Mechanisms Mediating Enhanced Sympatho-Activation During Exercise in Hypertension

Wayne State University, Detroit MI

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Abstract

? 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, renal disease, and congestive heart failure. When hypertensive patients engage in strenuous exercise, sympathetic nerve activity can rise to dangerously high levels causing markedly exaggerated increases in arterial pressure and heart rate 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 unknown. Many studies 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 exercise thereby causing excessive activation of the muscle metaboreflex. Furthermore, the mechanisms of the muscle metaboreflex are intimately dependent on the arterial baroreflex. Although, there is evidence 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 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 systemic 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 expanded this model to the patho-physiological state of hypertension. We propose the first longitudinal study of the effects of hypertension on integrative mechanisms mediating neural control of cardiovascular function during exercise. Our approach is to study the same animal before and after the induction of hypertension thereby each animal serves as its own control. 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.