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Cardiovascular Research 2004 61(2):238-246; doi:10.1016/j.cardiores.2003.11.024
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Copyright © 2004, European Society of Cardiology

Interactions between the sympathetic nervous system and the kidneys in arterial hypertension

Olaf Grisk* and Rainer Rettig

Department of Physiology, Ernst-Moritz-Arndt-University of Greifswald, Greifswalder Str. 11c, D-17495 Karlsburg, Germany

* Corresponding author. Tel.: +49-3834-8619300; fax: +49-3834-8619310. grisko{at}uni-greifswald.de

Received 1 September 2003; revised 31 October 2003; accepted 18 November 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
 References
 
Elevated sympathetic activity changes renal function and accelerates the development of hypertension. Principles of sympatho-renal interactions in chronic hypertension are reviewed. Alterations in the ontogeny of the sympathetic nervous system and the kidney, inherited abnormalities in sensory receptor function and exaggerated responsiveness to mental stress contribute to inappropriately high sympathetic activity in primary or essential hypertension. Careful characterization of clinical study populations shows that elevated sympathetic activity and "essential" hypertension are not unequivocally associated. Prospective clinical studies which investigate a broader array of physiological functions and experiments in recombinant inbred rodents with less traumatic nerve recording techniques than currently available will help to define under which conditions elevated sympathetic activity is indeed a cause of primary hypertension. Signals arising from the kidney which activate the renin–angiotensin system and afferent renal nerves increase sympathetic activity. These mechanisms importantly contribute to the pathogenesis of hypertension secondary to renal artery stenosis and end-stage renal disease.

KEYWORDS Arterial hypertension; Kidney; Sympathetic nervous system


   1. Introduction
Top
 Abstract
 1. Introduction
2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
 References
 
The sympathetic nervous system contributes importantly to arterial pressure control under varying conditions by modifying cardiac output, peripheral vascular resistance and renal function. The system can exert powerful acute pressor actions and participates in the pathophysiology of chronic arterial hypertension. The renal volume/pressure control system is regarded to dominate physiological long-term arterial pressure regulation because of its infinite capability to return altered arterial pressure to its original level by increasing or decreasing water and electrolyte excretion in response to elevated or reduced systemic arterial pressure [1]. Activation of sympathetic nerves to the kidney increases tubular sodium reabsorption, renin release and renal vascular resistance [2]. These actions contribute to long-term arterial pressure elevations by shifting the pressure-natriuresis curve to the right [2]. Signals generated in renal sensory receptors and conducted via renal afferent nerves modify efferent sympathetic nerve activity with consequences for arterial pressure regulation [2]. The aim of the present paper is to review recent work that demonstrates how the kidneys and the sympathetic nervous system interact in the pathophysiology of experimental and human arterial hypertension.


   2. Quantification of renal sympathetic nerve activity
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
 References
 
Any in-depth consideration of the interaction between the sympathetic nervous system and the kidney in arterial hypertension relies on reliable methods to quantify renal sympathetic nerve activity (RSNA). In experimental animals RSNA can be assessed by multifiber or single unit recordings of electrical activity. With multifiber recordings RSNA cannot be compared reliably in terms of absolute voltages. To compensate for this problem several investigators have used sophisticated methods of nerve traffic analysis. An important methodological progress has recently been made by the introduction of telemetric renal nerve recordings in rabbits [3]. Once this technology becomes available for smaller rodents it will allow for long-term recordings of RSNA in more widely used animal models of arterial hypertension.

For obvious reasons RSNA cannot be directly assessed in humans and measurements of SNA in peroneal nerves are only indirect evidence for what may happen in renal sympathetic nerves. To obtain an estimate of renal sympathetic nerve activity in humans, radiotracer techniques have been applied to measure norepinephrine spillover in renal venous plasma [4,5].


   3. Primary or essential hypertension
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
 References
 
There is ample evidence for elevated sympathetic nerve activity in experimental and human primary (essential) hypertension. The sympathetic nervous system may act through the kidney to cause or maintain arterial hypertension. The hypertensinogenic effects of the sympathetic nervous system on the kidney may start as early as ontogeny.

