105The activating factors of these deficiencies are still not identified [ 126 ], although
recent research seems to indicate high sodium intake and elements that favor the
insulin resistance state such as diets high in carbohydrates and fat. There are also
surging issues regarding the altered abilities of intrarenal sodium sensors, given the
sensitization effects of high sodium intake and volume expansion on the renal dopa-
minergic system. Experimental studies have ascertained the correlation between
impaired renal dopamine production and failure to eliminate acute increase in
sodium load on genetically altered rat populations [ 127 ].
There are two types of receptors associated with the physiology of dopamine,
namely, D1-like receptors (D1 and D5) and D2-like receptors (D2, D3, and D4) [ 128 ].
In normal status, dopamine synthesized at the renal level behaves as an autocrine/
paracrine/natriuretic hormone and initiates the inhibition of apical and basolateral ion
transports and exchanges resulting in decreased tubular sodium reabsorption [ 129 ].
The binding of stimulatory guanine nucleotide-binding proteins (G proteins, such as
Gαs and Golf) on D1-like receptors leads to the activation of multiple cellular signal-
ing systems such as adenylyl cyclase and phospholipase C (PLC) [ 130 ]. Therefore, it
seems that a defective coupling of the D1-like receptors to their G protein complex
could be responsible for the disturbances in the sodium processing systems which are
recorded in hypertension [ 131 ]. Current research suggests that in rats as well as in
humans the uncoupling of D1-like receptors from the G protein/effector complex
could be caused by their ligand-independent hyperphosphorylation and desensitiza-
tion [ 132 ]. These processes may be determined by the inability of D1-like agonists to
increase the activity of a specific enzyme, protein phosphatase 2A [ 133 ], which plays
an essential role in the regulation of the G protein- coupled receptor function.
Therapeutic correlation Recent studies show that direct interstitial stimulation of
D1-like receptors with fenoldopam, a selective receptor agonist, triggers natriuresis
via an angiotensin type 2 receptor mechanism, with possible further implications in
the therapeutic management of hypertension [ 134 ].
On the other hand, experimental research identified the genetically determined
defective coupling of D1 receptors to the G protein/adenylyl cyclase complex as the
possible culprit in the impairment of the renal dopaminergic system [ 132 ]. The
defect is identifiable prior to the initiation of hypertension and is consistent with the
hypertensive phenotype while not being relayed to other humoral agents. It appears
to be a “mistargeting” mechanism which is not caused by a mutation in the primary
sequence and is yet to be identified [ 135 ]. Moreover, the defect could not be recorded
in other renal locations outside the proximal tubules. This receptor impairment
results in the failure of D1 agonists to inhibit Na+/H+ exchange activity. Furthermore,
apparently, the decreased renal sodium excretion after dopamine administration is
related to decreased cyclic AMP synthesis and to the impaired ability of dopamine
to inhibit Na+,K + −ATPase activity. Besides dopamine, experimental studies on
rats show that toxin-sensitive G proteins (pertussis and cholera toxin) are directly
involved as well in the regulation of proximal tubule Na+, K+-ATPase activity, their
activity being abnormal in hypertensive rat populations, resulting in enhanced salt
reabsorption in the kidney [ 136 ].
7 Pathophysiological Insights in Resistant Hypertension