Role Of Renal Sympathetic Nerves Research Articles

Update on Renal Sympathetic Denervation for the Treatment of Hypertension.

Hypertension is a leading risk factor for all-cause mortality in adults; however, medication non-adherence and intolerance present an enormous treatment challenge. Given the critical role of renal sympathetic nerves in neurogenic control of blood pressure and pathophysiology of hypertension, renal sympathetic denervation (RDN) has been explored as a therapeutic strategy in hypertension treatment over the last 15years. In this review, we will discuss the role of renal sympathetic nerves in the pathophysiology of hypertension, provide an update on the available evidence regarding the short- and long-term safety and effectiveness of RDN in the treatment of hypertension, and consider its future perspectives. RDN is a percutaneous endovascular catheter-based neuromodulation approach that enables ablation of renal sympathetic nerve fibers within the adventitial layer of the renal arteries using radiofrequency (most extensively studied), ultrasound energy, or neurolytics (e.g., alcohol). In the last decade, advancements in procedural techniques and well-designed sham-controlled trials utilizing 24-h ambulatory blood pressure measurements have demonstrated that RDN has an excellent safety profile and results in a modest reduction of blood pressure, in a wide range of hypertensive phenotypes (mild to resistant), irrespective of antihypertensive drug use and this effect is sustained over a 3-year period. Superiority of a particular RDN modality has not been yet established. Despite strong evidence demonstrating efficacy and safety of RDN, current data does not support its use as a primary approach in the treatment of hypertension due to its modest treatment effect and concerns around long-term sustainability. Perhaps the best utility of RDN is in hypertensives intolerant to antihypertensive medications or as an adjunct to aldosterone antagonists in the management of resistant hypertension. Patient selection will be critical to demonstrate a meaningful benefit of RDN. Future well-designed studies are necessary to determine predictors and measures of response to RDN, long-term efficacy given question of renal nerve regeneration, comparison of available technologies, safety in patients with advanced kidney disease, and improvement in patient quality of life measures.

Afferent renal nerves mediate hypertension and renal cystogenesis in a preclinical model of polycystic kidney disease

Polycystic kidney disease (PKD) remains a debilitating and chronic condition, and a common cause of end‐stage renal disease. In addition to renal pathology, hypertension is often presented. Renal sympathetic nerves are well‐known to contribute to renal function and arterial pressure homeostasis, which in turn, may be a novel therapeutic target for hypertension in PKD. Moreover, ablation of the renal sympathetic nerves purportedly mitigates cystic development in a preclinical model of PKD; however, the contribution of efferent of afferent renal nerves in this effect remains unknown. We recently developed a novel method to specifically ablate afferent renal nerves, leaving efferent nerves intact. In this study, we aimed to elucidate the role of renal sympathetic nerves in PKD‐induced hypertension and cystic development, as well as reveal the contribution of the individual efferent and afferent renal nerve populations. We hypothesized efferent renal nerves mediate renal cystogenesis and hypertension in the PKD rat, whereas afferent renal nerves play no role in this disease. To test this hypothesis, we performed a bilateral renal denervation (RDx), afferent‐specific RDx (ADx), or sham surgery on four‐week‐old male and female PKD rats (total n=36; 12/group; 6M/6F). Arterial pressure was measured by radiotelemetry. At 10 weeks of age, rodents were euthanized, and renal samples were collected for blinded histological analysis of cystic development. Renal function was estimated by plasma creatinine (PC) and blood urea nitrogen (BUN). Data was analyzed by a two‐way ANOVA, across sex and treatment groups (α=0.05). Data presented as mean+SEM. At 10 weeks of age, 24‐hour mean systolic arterial pressure (SBP) was lower (p<.05) in RDx (125±2) and ADx (123±3) vs. Sham (132±3 mmHg). Renal cystic index (%cyst/total area) was also reduced (p<.05) in both RDx (9.6±2.1%) and ADx (10.1±1.6%) compared to Sham (14.7±1.9%). No influence of sex was observed in either SBP or cystic index. No effect of treatment or sex was observed on indirect measurements of renal function (i.e. PC and BUN). Based on these findings, we reject our original hypothesis, as ADx mirrored the arterial pressure and cystogenesis effects observed with ablation of both efferent and afferent nerves (i.e. RDx). We conclude that afferent renal nerves contribute to the renal cystogenesis and hypertension in this model of PKD, in which either targeted ablation of afferent renal nerves may be a novel and effective therapeutic approach to PKD treatment. Though the mechanism of ADx treatment remains unclear, we hypothesize that afferent renal nerves mediate cystogenesis and arterial pressure through the suppression vasopressin (AVP), as AVP release is mediated in part by afferent renal nerve activation. Additionally, pharmacological antagonism of AVP activity (i.e. V2 receptor inhibition) in the collecting ducts is an effective clinical therapy to suppress PKD cystogenesis. Further studies are currently underway to elucidate the role of AVP regulation as a potential mechanism by which afferent nerves mediate renal cystogenesis and hypertension in this model.Support or Funding InformationThis project was supported in part by NIH HL116476 (JWO) and AHA 17POST33661003 (CTB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats.