3.1. Development of renal sympathetic innervation
The development of the kidney has been extensively studied in normotensive and hypertensive rats [6–14]. In this species afferent renal innervation has fully developed around birth while efferent sympathetic renal innervation continues to develop from embryonic day 16 through postnatal day 21 [6]. During postnatal weeks 2–4, a steep rise in renal norepinephrine concentration and turnover occurs [7]. Afferent and efferent renal innervation depend on the actions of neurotrophins such as nerve growth factor (NGF), neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) [8]. Besides its role in the development of renal innervation GDNF is also required for normal renal morphogenesis in rats and mice [9]. The actions of GDNF on the developing kidney may have a major impact on long-term arterial pressure. Thus, mice carrying only one copy of the GDNF gene have fewer and larger glomeruli associated with an increase in arterial pressure by about 20 mm Hg compared to wild type controls [15].

Interestingly, whole kidney glomerular filtration rate (GFR) and renal blood flow are normal in GDNF +/- mice [15] and the mechanisms by which a diminished GDNF action during ontogeny causes long-term blood pressure to rise are currently not well understood. Circumstantial evidence suggests that these mechanisms may be related to the trophic actions of GDNF. Thus, in normotensive Sprague–Dawley rats the maturation of noradrenergic projections to various organs including the kidney coincides with a decline in local DNA synthesis [7] indicating that the sympathetic nervous system may have negative trophic effects during renal development. In keeping with this finding, neonatal sympathectomy elicits elevations in renal RNA and protein concentrations during renal maturation, i.e., during postnatal days 10–20 [14]. In spontaneously hypertensive rats (SHR) renal sympathetic innervation is enhanced [10,16,17] and neonatal sympathectomy is associated with a decrease in long-term arterial pressure. Together, these findings suggest that a certain level of trophic stimulation during renal development may be required in order to maintain arterial pressure at a normal level whereas a lack of trophic stimulation such as in GDNF +/– mice or in rats with increased renal sympathetic innervation may contribute to the pathogenesis of arterial hypertension.

On the other hand, renal sympathetic hyperinnervation alone is probably not sufficient to cause arterial hypertension. Thus, in SHR renal sympathetic innervation is more dense [16] and develops faster [10] during the first two postnatal weeks than in normotensive Wistar–Kyoto rats (WKY). Furthermore, renal norepinephrine content is approximately two times higher in newborn [10] and approximately 1.5–3 times higher in adult SHR [17] compared to age- and sex-matched WKY. Since renal NGF mRNA expression was elevated in newborn SHR compared to WKY [11] or normotensive Donryu rats (DRY) [12] it has been suggested that this factor may contribute to renal sympathetic hyperinnervation in SHR [13]. In order to investigate the effects of NGF on renal sympathetic innervation and long-term arterial pressure, normotensive Wistar rats were treated with the substance from birth to postnatal week 8. This treatment resulted in noradrenergic hyperinnervation of several organs including the kidney [18]. However, long-term arterial pressure was not elevated [18].

To further investigate the role of early renal sympathetic innervation for the development of primary hypertension, we transplanted kidneys from neonatally sympathectomized SHR into untreated SHR recipients [19] (Fig. 1). SHR recipients of a kidney from hydralazine-treated donors served as controls. Transplantation of a kidney from sympathectomized donors was associated with a decrease in long-term arterial pressure of about 20 mm Hg and a reduction in sodium sensitivity of arterial pressure. These findings suggest that neonatal sympathetic innervation in SHR causes changes in renal function that are involved in the development and maintenance of hypertension. The nature of these alterations is currently unclear. Initial studies did not show major effects of neonatal sympathectomy on renal morphology [19]. A detailed investigation of neonatal sympathectomy-induced changes in SHR renal function is currently in progress.


