NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Kopp UC. Neural Control of Renal Function. San Rafael (CA): Morgan & Claypool Life Sciences; 2011.

Cover of Neural Control of Renal Function

Neural Control of Renal Function.

Show details

Chapter 4Neural Control of Renal Tubular Function

4.1. RENAL DENERVATION

Studies in dogs performed >150 years ago introduced the phenomenon of denervation diuresis and natriuresis [21]. Because many of the early studies showed concomitant increases in renal blood flow and urinary sodium excretion following denervation of the kidneys, any direct neural effect on tubular sodium reabsorption was long dismissed. However, in the 1960s, it was recognized that acute renal denervation could result in increases in urinary flow rate and sodium excretion in the absence of changes in renal hemodynamics [58]. In the early 1970s, the crucial anatomical evidence for direct innervation of the renal tubules was demonstrated by Barajas et al. [5]. The adrenergic nerve terminals with norepinephrine-containing vesicles are in close contact with the basolateral membrane of tubular cells (Figure 2.2). These studies provide anatomical support for norepinephrine to be released from these nerve terminals and activate adrenoceptors on the basolateral membrane with a resultant increase in tubular sodium reabsorption. As discussed above, all parts of the nephrons are innervated by sympathetic nerves [510].

The anatomical studies have been supported by micropuncture studies showing that acute renal denervation results in decreased absolute and fractional proximal tubular reabsorption of sodium and water [16, 17, 19], in the loop of Henle [20, 33] and in the distal convoluted tubule [20, 245]. Thus, renal denervation decreases solute and water reabsorption in virtually all segments of the nephron. In addition, the magnitude of the quantitative effect of renal denervation on segmental tubular reabsorption is in general proportion to the density of innervation in the nephron segments: thick ascending limb of loop of Henle > proximal convoluted tubule > distal convoluted tubule. Importantly, the decreased sodium reabsorption in the various portions of the nephron was demonstrated in the absences of changes in total kidney glomerular filtration rate, single nephron glomerular filtration rate, renal interstitial hydrostatic pressure, peritubular capillary oncotic or hydrostatic pressures [58].

Among possible mechanisms leading to the decreased proximal tubular reabsorption following renal denervation is decreased Na+-K+-ATPase activity [199]. Na+-K+-ATPase generates energy for transcellular transport of sodium and many substances that are co- or countertransported with sodium in the proximal tubule. Therefore, decreased Na+-K+-ATPase activity may explain the effects of renal denervation on proximal tubular transport of a wide variety of solutes, including bicarbonate [42], chloride [42], phosphate [182, 236] and glucose [234]. Taken together, there is considerable evidence for changes in ERSNA regulating various transport processes in the proximal tubule [235].

An important point to consider when interpreting the effects of renal denervation on renal function is that special care needs to be applied to verification of the renal denervation. The kidney is innervated by numerous nerves, and it is generally agreed that only severing nerves that are visible is not enough, even if the denervation is performed using a microscope. The surgical procedure of cutting all nerves has to be complemented by applying phenol to the renal artery. Frequently, a decrease in renal tissue norepinephrine content has been offered as evidence of complete renal denervation. However, this generally requires 2–3 days to occur so that this method cannot be used to immediately verify the completeness of an acute renal denervation at the time it is performed. In addition, after renal denervation, the renal vasoconstrictor response to renal sympathetic nerve stimulation and basal urinary sodium excretion returns toward normal values at a time (14–24 days) when renal tissue norepinephrine content is still <30% of the control value [126]. Thus, functional reinnervation, as reflected by physiological assessment, precedes and is not accurately reflected by biochemical measurements of renal tissue norepinephrine content. The time for reinnervation is species dependent. In the dog, renal denervation reduced renal tissue norepinephrine content to zero when first measured at 2 weeks with almost full recovery at 16 weeks [191, 192]. In human renal transplant patients (between 6 weeks and >27 months postrenal transplantation), lower body negative pressure sufficient to decrease mean arterial pressure and increase both heart rate and plasma norepinephrine concentration produced renal vasoconstrictor responses that were one-third to one-half of those observed in normal subjects [100]. Although this was interpreted as evidence for residual partial functional denervation, since the transplanted kidneys did exhibit a degree of renal vasoconstriction, this also indicates that partial functional reinnervation may have occurred.