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.

The role of renal sympathetic nerves in ischemia reperfusion injury.

Decreased blood flow supply to the kidneys known as renal ischemia/reperfusion is a common occurrence during various clinical and surgical settings. This remains highly concerning as it is a major cause of acute kidney injury (AKI). The kidneys have a rich supply of efferent and afferent sympathetic nerves playing a crucial physiological role in regulation of renal function. Studies in animal models of renal ischemia/reperfusion injury have indicated that very early during an ischemic event, the sympathetic nerves are activated and in concert with decreased nitric oxide availability, increased angiotensin II and several other molecules results in renal damage. Renal sympathetic inhibition or denervation seems to prevent or decrease some of the renal damage induced by ischemia/reperfusion injury but the evidence at present is based on animal studies and remains to be confirmed in the clinical setting. Remote ischemic preconditioning (IPC) has gained a lot of interest as a strategy to limit ischemia/reperfusion damage with some recent evidence suggesting that intact sympathetic nerves may be relevant in mediating protective effects. In this article, we review the experimental studies and emerging clinical studies that have investigated the role of sympathetic nerves following ischemia/reperfusion injury and studies exploring the role of sympathetic nerves in IPC and preventing tissue dysfunction induced by renal ischemia/reperfusion.

A clinician's perspective of the role of renal sympathetic nerves in hypertension.

The renal sympathetic nerves have significant contribution to the control of different aspects of kidney function. Early animal studies of renal denervation in a large number of different models of hypertension showed that that RDN improved BP control. Recently, data from prospective cohorts and randomized studies showed that renal denervation therapy (RDN) is a safe procedure but is associated with only modest reduction of ambulatory blood pressure (BP) in patients on intensive medical therapy. The main goal of this article is to review the results of preclinical and clinical studies on the contribution of the renal sympathetic nervous system to hypertension and the therapeutic applications of catheter-based renal denervation.

Renal Denervation and Hypertension

Essential hypertension remains one of the biggest challenges in medicine with an enormous impact on both individual and society levels. With the exception of relatively rare monogenetic forms of hypertension, there is now general agreement that the condition is multifactorial in nature and hence requires therapeutic approaches targeting several aspects of the underlying pathophysiology. Accordingly, all major guidelines promote a combination of lifestyle interventions and combination pharmacotherapy to reach target blood pressure (BP) levels in order to reduce overall cardiovascular risk in affected patients. Although this approach works for many, it fails in a considerable number of patients for various reasons including drug-intolerance, noncompliance, physician inertia, and others, leaving them at unacceptably high cardiovascular risk. The quest for additional therapeutic approaches to safely and effectively manage hypertension continues and expands to the reappraisal of older concepts such as renal denervation. Based on the robust preclinical and clinical data surrounding the role of renal sympathetic nerves in various aspects of BP control very recent efforts have led to the development of a novel catheter-based approach using radiofrequency (RF) energy to selectively target and disrupt the renal nerves. The available evidence from the limited number of uncontrolled hypertensive patients in whom renal denervation has been performed are auspicious and indicate that the procedure has a favorable safety profile and is associated with a substantial and presumably sustained BP reduction. Although promising, a myriad of questions are far from being conclusively answered and require our concerted research efforts to explore the full potential and possible risks of this approach. Here we briefly review the science surrounding renal denervation, summarize the current data on safety and efficacy of renal nerve ablation, and discuss some of the open questions that need to be addressed in the near future.