Figure 1
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  		Fig. 1 Time course of telemetrically recorded mean arterial pressure (MAP) in SHR transplanted with a kidney from hydralazine-treated donors (circles, n = 10) and in SHR transplanted with a kidney from neonatally sympathectomized donors (triangles, n = 10). Asterisks indicate significant differences between groups (p<0.05). Recipients of a kidney from neonatally sympathectomized donors showed less sodium sensitivity and lower final arterial pressure levels. Reprinted with permission from Ref. [19].

 
There is evidence from clinical studies [5] that sympathetic innervation of cardiovascular organs including the kidney is enhanced in patients with essential hypertension. The specific contribution of the enhanced sympathetic innervation to the pathogenesis of essential hypertension remains to be determined.

3.2. Renal sympathetic nerve activity in primary (essential) hypertension
In several experimental forms of primary and obesity-related hypertension there is widespread increased sympathetic nerve activity. Recent evidence for increased sympathetic nerve activity in SHR versus WKY includes (1) elevated norepinephrine concentrations and tyrosine hydroxylase activities in skeletal muscle and white adipose tissue [20], (2) increased excitability of superior cervical ganglion cells [21], and (3) increased plasma norepinephrine levels [20], although the latter have not always been confirmed [22].

There is also evidence for increased sympathetic nerve activity in obese compared to lean Zucker rats. Thus, ganglionic blockade decreased blood pressure more in obese than in lean Zucker rats, indicating a stronger dependence of blood pressure on sympathetic activity in obese than in lean rats [23]. Furthermore, sympathetic nerve activity to brown adipose tissue was higher in obese than in lean Zucker rats, although this difference was not statistically significant [24].

Studies in essential hypertensive humans also indicate that there is widespread increased sympathetic nerve activity. Thus, cardiac norepinephrine spillover [25] and muscle sympathetic nerve activity (MSNA) [26–28] were elevated in essential hypertensive patients compared to normotensive controls.

Many of the above mentioned indices of increased sympathetic nerve activity in hypertension do not necessarily mean that the activation includes renal sympathetic fibres. Thus, peripheral sympathetic nerve activity in response to reflex activation or centrally generated sympathetic tone may be subject to organ specific differential regulation. The following two examples from recent experimental and clinical work in normotensive subjects may serve to illustrate this point. Firstly, in Sprague–Dawley rats the gain of arterial baroreflex-induced changes in sympathetic nerve activity was higher in renal than in adrenal or lumbar sympathetic fibres [29]. Secondly, in healthy humans acute intravenous administration of the angiotensin I-converting enzyme (ACE) inhibitor, enalaprilat, caused a 50% rise in renal norepinephrine spillover while cardiac and total body norepinephrine spillover remained unchanged indicating selective activation of RSNA probably due to low-pressure baroreceptor unloading [30].

Several recent studies [4,31–34] show that the increased sympathetic nerve activity found in experimental and clinical primary (essential) and obesity-related hypertension almost invariably includes renal sympathetic nerves. Thus, RSNA was higher in SHR than in normotensive inbred rats, and elevated RSNA cosegregated with an increase in arterial pressure. A recent study [31] comparing SHR and WKY suggests that increased oxygen radical formation may contribute to the chronically elevated RSNA in SHR. Thus, intravenous administration of the superoxide dismutase mimetic, tempol, (30 mg/kg) reduced arterial pressure by 40 mmHg in SHR and by only 20 mm Hg in WKY. The decrease in blood pressure was accompanied by a reduction in RSNA of 60% in SHR and only 30% in WKY [31]. Elevated RSNA was also found in conscious obese versus lean Zucker rats [32] and in Wistar fatty versus Wistar lean rats [33]. Finally, in patients with essential and obesity-related hypertension renal norepinephrine spillover was elevated by approximately 50% compared to lean normotensive controls [4,34].

