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juxtaglomerular baroreceptor-mediated suppression of renin secretion. With high
renal perfusion pressure and concomitant Ang II-mediated postglomerular vasocon-
striction, GFR and filtration fraction would increase, and, despite high proximal
tubular reabsorption, the net amount of sodium delivered to the macula densa returns
to normal, eliminating the initial drive for renin secretion. Therefore, in the steady
state, the initial neurally driven increase in renin secretion would be offset by the
renin- suppressive factors including high blood pressure and normalization of the
amount of sodium delivered to the macula densa, resulting in hypertension with a
normal PRA. This time course is reflected in longitudinal measurements of PRA in
a sympathetically mediated form of obesity hypertension in dogs [ 7 ]. Initial
increases in sympathetic activation, reflected by increased plasma NE concentration
associated with weight gain over the first 1–2 weeks, are paralleled by significant
increases in PRA. Subsequently, as hypertension develops, PRA gradually returns
to control levels by the fourth week. This study indicates that PRA levels may not
reflect the importance of the chronic neural drive for RAS activation in mediating
hypertension. As the RAS is the prominent modulator of pressure natriuresis, nor-
mal PRA in the context of sympathetic activation and hypertension may rather indi-
cate an inappropriate level of RAS activity. This contention is supported by studies
showing that pharmacological suppression of RAS with an angiotensin converting
enzyme (ACE) inhibitor effectively lowers blood pressure in established obesity
hypertension despite apparently normal levels of PRA [ 8 ]. Furthermore, removal of
the neural drive for renin secretion in obese hypertensive dogs by either global sup-
pression of sympathetic activity via baroreflex activation therapy (BAT) or renal
denervation (RDN) (these approaches are discussed below) lowers blood pressure
to normal levels while significantly reducing PRA to below normal levels. In sum-
mary, the neural drive for renin secretion and the consequent inability of the kidneys
to maintain normal the normal pressure natriuresis by adequately suppressing RAS
are paramount in mediating long-term hypertension in response to heightened
RSNA.
Sympathetic Overactivation in Resistant Hypertension
Evidence of Sympathetic Activation in Resistant Hypertension
Mounting evidence indicates that excessive activation of the sympathetic nervous
system is associated with both the development and progression of primary hyper-
tension [ 5 , 9 , 10 ]. As compared to normotensive subjects, muscle sympathetic nerve
traffic is higher in prehypertensive and borderline hypertensive subjects, indicating
that sympathetic activation precedes and likely contributes to the pathogenesis of
essential hypertension. Furthermore, for patients in the same age group the level of
muscle sympathetic nerve activity parallels the severity of hypertension, such that
resistant hypertensives display the strongest sympathetic activation [ 9 ], suggesting
R. Iliescu and D.N. Şerban