108
also surface abundance, increasing ENaC availability at the apical membrane,
which proves that the mechanism in which ethanol interferes with salt and water
transport is extremely complex. Further research is required in order to ascertain
the relevance of ethanol concentration and chronic consumption in the etiology
and dynamics of RH, and, given that oxidative stress is the main culprit for the
variations in ENaC activity after ethanol administration, it is essential to under-
stand the reasons for which it enhances ENaC activity under the influence of cer-
tain factors (such as ethanol) [ 148 ].
Genetic mutations through targeted substitution of the tryptophan residues in the
transmembrane domain lead to an increased steady state at hyperpolarizing voltage
potentials associated with transient activation times [ 149 ], while through site-
directed mutagenesis the inhibitory effect of external sodium concentrations can be
altered, an acidic cleft being the main ligand-binding locus for ENaC and possibly
for other members of the ENaC/ASIC superfamily [ 150 ].
Other Molecules
The sodium pump ligand, ouabain, is currently investigated as a possible main char-
acter in the etiopathogeny of salt-dependent hypertension, as high levels of ouabain
appear to be involved in the sustained increased of sympathetic nerve activity elic-
ited by high sodium intake, participating in a hypothalamic signaling pathway
together with aldosterone, ENaC, and angiotensin II, while at the periphery ouabain
synthesized by the adrenal cortex increases vasoconstriction through specific sig-
naling pathways [ 151 ].
At the cardiovascular level, ouabain, through its function as a growth factor, may
be involved in the vascular remodeling associated with RH, and it has been associ-
ated both to left ventricular dysfunction and hypertrophy.
Ouabain seems to be a component of a new CNS-humoral axis, which intercon-
nects the central nervous system with RAAS and sodium regulation system, con-
tributing to the chronic pressor effect of brain angiotensin II [ 152 ]. Within the same
framework, ouabain seems to stimulate through specific pathways, activated also by
sympathetic activity, the endogenous ligand of alpha(1) sodium pump, adrenocortical
marinobufagenin, which inhibits renal Na-K-ATPase and increases blood pressure
[ 153 , 154 ]. Moreover, a genetic pathway has been described, associated with both
acute and chronic salt variations, that involves the uromodulin gene [ 155 ], which
modulates tubular sodium excretion, while the lanosterol synthase gene, related to
the synthesis of endogenous ouabain, influences vasoconstrictor activity which
modulates circulating ouabain levels.
Therapeutic correlation The complex physiopathologic relationship between salt
intake, genetic control of renal sodium processing, and endogenous ouabain effect
is still incompletely deciphered. However, new antihypertensive agents [ 156 ] are
being currently tested that selectively antagonize the effects of ouabain and another
A. Burlacu and A. Covic