In order to further investigate the role of renal sympathetic nerve activity for the development of primary hypertension researchers sought to specifically stimulate or block this pathway. Increased RSNA can be mimicked by infusion of norepinephrine into the renal artery with minimal spillover into the systemic circulation. In rats [35] and dogs [36,37] this manoeuvre causes arterial hypertension. The mechanisms mediating this form of experimental hypertension are controversial. Volume expansion was excluded in two studies [35,36], but may have occurred in the third [37]. Interestingly, in the latter study [37] the decreased renal sodium excretion in norepinephrine-infused dogs was not necessarily associated with an increase in blood pressure, shedding further doubt on the role of volume expansion in this model of hypertension.

The renal artery norepinephrine infusion approach has several limitations. It does neither mimic the temporal and spatial pattern of norepinephrine release from renal sympathetic nerves nor does it account for the role of co-transmitters such as neuropeptide Y or ATP. Furthermore, spillover of norepinephrine into the systemic circulation is hard to avoid and may account for the failure to detect significant volume expansion in this model [1].

An alternative approach to study the role of renal sympathetic nerves for the pathogenesis of experimental hypertension is by performing renal denervation in young genetically hypertensive animals. Selective renal denervation in juvenile genetically hypertensive animals delays, but does not completely prevent the development of hypertension [2]. Even complete neonatal sympathectomy does not reduce arterial pressure to entirely normotensive levels [19]. On first glance, these data suggest that increased renal sympathetic nerve activity plays a major role in the pathogenesis of experimental primary hypertension. However, they should be interpreted with caution. Thus, long-term arterial pressure reductions in SHR can also be achieved by measures that do not directly interfere with RSNA. For example, transient treatment of prehypertensive SHR with an ACE inhibitor [38], an AT1 receptor blocker, or hydralazine [39] (own unpublished observations) elicited chronic reductions in arterial pressure that lasted well beyond the cessation of treatment.

Furthermore, in experimental renal cross-transplantation studies [40,41] recipients of a solitary SHR kidney invariably developed post-transplantation hypertension although the transplanted kidney was obviously denervated and there was essentially no sympathetic reinnervation during the experiment [42]. The development of hypertension in recipients of an SHR kidney graft was not accompanied by sympathetic activation [43]. To further investigate the potential role of the recipients' sympathetic nervous system for renal post-transplantation hypertension we transplanted kidneys from untreated young SHR into neonatally sympathectomized F1 hybrids derived from crossing SHR and WKY [19]. SHR kidney grafts increased arterial pressure by about 20 mm Hg in sympathectomized and by about 35 mm Hg in sham-treated recipients [19]. These data indicate that a generalized reduction of sympathetic tone resets the renal volume/pressure control system to reduced arterial pressure levels and blunts the arterial pressure rise induced by an SHR kidney graft (Fig. 2).


Figure 2
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  		Fig. 2 Mean arterial pressure (MAP) in sympathectomized (SHRxWKY)-F1 hybrids (F1H) (closed symbols, n = 10) and sham treated F1H (open symbols, n = 8) prior to transplantation with an SHR kidney and 6 weeks after renal transplantation. Asterisks indicate significant differences between groups (p<0.001). {ddagger} indicates a significant interaction between the factors treatment (sympathectomy, sham-treatment) and time after transplantation of an SHR kidney (p<0.05). There was an exaggerated arterial pressure rise in recipients with intact sympathetic nervous system compared to sympathectomized recipients. Reprinted with permission from Ref. [19].

 
The modulatory role of the sympathetic nervous system in human hypertension is evident from the well known antihypertensive effects of various types of treatment which block sympathetic activity either centrally or peripherally. On the other hand, hypertension in humans may develop under conditions where sympathetic tone is greatly reduced. Thus, in a study population of 117 patients with autonomic failure more than 50% had supine hypertension [44]. A recent study [45] showed that in adult humans with low birth weight—a group with a high prevalence of arterial hypertension—resting MSNA was lower than in subjects with normal birth weight. To our knowledge there is currently no data on renal norepinephrine spillover in this particular group of humans. In young borderline hypertensive subjects neither MSNA [46] nor resting plasma catecholamine concentrations were elevated compared to normotensive controls [46,47]. Conversely, normotensive obese subjects showed a similar rise in renal norepinephrine spillover as observed in both lean hypertensive and obese hypertensive patients [34]. Several studies in humans showed that increased bodyweight with and without hypertension was associated with elevated MSNA and plasma norepinephrine concentrations [26,28,34,46].