Renal Ischemic Injury Affects Renal Hemodynamics and Excretory Functions in Sprague Dawley Rats: Involvement of Renal Sympathetic Tone

The role of renal sympathetic nerves in the pathogenesis of ischemic acute renal failure (ARF) and the immediate changes in the renal excretory functions following renal ischemia were investigated. Two groups of male Sprague Dawley (SD) rats were anesthetized (pentobarbitone sodium, 60 mg kg−1 i.p.) and subjected to unilateral renal ischemia by clamping the left renal artery for 30 min followed by reperfusion. In group 1, the renal nerves were electrically stimulated and the responses in the renal blood flow (RBF) and renal vascular resistance (RVR) were recorded, while group 2 was used to study the early changes in the renal functions following renal ischemia. In post-ischemic animals, basal RBF and the renal vasoconstrictor reperfusion to renal nerve stimulation (RNS) were significantly lower (all p < 0.05 vs. control). Mean arterial pressure (MAP), basal RVR, urine flow rate (UFR), absolute and fractional excretions of sodium (UNaV and FENa), and potassium (UKV and FEK) were higher in ARF rats (all p < 0.05 vs. control). Post-ischemic animals showed markedly lower glomerular filtration rate (GFR) (p < 0.05 vs. control). No appreciable differences were observed in urinary sodium to potassium ratio (UNa/UK) during the early reperfusion phase of renal ischemia (p > 0.05 vs. control). The data suggest an immediate involvement of renal sympathetic nerve action in the pathogenesis of ischemic ARF primarily through altered renal hemodynamics. Diuresis, natriuresis, and kaliuresis due to impaired renal tubular functions are typical responses to renal ischemia and of comparable magnitudes.

The Role of Renal Sympathetic Nerves in Hypertension: Has Percutaneous Renal Denervation Refocused Attention on Their Clinical Significance?

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal artery, contribute to the pathogenesis of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent nerves should result in long-term attenuation of the hypertension. The importance of the renal nerves in patients with hypertension can now be defined with the novel development of percutaneous minimally invasive renal denervation from within the renal artery using radiofrequency energy as a therapeutic strategy. Studies thus far show that catheter-based renal denervation in patients with refractory hypertension lowers systolic blood pressure 27 mm Hg by 12 months with estimated glomerular filtration rate remaining stable. An attenuation of hypertension of this magnitude by catheter-based renal sympathetic denervation in combination with pharmacologic therapy is likely to be valuable in decreasing the risks of stroke, left ventricular hypertrophy, heart failure, and chronic renal failure.

Renal Denervation as a Therapeutic Approach for Hypertension

Hypertension, heart failure, and chronic kidney disease represent a significant and growing global health issue. Current therapeutic strategies for these conditions are mainly based on lifestyle interventions and pharmacological approaches, but the rates of control of blood pressure and the therapeutic efforts to prevent progression of heart failure, chronic kidney disease, and their sequelae remain unsatisfactory, and additional options are required. The contribution of renal sympathetic nerve activity to the development and progression of these disease states has been convincingly demonstrated in both preclinical and human experiments. Preclinical experiments in models of hypertension, myocardial infarction, heart failure, chronic kidney disease, and diabetic nephropathy have successfully used renal denervation as both an experimental tool and a therapeutic strategy.1–6 In the absence of appropriate drugs to pharmacologically reduce blood pressure in severely hypertensive patients, therapeutic splanchnicectomy and even radical surgical sympathectomy were used since the 1930s. In patients with end stage renal disease (ESRD) and uncontrollable hypertension, an even more radical approach, such as bilateral nephrectomy, is sometimes considered. Surgical renal denervation has been shown to be an effective means of reducing sympathetic outflow to the kidneys, increasing urine output (natriuresis and diuresis), and reducing renin release, without adversely affecting other functions of the kidney, such as glomerular filtration rate and renal blood flow. The human transplant experience has clearly demonstrated that the denervated kidney reliably supports electrolyte and volume homeostasis in free-living humans. On the basis of these findings and in view of the demand for alternative treatment options, targeting the renal sympathetic nerves as a major player in the pathophysiology of hypertension, kidney disease, and heart failure is a very attractive therapeutic approach. ### Role of Renal Sympathetic Nerves in Cardiovascular and Kidney Disease The renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure), …

