106
In normal status, D1-like and D2-like receptors are the initiators of several
signaling pathways which result in activation of adenylyl cyclase, increased cyclic
adenosine 3′,5′-monophosphate (cAMP) levels, protein kinase activation, stimula-
tion of phospholipase Cβ1 in renal tubules, suppression of protein kinase B signal-
ing pathway, and activation of mitogen-activated protein kinase while concurrently
interacting with one another and creating new signaling pathways, which in turn
increase phospholipase C (PLC) stimulation in renal cortical cells [ 129 ].
Deficiencies in these signaling pathways lead to inhibition of Na+, K+-ATPase
determined by an impaired activation of phospholipase C and protein kinase
C. Recent experimental investigations bring supplementary evidence as to the signi-
fication of the decrease in levels of the specific antipeptide Gq/11 alpha and impaired
metabolism of arachidonic acid, a product of phospholipase A2, which, together
with the decreased activation of G proteins, contribute to the decreased dopaminer-
gic inhibition of sodium pump activity [ 137 ]. Additionally, it has been suggested
that the dopamine D1 receptor-mediated stimulation of PLC is a consequence of
protein kinase A activation, which increases PLC-gamma in cytosol and cell mem-
brane with the contribution of protein kinase C activation [ 138 ].
Therapeutic correlation Studies on black normotensive and hypertensive salt-
sensitive versus salt-resistant subjects have shown a deficiency in the renal dopami-
nergic system that triggers the natriuretic response to high sodium intake only in
salt-resistant subjects and only under low-sodium diets. It seems that this deficiency
is associated with a decreased decarboxylation of dopa into dopamine [ 139 ].
Epithelial Na+ Channel Proteins
The traditional approach of epithelial Na+ channel (ENaC) proteins discusses them
from the point of view of their involvement in the salt and water processes involved
in blood pressure regulation from the aldosterone-sensitive renal cortical-collecting
duct, as the closing effector element of the renin-angiotensin-aldosterone system
(RAAS) [ 140 ].
Nevertheless, recent studies have brought evidence in support of three essential
nontubular roles of these proteins [ 141 ]. The first role is related to their activity in
the central nervous system. Thus, ENaC from the choroid plexus and cardiovascular-
regulatory brain stem nuclei act as sensors of the cerebral spinal fluid for variations
in sodium balance and participate in sodium regulation mechanism by eliciting an
increased sympathetic activity as response to high sodium levels in order to induce
vasoconstriction and proximal tubule natriuresis. Moreover, a recent study reports
that enhanced expression of ENaC generates salt-induced pressor activity [ 142 ].
The second location for ENaC intervention is at the vascular level, where one of
their roles is the intervention in endothelial cell function, where they mediate shear
stress and endothelial membrane stiffness, in a newly discovered, but still incom-
pletely investigated, pathway for regulation of vascular tone, while the second role
is as mechanosensors that initiate the vascular smooth muscle cell-mediated myogenic
A. Burlacu and A. Covic