These findings indicate that elevated sympathetic and in particular elevated renal sympathetic activity is not a specific sign of (essential) hypertension. Possibly, a subgroup of obese patients may be able to compensate for elevated RSNA and does not develop high blood pressure. On the other hand, elevated RSNA may be an epiphenomenon of both obesity and hypertension which when present can worsen hypertensive disease. Prospective studies and careful stratification of patients according to anamnestic and clinical data [34,45] will help to further determine the causal role of elevated (renal) sympathetic activity in the pathogenesis of human essential hypertension.

3.3. Arterial baroreceptors and renal sympathetic nerve activity
There is evidence that compromised arterial baroreceptor reflex function may lead to salt-sensitive hypertension [48–51], possibly via increased RSNA. Thus, the generalized destruction of primary sensory afferents by neonatal capsaicin treatment facilitated the development of salt-induced hypertension in rats [50,51]. In a more specific approach chronic sinoaortic baroreceptor denervation caused normotensive rats to respond to a high-salt diet with increased renal sodium retention associated with an increase in arterial pressure [48,49]. Furthermore, chronic sinoaortic denervation increased the fluctuations in frequency and amplitude of synchronised renal sympathetic discharges [52] (Fig. 3). The discharge patterns of renal sympathetic nerves determine the degree of renal vasoconstriction and antinatriuresis [53]. These findings suggest that an impaired arterial baroreceptor reflex function may facilitate the development of salt-sensitive hypertension via its effects on RSNA.


Figure 3
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  		Fig. 3 Histograms show relative frequencies of synchronized renal sympathetic nerve discharges with regard to their amplitude (A) and time interval (B). Data were obtained from 15 min recordings in conscious freely moving rats (n = 9 per group) which underwent sham surgery (dotted lines) or sinoaortic denervation (solid lines) three weeks before the recordings. Sinoaortic denervated rats showed slightly greater fluctuations in the amplitude of synchronized renal sympathetic nerve activity compared to controls. Mode of time intervals between discharges and variability of the time intervals between synchronized discharges were substantially elevated in sinoaortic denervated rats (data from Ref. [52]).

 
In keeping with this hypothesis many studies demonstrated an altered arterial and cardiopulmonary baroreceptor reflex regulation of RSNA in inbred genetically hypertensive versus normotensive rats (for review, see Ref. [2]). Recent evidence from cosegregation studies [54–56] suggests, however, that the impaired cardiopulmonary reflex regulation of RSNA seen in genetically hypertensive animals may not be causally linked to hypertension. Thus, neither the degree of RSNA inhibition nor the diuretic and natriuretic responses to volume loading correlated with arterial pressure in backcross populations from SHRxWKY-F1-hybrids and WKY that were kept on a high-salt diet [55]. Hypertension did, however, cosegregate with a decreased responsiveness of renal afferent nerve activity to elevations in renal pelvic pressure [56] suggesting that a sensory system different from classical arterial and cardiopulmonary baroreceptors may be related to salt-sensitive hypertension.

Some degree of sensory dysfunction has also been found in human essential hypertension, although its exact role in the pathogenesis of hypertension has not been precisely defined. Thus, the range of arterial baroreflex-induced changes in heart rate was blunted by approximately 40% in essential hypertensive patients compared to normotensive controls [27]. On the other hand, arterial baroreflex-induced changes in MSNA were unaltered except for being reset to higher arterial pressure levels [27]. Since the sensitivity of baroreflex-induced changes in heart rate is to a large extend genetically determined [57] inherited variations in arterial baroreflex sensitivity may contribute to the genetically determined risk to develop hypertension.

