151on the juxtaglomerular cells leads to increased renin secretion with attendant antin-
atriuretic effects mediated by angiotensin II and aldosterone. Both the direct and
indirect actions of renal adrenergic innervation provide the mechanistic basis for the
idea that increased RSNA plays a causative role in the development of hypertension.
Indeed, mounting evidence indicates that several forms of experimental and clinical
hypertension are associated with increased RSNA and that complete removal of
adrenergic influences on the kidneys by renal denervation attenuates or abolishes
the hypertension [ 5 ].
Despite the clear role of RSNA in promoting and maintaining hypertension, the
relative contribution of the renal mechanisms involved has been difficult to assess.
Acute experimental studies where RSNA was progressively increased through
direct electrical stimulation of renal sympathetic nerves indicated that the lowest
levels of renal sympathetic nerve activation promote renin secretion, followed by
reductions in sodium excretion and ultimately decreases in glomerular filtration rate
(GFR) and renal blood flow (RBF), as the stimulation levels increase [ 3 , 6 ]. These
findings may suggest that relevant increases in RSNA that may be found chronically
in undisturbed conditions would mainly promote antinatriuresis and hypertension
by indirect effects on renin secretion and potentially direct tubular stimulation of
sodium reabsorption, while direct vasoconstriction would occur only with supra-
physiological levels of RSNA. Precise quantification of these mechanisms in the
chronic setting is not only technically difficult but complicated by their interdepen-
dence. Experimental studies indicate that the acute effects of renal adrenergic stim-
ulation are either not sustained over long term or eventually masked by compensatory
mechanisms. Direct intrarenal infusion of norepinephrine (NE) in uninephrecto-
mized dogs led acutely to a two- to threefold increase in plasma renin activity
(PRA), accompanied by significant reductions in total and fractional sodium excre-
tion, as well as GFR and renal plasma flow, consistent with the highest level of renal
adrenergic activation, as mentioned above. However, although the same rate of NE
infusion was maintained throughout 7 days, at the end of the study chronic hyper-
tension was associated only with higher than normal levels of PRA, while all other
renal functional alterations had waned off [ 6 ].
A thorough understanding of the complex interplay between the direct and indi-
rect factors involved in the chronic control of renal function by RSNA is warranted
in order to interpret the commonly used end points in experimental and clinical
studies.
Increased renin secretion initiated by neural activation of juxtaglomerular cells
leads to increased generation of Ang II, which promotes sodium reabsorption in the
proximal tubule, mainly by reducing peritubular capillary hydrostatic pressure,
owing to the prominent vasoconstriction of the efferent arterioles. In the absence of
increased filtration, increased proximal tubular reabsorption would lower the
amount of sodium delivered to the macula densa, which provides an additional drive
for renin secretion. If increased RSNA includes direct tubular actions that increase
sodium reabsorption, this effect would enhance the macula densa signal for renin
secretion. However, as extracellular fluid volume accumulates due to impaired renal
excretory capacity, blood pressure increases, which in turn activates the
10 Secondary Causes: Work-Up and Its Specificities in CKD: Influence of Autonomic...