4.2. INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY

4.2.1. Direct Activation of the Renal Nerves

The denervation studies discussed above suggested that there exists a level of ERSNA that could directly affect renal tubular sodium and water reabsorption independently of changes in renal hemodynamics. In fact, a study in anesthetized dog in the early 1970s showed that there do exist renal nerve frequencies that decrease urinary sodium excretion in the absence of changes in renal hemodynamics [165]. These findings were subsequently confirmed by numerous studies in different species [58]. The antinatriuretic responses were abolished by renal α-adrenoceptor blockade with phenoxybenzamine [260] or selective renal α1-adrenoceptor blockade with prazosin [203]. The findings that azetazolamide reduced the decreases in urinary sodium and bicarbonate excretion produced by low-level renal nerve stimulation [204] suggest an involvement of the apical Na+/H+ exchanger. In view of these findings, it is interesting to note that the α1-adrenoceptor agonist phenylpehrine increased the activity of the sodium–hydrogen exchanger (NHE)3 in isolated renal proximal tubular cells [172, 173]. Likewise, norepinephrine has been shown to increase the activity of various transporters in different renal tubular segments: NHE1, NHE3, and sodium bicarbonate cotransporter (NBC) in proximal tubule and the Na–K–2Cl cotransporter (NKCC2) in thick ascending limb of Henle's loop. Most likely, the increased activity of the various transporters coupled to sodium is, at least in part, related to increased norepinephrine-mediated activation of basolateral Na+/K+-ATPase [2].

Renal micropuncture studies showed that low-level renal nerve stimulation increased late proximal tubular fractional and absolute sodium and water reabsorption [18]. Tubular sodium reabsorption in the thick ascending limb of the loop of Henle is also modulated by changes in ERSNA. In this section of the tubules, low-frequency renal sympathetic nerve stimulation increased sodium chloride but not water reabsorption, the thick ascending limb being water impermeable [61]. The increased sodium reabsorption in proximal tubule and the ascending limb of the loop Henle was associated with antidiuresis and antinatriuresis in the absence of any changes in renal hemodynamics.

4.2.2. Reflex-Mediated Increases and Decreases in the Activation of the Renal Nerves

An important consideration is whether direct electrical stimulation of the renal sympathetic nerves produces changes in renal sodium and water that would be expected to occur in response to reflex increases in ERSNA. Numerous studies applying various techniques to increase ERSNA, including carotid baroreceptor unloading, nonhypotensive bleeding, and head-up tilt, showed that the increased ERSNA was associated with decreases in urinary flow rate and sodium excretion in the absence of renal hemodynamic changes [58]. An example of the many studies examining the effects of reflex increases in ERSNA on renal function is a study in conscious dogs exposed to head-up tilt, which decreases central venous volume/pressure [189]. Tilting trained dogs for an extended period of time resulted in increases in ERSNA that were sustained during the period of tilting. The increases in ERSNA were associated with decreases in urinary flow rate and sodium excretion in the absence of changes in glomerular filtration rate. Prior renal denervation abolished the antinatriuretic and antidiuretic responses to the head-up tilt. In the absence of the confounding issues of anesthesia and surgery, these studies indicate that sustained reflex increases in ERSNA directly increase renal tubular sodium and water reabsorption resulting in antidiuresis and antinatriuresis.

Because a physiological control system usually operates in a bidirectional manner, it would be anticipated that reflex interventions that decrease ERSNA would result in decreases in renal tubular sodium and water reabsorption with diuresis and natriuresis in the absence of changes in renal hemodynamics, i.e., responses similar to those following acute renal denervation. Among the many maneuvers used to reflexly decrease ERSNA are left atrial distention, volume expansion, and head-out water immersion [58]. The maneuvers increase central cardiopulmonary blood volume, the compartment that contains volume receptors which, sensing an overfullness of the circulation, increase the diuretic and natriuretic capacity of the kidney to restore homeostatic equilibrium. Intravascular volume expansion produces an increase in left atrial pressure that is correlated with the simultaneous decrease in ERSNA; bilateral cervical vagotomy abolishes the decrease in ERSNA. Evidence that the decrease in ERSNA that occurs during the intravascular volume expansion contributes to the associated diuresis and natriuresis derives from several studies performed in conscious animals. In conscious rats, dogs, monkeys, and sheep, prior bilateral renal denervation attenuates the diuretic and natriuretic response to acute intravascular volume expansion. Thus, the withdrawal of ERSNA that occurs during volume expansion is a significant contributor to the diuretic and natriuretic responses observed.