Sensory dysfunction in human hypertension may not be strictly confined to the cardiovascular system. Thus, young subjects at risk for hypertension had decreased pain perception giving rise to the hypothesis that there may be a common physiological mechanism for sensory dysfunction and increased blood pressure [58].

3.4. Responsiveness to mental stress
The assessment of sympathetic activity in animals and humans invariably includes some kind of manipulation which may be associated with mental stress. Differences in so-called "baseline" sympathetic activity between hypertensive and normotensive subjects may therefore partly reflect a differential responsiveness to mental stress. While this can be a problem with certain experiments, mental stress is part of daily life and the responsiveness to stress may be relevant for the pathogenesis of arterial hypertension.

It is well established that SHR respond with greater increases of plasma catecholamine concentrations and renal as well as adrenal sympathetic nerve activity to mental stressors than WKY. The traits hyperactivity and hyperreactivity to mental stress have been genetically separated from hypertension in inbred lines derived from SHR and WKY [59] indicating that elevated neurohumoral reactivity to stress is not a prerequisite for the development of hypertension in SHR. The precise role of renal sympathetic nerves in the pathophysiology of hypertension in the new inbred line which is hypertensive but not hyperactive [59] has not been investigated.

On the other hand, mental stress can induce hypertension in borderline hypertensive rats (F1-hybrids derived from female SHR and male WKY) and stress-induced hypertension can be prevented by renal denervation (reviewed in Ref. [2]). In a backcross population derived from borderline hypertensive rats and WKY kept on a high salt diet a positive correlation between arterial pressure and the extent of RSNA increase in response to air jet stress was observed [60], suggesting that increased responsiveness of RSNA to stress may play a major role in this form of hypertension.

Intermittently elevated plasma and tissue catecholamine levels as they may occur during mental stress may have effects on the cardiovascular system that last well beyond the acute situation. Thus, in a study in normotensive rats blood pressure increased during systemic infusion of the {alpha}1-adrenoreceptor agonist, phenylephrine, and returned to normal when the infusion was stopped [61]. When phenylephrine-pretreated animals were exposed to a high salt diet later in life they developed hypertension associated with elevated blood pressure variability, increased urinary protein excretion and tubulointerstitial damage [61]. These experimental findings demonstrate that stress-induced catecholamine surges may enhance the propensity to develop renal damage and arterial hypertension in response to environmental factors such as increased sodium chloride intake.

There is evidence from clinical studies that the ability to autoregulate GFR during mental stress-induced elevations in arterial pressure may be reduced in hypertensive patients. In young borderline hypertensive humans mental stress caused a rise in GFR by 10±6 ml/min per 1.73 m2 compared to 6±7 ml/min per 1.73 m2 in normotensive controls [62]. This was associated with a similar reduction of renal plasma flow (RPF) in both groups but with slightly higher plasma renin activity in borderline hypertensive subjects [62]. A study in elderly patients with isolated systolic hypertension [63] also demonstrated an increase in GFR in response to mental stress in hypertensives which was not seen in normotensive controls. In contrast to the study performed in young borderline hypertensive subjects [62] the rise in GFR observed in elderly patients was accompanied by an elevation in RPF [63]. In another study [64] hypertensive subjects showed a similar increase in arterial pressure but a lower rise in urinary sodium excretion in response to mental stress than normotensive subjects. In the same study [64] changes in GFR, plasma angiotensin II concentration and renal sodium excretion in response to mental stress were not different between normotensive subjects with and without a family history of hypertension, suggesting that hypertension and alterations in renal hemodynamic and excretory responses to mental stress may develop concomitantly. The altered renal responses to mental stress may be indicative of pathologic changes in preglomerular vessel function which cause a compromised myogenic response. This in turn may exacerbate the development of glomerular damage due to elevations in glomerular capillary pressure.


