DESCRIPTION (provided by applicant): Hypertension affects nearly 1 in 3 of all adults in the U.S. and is well recognized as a major risk factor for a broad range of cardiovascular diseases such as stroke, congestive heart failure, renal disease, and congestive heart failure. Although the beneficial effects of daily exercise are well known, in patients with established hypertension abnormally large increases in sympathetic nerve activity, arterial pressure and heart rate often occur in response to exercise which precludes advisement of any strenuous physical activity due to the dangerous elevations in arterial pressure which increase the probability of sudden, adverse cardiovascular events such as myocardial infarction and stroke. The mechanisms mediating these abnormal cardiovascular responses to exercise in hypertension are virtually unknown. Many studies from a variety of laboratories using a number of species, including humans, have shown that activation of the metabolically sensitive afferents within the active skeletal muscle (termed the muscle metaboreflex) can elicit profound increases in sympathetic nerve activity. Impaired cardiac function in hypertension due to elevated afterload, cardiac hypertrophy, tonic coronary vasoconstriction and impaired ability to increase ventricular contractility may lead to lower skeletal muscle blood flow during dynamic exercise thereby causing excessive activation of the muscle metaboreflex. Furthermore, the mechanisms of the muscle metaboreflex are intimately dependent on the arterial baroreflex. Although, it is known that hypertension impairs baroreflex function at rest, whether exercise further alters baroreflex function in hypertension is unknown. This proposal is focused on determining the role of the muscle metaboreflex in mediating the altered cardiovascular response to dynamic exercise and the involvement of the arterial baroreflex in mediating these responses. Our laboratory is uniquely poised to address this issue. Over the last two decades we have developed a powerful and highly innovative and technically complex conscious, chronically instrumented canine model using "state of the art" instrumentation which permits the continuous beat-by-beat monitoring of wide variety of hemodynamic parameters and multiple indices of ventricular function in order to assess the strength and mechanisms of cardiovascular reflexes at rest and during dynamic exercise in normal animals and after induction of disease states. We have now expanded this model to the patho- physiological state of hypertension. Our approach is to study the same animal before and after the induction of hypertension thereby each animal serves as its own control. The significance of the project is underscored by the near total lack of information on the effects of hypertension on cardiovascular responses to exercise and these results may aid in the prescription of exercise regimes for hypertensive patients as well as increasing our understanding of the impact of hypertension on neural control of the circulation during one of the greatest challenges to cardiovascular control - whole body strenuous dynamic exercise. PUBLIC HEALTH RELEVANCE: Hypertension affects nearly 1 in 3 of all adults in the U.S. and is well recognized as a major risk factor for a broad range of cardiovascular diseases such as stroke, congestive heart failure, atherosclerosis, renal disease, and congestive heart failure. Although regular exercise is well known to have a multitude of beneficial effects, in patients with well established hypertension abnormally large increases in arterial pressure and heart rate in response to exercise often occur which may preclude advisement of any strenuous physical activity due to the dangerous elevations in arterial pressure which increase the probability of sudden, adverse cardiovascular events such as myocardial infarction and stroke. The mechanisms mediating these abnormal cardiovascular responses to exercise in hypertension are virtually unknown. This proposal is focused on increasing our understanding of the role of sensory nerves that respond to changes in metabolite concentration in the active muscles and those that sense changes in blood pressure in mediating the abnormal responses to exercise in hypertension.

Project Narrative Hypertension affects nearly 1 in 3 of all adults in the U.S. and is well recognized as a major risk factor for a broad range of cardiovascular diseases such as stroke, congestive heart failure, atherosclerosis, renal disease, and congestive heart failure. Although regular exercise is well know to have a multitude of beneficial effects, in patients with well established hypertension abnormally large increases in arterial pressure and heart rate in response to exercise often occur which may preclude advisement of any strenuous physical activity due to the dangerous elevations in arterial pressure which increase the probability of sudden, adverse cardiovascular events such as myocardial infarction and stroke. The mechanisms mediating these abnormal cardiovascular responses to exercise in hypertension are virtually unknown. This proposal is focused on increasing our understanding of the role of sensory nerves that respond to changes in metabolite concentration in the active muscles and those that sense changes in blood pressure in mediating the abnormal responses to exercise in hypertension.