A clear demonstration of the important contribution of ERSNA to the diuretic and natriuretic responses to central cardiopulmonary volume expansion was provided by studies in conscious dogs exposed either to head-out water immersion [96, 97, 188], a maneuver which translocates fluid from peripheral portions of the body to the intrathoracic circulation, thereby increasing both cardiopulmonary blood volume and left atrial pressure, or to left atrial balloon inflation [187], a more selective activation of left atrial receptors. In response to either head-up water immersion or left atrial balloon inflation, there were sustained nonadapting decreases in ERSNA and increases in urinary flow rate and sodium excretion that were completely abolished by either cardiac (afferent limb) or renal (efferent limb) denervation [187] (Figure 4.1). These studies in conscious dogs provide compelling evidence that left atrial receptor-mediated withdrawal of ERSNA produces the natriuresis and contributes substantially to the diuresis produced by left atrial distension.

FIGURE 4.1. In conscious dogs, inflating a balloon placed in the right atria results in decreases in renal sympathetic nerve activity and increases in urine flow rate and urinary sodium excretion, all of which are blocked by cardiac denervation (CD).

FIGURE 4.1

In conscious dogs, inflating a balloon placed in the right atria results in decreases in renal sympathetic nerve activity and increases in urine flow rate and urinary sodium excretion, all of which are blocked by cardiac denervation (CD). Renal denervation (more...)

4.3. ADRENOCEPTORS

The antidiuretic and antinatriuretic responses to direct low-frequency and reflex renal sympathetic nerve stimulation were abolished by phenoxybenzamine, an α1-/α2-adrenoceptor antagonist [259, 260]. The antinatriuretic and antibicarbonaturic responses to low-frequency renal sympathetic nerve stimulation are mediated by postsynaptic αl-adrenoceptors located at neuroeffector junctions on the basolateral aspect of the tubule throughout the nephron as shown in various species, including dogs, rabbits, and rats [58].

As discussed above, αl-adrenoceptors mediate the effect of ERSNA on proximal convoluted tubule to increase Na+/H+ exchange and water, chloride, and bicarbonate reabsorption [34, 35, 42]. In innervated kidneys of anesthetized surgically prepared rats, microperfusion of the proximal convoluted tubule (Sl) with either a glomerular ultrafiltrate-like or a sodium chloride solution demonstrated that the α1-adrenoceptor antagonist prazosin and renal denervation decreased chloride absorption to the same extent, whereas the α2-adrenoceptor antagonist rauwolscine had no effect. These findings demonstrate that activation of α1-, but not α2-adrenoceptors mediates the tonic effect of basal ERSNA to increase chloride reabsorption in the rat proximal convoluted tubule [252].

Despite the fact that renal α2-adrenoceptors exist in relative abundance over renal αl-adrenoceptors, there is no evidence that they mediate any of the direct renal tubular actions of low-frequency renal sympathetic nerve stimulation. α2-Adrenoceptors are located extrasynaptically, where they may be activated by circulating norepinephrine and/or epinephrine [207, 228]. These extrasynaptic α2-adrenoceptors are thought to mediate responses to stimuli that operate via the adenylyl cyclase–cAMP system, since α2-adrenoceptor agonists inhibit adenylyl cyclase activity and cAMP accumulation [102, 247]. The effect of α2-adrenoceptor agonists to inhibit adenylyl cyclase activity and cAMP accumulation is not seen in the basal (i.e., unstimulated state), but is most prominently observed after administration of an agent that stimulates adenylyl cyclase and cAMP accumulation (e.g., ADH) [208].

There have been many in vivo and in vitro studies designed to determine the subtype of α1-adrenoceptors, which mediates the antidiuretic and antinatriuretic responses to increases in ERSNA. These studies have examined the effects of various antagonists of either α1A- or αlB-adrenoceptors on the responses to α1-adrenoceptor agonists. Whereas the results from studies in normal healthy rats favor the conclusion that activation of α1B-adrenoceptors mediates the antidiuretic and antinatriuretic responses and α1A-adrenoceptors the vasoconstrictor responses to α1-adrenoceptor agonists, a note of caution is warranted due to the lack of absolute selective antagonists of α1A and α1B receptors.

β-adrenoceptors are present on the various tubular sections, and activation of these receptors may alter the transport properties of various tubular segments [58]. Because β1- and β2-adrenoceptor antagonists' lack of effects on the renal excretory responses to low-frequency renal sympathetic nerve stimulation, it is likely that the β-adrenoceptors are extrajunctional in location.

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK57246

Views

  • PubReader
  • Print View
  • Cite this Page

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...