   4. Renovascular hypertension and angiotensin II
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
5. End-stage renal disease
 6. Conclusion
 References
 
There is evidence for widespread sympathetic activation in renovascular hypertension. In rats both one-kidney, one-clip and two-kidney, one-clip hypertension are associated with elevated plasma norepinephrine levels [65]. In two-kidney, two-clip hypertensive dogs, plasma catecholamine concentrations and norepinephrine spillover rate were significantly increased [66]. Based on MSNA recordings and measurements of total body norepinephrine spillover several [67–69] but not all studies [27] found elevated sympathetic activity in patients with renovascular hypertension. Direct evidence for elevated RSNA in renovascular hypertension is limited. This is in part due to technical difficulties of measuring RSNA in experimental clip-induced renovascular hypertension. A study in two-kidney, one-clip hypertensive rabbits [70] suggests that RSNA to the non-clipped kidney is reduced. In keeping with these results plasma epinephrine and norepinephrine concentrations were higher in renal venous blood from the stenotic than the non-stenotic kidney in patients with renovascular hypertension [71]. The higher renal venous plasma catecholamine concentrations may be due to activation of RSNA to the stenotic kidney [71].

Alterations of arterial baroreflex regulation of sympathetic activity are also present in renovascular hypertension. Experimental data suggest that these reflex alterations may change with the course of the disease. In two-kidney, one-clip hypertensive rabbits the gain and range of arterial baroreflex-induced changes in RSNA to the non-clipped kidney was reduced, 3 weeks after renal artery clipping, but tended to normalize in the chronic phase of renovascular hypertension [70]. In chronic human renovascular hypertension the arterial baroreflex regulation of MSNA was reset to higher arterial pressure levels but was unchanged with regard to its range and sensitivity compared to normotensive subjects [27].

Circulating angiotensin II may contribute to elevated sympathetic activity in renovascular hypertension by its actions on the central nervous system (reviewed in Ref. [72]) or by activation of postganglionic sympathetic neurons [73,74]. In addition, elevated renal angiotensin II levels may contribute to altered regulation or stimulation of RSNA in renovascular hypertension by suppression of inhibitory reno-renal reflexes as has been recently shown in chronic heart failure rats [75]. The contribution of angiotensin II to elevated sympathetic nerve activity in renovascular hypertension is supported by experimental pharmacological interventions. Thus, acute reductions of mean arterial pressure in two-kidney, one-clip hypertensive rats with the angiotensin II AT1 receptor blocker, losartan, or the ACE inhibitor, lisinopril, for 120 min caused only transient reflex increases in splanchnic sympathetic nerve activity [76], whereas similar arterial pressure reductions with sodium nitroprusside caused a sustained increase in splanchnic nerve activity [76].

The effects of the renin–angiotensin system on sympathetic activity are also evident from data in renovascular hypertensive patients. Thus, the successful dilation of a stenotic renal artery lowers not only plasma renin activity but also MSNA [67]. Furthermore, plasma renin activity and plasma angiotensin II levels correlated well with MSNA and total body norepinephrine spillover [68]. Similar to experimental data [76] acute arterial pressure reduction by 15 mm Hg with dihydralazine but not with the ACE inhibitor, enalaprilat, elicited increased sympathetic activity in patients with renovascular hypertension as evidenced by a 50% rise in total body norepinephrine spillover and a 15% increase in peroneal sympathetic nerve activity [77]. In contrast, enalaprilat but not dihydralazine increased renal norepinephrine spillover by 40% in renovascular hypertensive patients [77]. These data are difficult to interpret since norepinephrine spillover was measured from both kidneys together [77] and the reason for elevated renal norepinephrine spillover after ACE inhibition is not clear. Overall, activation of the plasma renin–angiotensin system contributes to a generalized sympathetic activation in renovascular hypertension. If angiotensin II contributes to apparent differences in efferent RSNA between the stenotic and the non-stenotic kidney as well as to abnormalities in reno-renal reflex function requires further investigation.


