153that while sympathetic overdrive directly contributes to the maintenance of hyper-
tension, the degree of sympathetic activity dictates the prevailing levels of blood
pressure. Excessive activation of the sympathetic nervous system in hypertension is
highly inhomogeneous. Measurements of organ-specific norepinephrine spillover
[ 11 ] and microneurographic nerve traffic recordings [ 5 ] revealed that hypertension-
related increases in sympathetic neural drive appear to involve only some of the
territories that receive sympathetic innervation, namely, the kidneys, heart, and
muscle. The magnitude of sympathetic outflow to these organs is two- to threefold
higher in hypertensive patients as compared to normotensives [ 11 ]. From a mecha-
nistic point of view, the heightened renal sympathetic outflow likely plays a major
role in the maintenance of high blood pressure levels through direct antinatriuretic
actions on the renal tubules and tonic influences on the RAS. While a primary
reduction in renal excretory capacity mediated by the increased RSNA would be
sufficient to cause sustained hypertension, concomitant sympathetically mediated
increases in total peripheral resistance and cardiac output may accelerate the pro-
gression of hypertension. In resistant hypertensive patients, renal sympathetic out-
flow is particularly enhanced, even more so than in untreated patients with
mild-to-moderately severe hypertension [ 10 ]. Furthermore, the pattern of muscle
sympathetic activation in these patients is characterized by increased frequency of
single fiber firing, with burst activity frequently superimposed within the same car-
diac cycle [ 12 , 13 ]. This indicates that in resistant hypertension, the heightened
sympathetic outflow relies not only on additional recruitment of individual fibers, as
commonly found in essential hypertensives, but also to augmented firing frequency,
suggesting specific mechanisms may be involved. While patients with resistant
hypertension have several comorbidities with known contribution to sympathetic
activation, such as obesity, sleep apnea, CKD or diabetes, the mechanisms impli-
cated in drug resistance in these patients are not fully understood.
Mechanisms of Sympathetic Activation in Resistant
Hypertension
The mechanisms leading to sympathoexcitation in essential hypertension are largely
elusive and only seldom substantiated by experimental or clinical evidence [ 12 ].
The arterial baroreflex is a powerful controller of central sympathetic and parasym-
pathetic outflow, and while its role in rapid buffering in blood pressure fluctuations
via adjustments in autonomic function has been clearly recognized, its capacity to
oppose sustained increases in blood pressure has long been dismissed based on
experimental evidence of baroreceptor resetting to the prevailing blood pressure
levels and transient hypertension following complete baroreceptor denervation [ 1 ].
However, recent experimental studies demonstrated sustained, baroreflex-mediated
suppression of renal sympathetic outflow leading to increased renal excretory func-
tion in hypertensive dogs during chronic infusion of supraphysiological doses of
10 Secondary Causes: Work-Up and Its Specificities in CKD: Influence of Autonomic...