Induction of Heme Oxygenase

Carbon monoxide (CO), produced within the body as a product of the catabolism of heme by the enzyme heme oxygenase (HO), has been reported to be a local vasodilator. One of its possible pathways is to stimulate guanylyl cyclase to produce cGMP as a second messenger.1 The parallel to NO, another gaseous signaling molecule that also works through cGMP-mediated pathways (although more potent), is obvious. In fact, the vasodilator actions of these 2 may be integrally linked. Both are endothelium derived.2 NO stimulation of cGMP may facilitate CO-mediated dilation of resistance vessels through calcium-activated potassium channels.3 However, the HO–CO story has not received the same interest and attention as NO, nor is it as generally well understood by those who work outside the field. In the present issue, we are presented with a provocative study by one of the well-established laboratories within the field of HO–CO. Wang et al4 focus on HO in the genetic model of hypertension, the spontaneously hypertensive rat (SHR). They report that 3 weeks of administration of hemin, the oxidation product of heme, which is both a substrate for and an inducer of HO, produced a profound 80-mmHg decrease in blood pressure that was sustained completely for 9 months after ceasing treatment (a duration in a rat’s life, which roughly translates into 17.5 human years). Although this is a remarkable, hopeful, and possibly profound observation, the study probably raises more questions than it answers. First, it is important to point out that this sustained decrease in blood pressure and reversal of hypertension is an unprecedented result. The potential importance of this observation is that a single 3-week treatment regimen induced a protracted reduction in blood pressure, long after treatment had ceased. To put this in perspective, treatment of virtually all forms of …

Role of Renal Sympathetic Nerves in Regulating Renovascular Responses to Angiotensin II in Spontaneously Hypertensive Rats

The purpose of this study was to test the hypothesis that renal sympathetic nerves modulate angiotensin II-induced renal vasoconstriction in kidneys from genetically hypertensive rats via Y1 receptors activating the Gi pathway. In isolated, perfused kidneys from spontaneously hypertensive rats, the naturally occurring renal sympathetic cotransmitter neuropeptide Y at 6 nM enhanced angiotensin II (0.3 nM)-induced changes in perfusion pressure by 47 +/- 7 mm Hg, and this effect was inhibited by BIBP3226 [N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-D-arginine amide)], a selective Y1 receptor antagonist (1 microM). We next examined whether periarterial nerve stimulation (5 Hz) enhances renal vascular responses to a physiological level of angiotensin II (100 pM). Kidneys were pretreated with prazosin (a selective alpha1-adrenoceptor antagonist) to block nerve stimulation-induced changes in perfusion pressure. In kidneys from spontaneously hypertensive rats, but not normotensive rats, periarterial nerve stimulation significantly augmented angiotensin II-induced changes in perfusion pressure (177 +/- 26% of response in absence of stimulation). BIBP3226, but not rauwolscine (a selective alpha2-adrenoceptor antagonist), abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. Pretreatment of hypertensive animals with pertussis toxin 3 days prior to kidney perfusion significantly (p < 0.000001) decreased mean blood pressure (203 +/- 2 versus 145 +/- 6 mm Hg in nonpretreated versus pertussis toxin-pretreated spontaneously hypertensive rats) and abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. We conclude that, in spontaneously hypertensive rats but not normotensive rats, sympathetic nerve stimulation enhances renal vascular responses to physiological levels of angiotensin II via a mechanism mainly involving Y1 receptors coupled to Gi proteins.

Renal sympathetic nerves do not modulate renal responses to haemorrhage in conscious lambs.

