Understanding the Exercise-Hypertension Paradox

Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. However, individuals with hypertension have impaired muscle blood flow and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to exercise intolerance and increased risk of stroke and heart attack. The cause of these impairments is not known, but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role. Two aims are proposed; Aim 1 will identify the physiological consequences of elevated oxidative stress in hypertension, and Aim 2 will utilize an antioxidant treatment to ameliorate the effects of an exaggerated EPR allowing the safe performance of a clinical exercise rehabilitation program which will then, itself, attenuate the EPR and reduce hypertension.

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.

Eligibility Criteria:
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.