107constriction, independent of neural influences. Their role as mediators in the mecha-
nism of renal blood flow autoregulation and protection from increased systemic
pressure has been supported by experimental studies as well, which have correlated
high blood pressure with increased level of ENaC proteins.
Ultrastructurally, the ENaC proteins consist of four homologous subunits (α, β,
γ, and δ) encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D, which
belong to the ENaC/degenerin superfamily, together with other related proteins
such as degenerin, described in nematodes, and acid-sensing ion channel (ASIC)
family, recorded in mammals. Their protein structure reflects the function of extra-
cellular proton and/or mechanosensors for either extracellular Na+, shear stress, or
strain [ 143 ].
Through their extracellular domain which interacts with the extracellular envi-
ronment, the ENaC proteins function as fine-tuning mechanisms on the long-term
regulation of renal Na+ and water balance and hence of blood pressure. Thus, ENaC
functions as convergence point of these signaling pathways as activation in central
ENaC leads to increased renal vascular resistance and increased Na+ renal reab-
sorption, while concurrently stimulating the RAAS system, which brings about
supplementary consequences in renal hemodynamics and salt/water transport.
Simultaneously, the functions of ENaC at the vascular level resulting in vasodilation
and myogenic-mediated vasoconstriction lead to increased renal tubular Na+/water
transport due to alterations in peritubular capillary pressure. Long-term loss of myo-
genic constriction results in renal injury associated with hypertension.
Therapeutic correlation Given their essential role in regulation of body salt and
water homeostasis, ENaC and ASIC proteins represent viable therapeutic targets for
a possible long-term control of resistant hypertension [ 144 ]. Studies report that H2S
prevents advanced glycation end products (AGEs)-induced ENaC activation in A6
cells, which could have an important significance in the management of diabetic
hypertension [ 145 ].
Furthermore, the inhibitory regulation of ENaC has been attributed to the inter-
vention of an intrinsic purinergic signaling system, which involves the metabotropic
P2Y2 purinergic receptor in the relay of paracrine ATP signaling. It has been shown
that mutations involving ENaC activity and defective regulation of this channel, such
as loss of purinergic inhibition or stimulation of P2Y2, result in abnormal variations
in blood pressure and Na excretion, which support the possible causative role of
purinergic signaling pathway of the distal nephron for specific form of hypertension
[ 140 ]. As to the stimulatory regulation of ENaC, experimental research has shown
the contribution of norepinephrine [ 146 ], by observing the presence of noradrenergic
nerve fibers in close proximity to ENaC-expressing cells, and of ethanol, which
probably increases intracellular oxidative stress through acetaldehyde [ 147 ].
These findings support the hypothesis that RH associated with alcohol con-
sumption does not fall within the category of true RH, and could be of a transient
nature, even if there are no studies investigating the degree of its reversibility in
the circumstances of complete alcohol abstinence. Moreover, effects of ethanol
exposure involved both ENaC gating, by increasing open state probability and
7 Pathophysiological Insights in Resistant Hypertension