The present study was designed to investigate the renal responses to hypotensive haemorrhage early in life and the role of renal sympathetic nerves in modulating these renal responses. To this end, experiments were carried out in conscious, chronically instrumented lambs with either intact renal nerves (n = 7, Intact) or bilateral renal denervation performed at the time of surgery (n = 5, Denervated). Parameters of renal function were measured before and after 20% haemorrhage (experiment 1) and 0% haemorrhage (experiment 2), the latter serving as a time control. The two experiments were performed in random order at intervals of 24-48 h. Within 20 min of hypotensive haemorrhage in intact lambs, glomerular filtration rate decreased by approximately 60%; this response was not altered by renal denervation. Since renal plasma flow remained constant after haemorrhage, the filtration fraction also decreased. After 20% haemorrhage, urinary flow rate decreased in intact lambs; this response was also not altered by renal denervation. Excretion rates of Na+ and K+ as well as urinary osmolality and free water clearance were not altered by haemorrhage in either intact or denervated lambs. These data provide the first description of renal responses to haemorrhage early in life. In addition, the present findings provide new information that renal responses to haemorrhage early in life do not appear to be modulated by renal sympathetic nerves.

Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys.

Studies were conducted to investigate the role of renal sympathetic nerves in the process of acquiring ischaemic tolerance in ischaemic preconditioned ischaemia-reperfused rat kidneys. Two periods of 3-min occlusion of bilateral renal arteries was performed prior to 30-min bilateral ischaemia and 90-min reperfusion in acute renal denervated or innervated kidneys. The glomerular filtration rate (GFR), fractional excretion of sodium (FENa) and lithium (FELi), and renal blood flow (RBF) were assessed in reperfused kidneys. Ischaemic preconditioning significantly improved values for all these parameters as compared with no treated ischaemia-reperfused kidneys. Denervation caused slight increase in GFR, diuresis and natriuresis without improving RBF after reperfusion. However, protecting effects of ischaemic preconditioning on renal function were disappeared in denervated kidneys, while in innervated kidneys the effects of ischaemic preconditioning were maintained. These results clearly showed that ischaemic preconditioning pre-treatment protects kidneys against ischaemia-reperfusion injury, and the effects are, at least in part, mediated by sympathetic nerves, as the protective effects were abolished by denervation.

Renal denervation alters cardiovascular and endocrine responses to hemorrhage in conscious newborn lambs.

To investigate the role of renal sympathetic nerves in modulating cardiovascular and endocrine responses to hemorrhage early in life, we carried out three experiments in conscious, chronically instrumented lambs with intact renal nerves (intact; n = 8) and with bilateral renal denervation (denervated; n = 5). Measurements were made 1 h before and 1 h after 0, 10, and 20% hemorrhage. Blood pressure decreased transiently after 20% hemorrhage in intact lambs and returned to control levels. In denervated lambs, however, blood pressure remained decreased after 60 min. After 20% hemorrhage, heart rate increased from 170 +/- 16 to 207 +/- 18 beats/min in intact lambs but not in denervated lambs, in which basal heart rates were already elevated to 202 +/- 21 beats/min. Despite an elevated plasma renin activity (PRA) measured in denervated (12.0 +/- 6.4 ng ANG I . ml-1 . h-1) compared with intact lambs (4.0 +/- 1.1 ng ANG I . ml-1 . h-1), the increase in PRA in response to 20% hemorrhage was similar in both groups. Plasma levels of arginine vasopressin increased from 11 +/- 8 to 197 +/- 246 pg/ml after 20% hemorrhage in intact lambs but remained unaltered in denervated lambs from baseline levels of 15 +/- 10 pg/ml. These observations provide evidence that in the newborn, renal sympathetic nerves modulate cardiovascular and endocrine responses to hemorrhage.

Role of sympathetic nerves for the stimulation of the renin system by angiotensin II receptor blockade.

