104
Among other protective agents in the pathophysiological dynamics of RH, stud-
ies report that vitamin D could ameliorate HT and renal damage, through genomic
and extra-genomic pathways [ 119 ], while vitamin D receptor-modulated expression
of heat-shock protein 70 has a protective intervention against angiotensin II-induced
HT and renal damage [ 120 ]. Estrogens have proven to be intervening in reduction
of vascular damage, mainly through the nuclear estrogen receptor alpha, and pro-
tecting against angiotensin II-induced hypertension [ 121 ]. Additionally, overexpres-
sion of Smad7 protein has a protective role in angiotensin II-mediated hypertensive
cardiac remodeling as well [ 122 ]. Downregulation of p22hox, an important compo-
nent of NADPH oxidase complex, plays a protective anti-inflammatory effect in
angiotensin II-induced oxidative stress, through suppression of MAPK and NF-kB
signaling pathways [ 123 ]. Melatonin hormone is involved in protection against
hypertension, as melatonin receptors are involved in regulation of the RAAS system
[ 124 ]. Finally, local kallikrein-kinin system (KKS) pathways are significantly
implicated in endogenous cardiovascular protective mechanisms [ 125 ], while stud-
ies substantiate the finding that kinins are mediators of these mechanisms, their role
in the cardiovascular system, as well as the interaction between KKS and RAAS
being still insufficiently investigated [ 125 ].
Sodium Involvement in Resistant Hypertension
Dopamine
The complex network of mechanisms involved in regulation of sodium balance in
physiological and pathological circumstances is extensively investigated in relation
with the events describing the genesis of RH. The processes surrounding sodium
excretion and reabsorption involve the interactive relationship between the renin-
angiotensin- aldosterone system (previously described in “RAAS Mechanisms”
section.) and the renal dopaminergic system, centered on the synthesis and activity
of intrarenal dopamine [ 126 ].
Increased levels of dopamine and the consequent over-activation of dopaminer-
gic receptors are triggered by high NaCl intake and result in decreased epithelial
sodium transport and increased sodium excretion, with additional stimulation of
antioxidant and anti-inflammatory pathways. Therefore, alterations in the essential
processes featuring dopamine such as biosynthesis, receptor expression, and signal
transduction are consistent with the imbalance in renal sodium excretion character-
istic for hypertension [ 127 ].
Therapeutic correlation Due to its essential role in sodium processing and regula-
tion of renal blood flow, current research brings about the possibility to use dopa-
mine as a nephroprotective agent in order to prevent renal failure. Further
investigation will have to show if this strategy is a viable option for critically ill
patients.
A. Burlacu and A. Covic