Hypertensive patients are known to display exaggerated rise in blood pressure (BP) during exercise but the underlying mechanisms are poorly understood. Normally, exercise is accompanied by decreased parasympathetic activity and increased sympathetic activity caused by central command and activation of thin fiber muscle afferents that reflexively increase sympathetic outflow and BP. Traditionally, muscle afferents were dichotomized as metaboreceptors, which are activated slowly and only during intense or ischemic muscle contraction, or mechanoreceptors, which respond quickly to even mild deformation of their receptive fields. The increase in SNA and BP caused by activation of these receptors, known as exercise pressor reflex, is normally buffered by activation arterial baroreceptors, which are reset to operate at higher BP range but at the same level of sensitivity. Our recent work in spontaneously hypertensive rats (SHR) and patients with essential hypertension indicated an exaggerated rise in sympathetic nerve activity (SNA) and BP during muscle contraction even in the absence of congestive heart failure. Furthermore, the latency of the sympathetic response during exercise is much shorter than normal and the threshold level of exercise intensity required to increase muscle SNA is much lower than normal, implicating mechanoreceptor mediation. Mechanisms responsible for overactive exercise pressor reflex (EPR) in hypertension remain unknown but an increasing body of evidence suggested a role for aldosterone in regulating resting central sympathetic outflow in both hypertensive rats and humans. Furthermore, local aldosterone synthesis in the brain has been shown to contribute to sympathetic activation and hypertension in the SHRs and Dahl-salt sensitive rats despite normal circulating levels of aldosterone. Whether aldosterone contributes to excessive sympathoexcitation and BP elevation during exercise remains unknown. Our pilot data in hypertensive rats and humans with normal and elevated serum aldosterone levels demonstrated a major role of aldosterone on exercise pressor reflex via mechanoreflex sensitization. Therefore, we now propose parallel translational studies in hypertensive rats and patients with primary hypertension and secondary form of hypertension caused by adrenal overproduction of aldosterone (primary aldosteronism), using multiple interventions to directly activate muscle mechanoreceptors, metaboreceptors, or arterial baroreceptors during exercise and microelectrode recordings of SNA to measure the reflex response. The distinctive features of this proposal include: (1) the use of state-of- the-art techniques (microelectrode recordings of SNA) to directly test mechanistic hypotheses in conscious humans; (2) assessment of mechanoreflex using a new paradigm which is developed in our laboratory which evokes sustained elevation in SNA and BP than other methods previously described in humans; and (3) the use of complimentary approach to asses central vs. peripheral effects of aldosterone on neural control of circulation during muscle contraction in the hypertensive rats.
Hypertensive patients often display an exaggerated rise in BP during exercise but the underlying mechanisms remain poorly understood. Because most antihypertensive drugs approved for clinical use are much less effective in reducing exercise BP than resting BP, complete understanding of pathogenesis of augmented pressor response to exercise in human hypertension is essential in improving their cardiovascular outcomes.
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