Hypertension afflicts a great number of individuals and is a major cardiovascular risk factor. Dynamic exercise training decreases high blood pressure, but the mechanisms are incompletely understood. Neural mechanisms play a key role in regulating acute changes in arterial pressure, whereas renal mechanisms participate to a greater extent in volume regulation and long term control of pressure. Renal sympathetic nerves modulate sodium reabsorption and renin secretion. Thus, neural and renal mechanisms function in an integrated and concerted manner to regulate arterial pressure. Exercise training may exert its benefit by modulating this integrated system. We hypothesize that in 2 kidney-1 clip hypertension (2K-1C HTN), a rat model of hypertension with an activated renin-angiotensin-aldosterone system and increased sympathetic activity, voluntary dynamic exercise training will decrease efferent renal sympathetic nerve activity (RSNA) by enhancing nitric oxide-induced GABAergic inhibition within the paraventricular nucleus (PVN). In turn, the decrease in efferent RSNA will increase urinary Na excretion by decreasing the abundance and function of the epithelial Na channel (ENaC) in the distal nephron. We have 3 specific aims: (1) To assess whether voluntary wheel exercise will decrease systemic arterial pressure, decrease efferent sympathetic vasomotor tone, and increase arterial baroreflex sensitivity in 2K-1C HTN rats; (2) To ascertain whether voluntary wheel exercise will enhance nitric oxide signaling within the PVN, resulting in increased nitric oxide-induced GABAergic inhibition of efferent RSNA and improved baroreflex function in 2K-1C HTN rats; and (3) To determine whether the attenuated RSNA associated with voluntary wheel exercise will decrease the number of ENaC in the distal nephron of 2K-1C HTN, thereby increasing urinary Na excretion and enhancing the ability to respond to physiological stress such as acute Na loading. We will use a classic pharmacologic approach as well as in vivo transfer of dominant negative constructs for neuronal nitric oxide synthase (nNOS) into the PVN in sedentary and exercise trained sham-clipped and 2K-1C HTN rats and ascertain their hemodynamic parameters, RSNA and baroreflex function in the conscious, unrestrained state. We will measure the abundance of ENaC in microsomes of rat renal cortex and evaluate renal function and urinary Na excretion in sedentary and exercise trained rats with and without renal denervation under normal and acute Na loading conditions. These studies will provide data to direct strategic pharmacologic and nonpharmacologic interventions for cardiovascular health that may be readily translated into clinical practice.
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