91We underline the fact that, even if the pathophysiological mechanism lying
behind RH is a complex multifactorial edifice founded on the sensible imbalance
between various elements in several key locations in the body, for theoretical
purposes we will discuss each of these elements separately, in an attempt to high-
light their individual contribution. Moreover, each pathway influences to a greater
extent the other described mechanisms.
Neurogenic Pathways
The neurogenic pathways involved in RH are based on the over-activation of already
known pathogenic pathways of essential hypertension. Thus we can identify a cen-
tral and a peripheral neurogenic dysfunction, which are discussed individually.
Central Neurogenic Dysfunction
Sympathetic Over-Activation
Hyperactivity of the central autonomic nervous system triggers neurogenic resistant
hypertension, and it is associated with abnormal homeostatic reflex control. Over-
activation of the sympathetic nervous system (SNS) is characteristic for young indi-
viduals (<45 years old) with effects on skeletal muscle vasculature, kidneys, and
heart, resulting in insulin resistance and hyperinsulinemia (through the effects on
glucose delivery), as well as left ventricular hypertrophy [ 1 , 2 ]. The sympathetic
pathway plays an essential role in the development and evolution of RH, from trig-
gering to resistance and progression [ 3 ]. Recent researches recorded two to three
times higher rate of sympathetic nerve firing in patients with true resistant hyperten-
sion, regardless of the design of the multidrug therapy [ 4 ].
In the activation of the sympathetic pathway, there are involved both specific
autonomic territories and peripheral reflex mechanisms comprising arterial barore-
ceptors, arterial chemoreceptors, and cardiopulmonary mechanoreceptors.
The possible origin of the sympathetic pathway is in the neurons from the ven-
trolateral periaqueductal gray, which send projections to the rostral ventrolateral
medulla in the brain stem. This integrative structure that also incorporates similar
projections from several locations plays an essential role in the control of tonic
sympathetic activation and tonic arterial pressure, as it has a direct connection with
the superior segment of the medulla through the upper centers of modulation for the
vasomotor sympathetic nerve discharge and blood pressure [ 5 ].
The SNS pathway is a subunit of the arterial baroreflex system which connects
the autonomic nervous system with the cardiovascular system, and therefore its
response is determined by the input received from the mechanoreceptors in the
7 Pathophysiological Insights in Resistant Hypertension