   5. End-stage renal disease
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
6. Conclusion
 References
 
End-stage renal disease may develop as a consequence of chronic hypertension irrespective of its aetiology and contributes to elevated mortality in hypertensive patients. Evidence is accumulating that activation of the sympathetic nervous system occurs in this condition at least in part as a consequence of chronic activation of sympathoexcitatory inputs through renal afferent nerves.

In keeping with this notion, rats with 5/6 nephrectomy developed hypertension which was accompanied by elevated norepinephrine turnover rates in several brain areas and which was prevented by renal afferent denervation (dorsal rhizotomy) [78]. Rats with an acute phenol-induced renal lesion also showed increases in arterial pressure, RSNA and norepinephrine turnover rate in several brain nuclei which were antagonized by angiotensin II AT1 receptor blockade [79]. Furthermore, in mice acute administration of cyclosporine A elicited arterial hypertension accompanied by increases in both afferent and efferent renal nerve activity [80]. However, in synapsin knock-out mice the cyclosporine A-induced increases in arterial pressure and RSNA were greatly attenuated and the cyclosporine A-induced activation of afferent renal nerve activity was abolished [80]. These findings indicate that a reflex activation of sympathetic nerve activity involving renal afferent nerves contributes to acute cyclosporine A-induced hypertension [80]. On the other hand, chronic cyclosporine A-induced nephropathy was not associated with hypertension in uninephrectomized Sprague–Dawley rats and renal denervation had no effect on the development of renal damage [81].

Similar to the above mentioned experimental data, haemodialysis patients with both native kidneys showed higher arterial pressure, increased MSNA and elevated peripheral vascular resistance compared to bilaterally nephrectomized patients [82]. Furthermore, renal transplanted patients with both native kidneys showed higher MSNA than patients in whom the diseased kidneys had been removed [83]. Recently, elevated plasma neuropeptide Y levels, plasma norepinephrine concentrations and arterial pressure have been demonstrated to be associated with left ventricular hypertrophy in patients with end-stage renal disease [84].

Together, experimental findings and data obtained from studies in humans indicate that changes within the failing kidney such as inflammation and scarring can chronically activate renal afferent nerves which in turn causes sympathetic activation and thus contributes to worsening of arterial hypertension.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
References
 
Inappropriately high levels of sympathetic activity contribute to both primary (essential) and secondary forms of hypertension. Experimental studies provide evidence that altered interactions between the sympathetic nervous system and the kidney during ontogeny can be involved in the pathogenesis of primary hypertension. Further mechanisms leading to elevated sympathetic tone in primary hypertension include elevated central sympathetic drive and exaggerated responsiveness to mental stress as well as inherited reductions in somatic and visceral sensory receptor sensitivity. Subtle pathologic changes in the kidney which develop during mild stages of essential hypertension may increase its sensitivity to rises in sympathetic activity as occur during daily life and thus accelerate the rise in arterial pressure. Serious pathological changes within the kidney as occur in end-stage renal disease directly activate the sympathetic nervous system via elevated afferent renal nerve activity.

Experimental studies going beyond comparisons of inbred genetically hypertensive and normotensive rodent strains by using segregating populations or recombinant inbred strains [54,85] will continue to contribute to our understanding of the complex relationship between the sympathetic nervous system and renal mechanisms in the pathogenesis of hypertension. In addition to the rapidly developing tools of molecular biology this requires high quality and high throughput physiological techniques that allow for the precise characterization of integrated systems.

Recent studies in carefully characterized human study populations show that elevated renal and muscle sympathetic nerve activity is not unequivocally associated with essential hypertension. Prospective clinical studies which investigate a broader array of physiological functions will help to define specific phenotypes associated with elevated sympathetic activity and elevated renal sympathetic activity in particular. Follow up of such study populations will help to define conditions under which elevated sympathetic activity acts as a causal factor for hypertension.


   Notes
 
Time for primary review 28 days


   References
Top
 Abstract
 1. Introduction
 2. Quantification of renal...
 3. Primary or essential...
 4. Renovascular hypertension and...
 5. End-stage renal disease
 6. Conclusion
 References
 

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