventh report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High BP) may be
eligible for this study.

- Blood pressure status will be assessed in triplicate in the laboratory during the
medical exam and during a 24 hour period using ambulatory blood pressure monitoring.

- Both methods must confer hypertension for study enrollment.

- Other than hypertension, all hypertensive patients will be otherwise healthy and free
of overt disease as assessed by:

- medical history;

- standard blood chemistries (chem. 7 panel),

- ECG at rest;

- limb vascular examination (ankle-brachial BP index > 0.9);

- resting BP > 140/90 mmHg; and

- skinfold % body fat assessment.

- Subjects will have a body mass index (BMI) between 19 and 30 and have plasma glucose
concentrations < 7.0 mmol/L under fasting conditions and < 11.1 mmol/L at 120 minutes
of an oral glucose tolerance test (OGTT), as defined by the American Diabetes
Association.

- To reduce heterogeneity of the hypertensive subjects while maintaining a "real world"
approach the following classes of drugs will be allowed;

- diuretics,

- angiotensin converting enzyme (ACE) inhibitors,

- and angiotensin II receptor blockers (ARB).

- Healthy normotensive subjects will be matched to their hypertensive counterparts and
will be free from overt cardiovascular disease according to the criteria described
above.

Inclusion/Exclusion criteria with specific reference to the exaggerated exercise pressor
reflex:

- Hypertensive subjects must exhibit a 10 mmHg or greater increase in MAP at 25% of
their workrate maximum during knee extension exercise to be included in this study.

- Established criteria defining a cut off for an "exaggerated" exercise pressor reflex
does not exist.

- Therefore, the investigators have set the operational definition at a 10 mmHg or
greater increase in MAP during 25% of workrate maximum knee extensor exercise.

- This 10 mmHg increase in MAP was chosen as this value closely matches the
investigators' preliminary data (Figure 1) and previous reports while concomitantly
corresponding to an increase in BP that is at least 2 standard deviations greater than
the normotensive response (i.e. 6 2 (SD) mmHg increase in MAP at 25% of their workrate
maximum).

- The magnitude of the exercise-induced increase in MAP will be determined during
preliminary testing.

- It should be noted that the magnitude of the pressor response is graded in relation to
exercise intensity, therefore, by establishing an inclusion criterion of 10 mmHg at
25% of workrate maximum, the lowest intensity to be used in the proposed studies, the
investigators have set a conservative standard for study enrollment.

Exclusion Criteria:

- Candidates demonstrating dyslipidemia based on the National Cholesterol Education
Program Guidelines of plasma total cholesterol > 240 mg/dl with LDL-cholesterol > 160
mg/dl will be excluded from participation.

- Hypertensive patients receiving dual or monotherapy treatment for hypertension may be
included.

- Less frequently prescribed classes of drugs for hypertension (beta blockers,
aldosterone receptor blocker, centrally acting sympatholytics, calcium channel
blocker, direct vasodilators, renin inhibitors, and alpha blockers) will be excluded.

- Additionally, subjects reporting a history of myocardial infarction, unstable cardiac
ischemia, recent cardiac catheterization, carotid artery disease, transient ischemic
attack will be excluded.

- Participants must have no orthopedic limitations that would prohibit them from
knee-extensor exercise or aerobic activity including cycle ergometry or treadmill
exercise.

- Due to the age requirement of the subjects women may be either pre or post-menopausal.

- All pre-menopausal women will be studied during days 1 - 7 of their menstrual cycle to
standardize the influence of female hormones.

- Women taking hormone replacement therapy (HRT) currently or in the preceding year will
be excluded from the proposed studies due to the direct vascular effects of HRT and
the variety of regimes employed.

- Participants will be made up of primarily Veterans.