To assess the relevance of sympathetic nerves for the stimulation of renin secretion and renin gene expression during effective angiotensin II type 1 receptor blockade in vivo. Male Sprague-Dawley rats were treated with the angiotensin II type 1-receptor blocker losartan (40 mg/kg) for 3 days. To examine the role of renal sympathetic nerves in the stimulation of the renin system by losartan, left kidneys were denervated 4 days prior to the treatment with losartan. Also, to examine the role of circulating catecholamines in the stimulation of the renin system by losartan, the animals were administered a combination treatment of losartan with the beta1-adrenoreceptor blocker metoprolol (50 mg/kg per day) for 3 days. Losartan treatment increased plasma renin activity about sevenfold and renal renin messenger RNA (mRNA) levels about fivefold and decreased systolic blood pressure from 118 to 95 mmHg. Administration of losartan elevated renin mRNA both in the innervated and in the denervated kidneys to the same level as it did in kidneys of normal animals. Losartan treatment increased plasma renin activity and renal renin mRNA levels in the beta1-blocker-treated rats to the same extent as it did in animals administered losartan only. These findings suggest that, under sub-chronic treatment with hypotensive doses of angiotensin II receptor blockers, sympathetic outflow plays no important mediator role in the characteristic stimulation of renin secretion and renin gene expression, suggesting that it is mainly a direct disinhibition of angiotensin II's action on the level of juxtaglomerular cells that accounts for the effect.

Renal denervation prevents intraglomerular platelet aggregation and glomerular injury induced by chronic inhibition of nitric oxide synthesis.

Nitric oxide (NO) inhibits platelet adhesion and aggregation in vitro. In vivo, chronic inhibition of NO synthesis induces nephrosclerosis and hypertension. Although the pathophysiological mechanism of this glomerular injury has not been clarified, sympathetic nerve activation, a potent procoagulant stimulus elicited by NO inhibition, may play a role. To investigate the role of renal sympathetic nerves in the development of renal injury induced by NG-nitro-L-arginine methyl ester (L-NAME), a specific NO synthesis inhibitor, we examined renal histological changes in four groups of Sprague-Dawley rats: (1) sham operated, vehicle treated; (2) sham operated, L-NAME treated; (3) denervated, vehicle treated, and (4) denervated, L-NAME treated. Following renal denervation or sham operation, L-NAME was administered orally for 4 weeks. Chronic NO inhibition induced platelet aggregation and erythrocyte stasis in the glomerular capillary lumen accompanied by electron-microscopic glomerular injury. Renal denervation abrogated platelet aggregation and glomerular injury in L-NAME-treated animals. Thus, chronic NO synthesis inhibition induced intraglomerular platelet aggregation and glomerular injury, which was attenuated by renal nerve denervation. These results suggest that intrinsic NO may have an antithrombotic effect in the glomeruli and may play a protective role in the progression of glomerular injury possibly mediated by renal sympathetic nerves.

Effects of renal denervation on cardiovascular response to furosemide in conscious lambs.

The cardiovascular response to furosemide in the newborn and the role of renal sympathetic nerves in influencing this response have not been investigated. We hypothesized that in conscious lambs, furosemide would decrease blood pressure, the response being accentuated in the absence of renal sympathetic nerves. Pulsatile pressures and heart rates were measured before and after furosemide (2 mg/kg) administration to chronically instrumented lambs with either bilateral renal denervation (denervated, n = 8) or renal nerves intact (intact, n = 6). In intact lambs, mean arterial pressure remained constant after furosemide; in denervated lambs there was an increase in arterial pressure 20 min after furosemide (P < 0.001), and control levels were reached by 100 min. Basal heart rate was higher in denervated than in intact lambs (P = 0.009). In both groups of lambs, heart rate increased 40 min after furosemide and remained elevated. These data provide new information that, in conscious newborn animals, renal sympathetic nerves influence the blood pressure response to furosemide, as well as basal control of heart rate.

Influence of renal nerves on renal function during development.

The present review summarizes recent studies describing the role of renal sympathetic innervation in the regulation of renal function during development. The afferent renal innervation appears early during fetal life and probably precedes the development of efferent renal nerves. There is suggestive evidence that renal nerves are required for the proper development of the kidney and that neurotrophic growth factors play an important role in renal embryogenesis and in renal tubular differentiation. Renal sympathetic innervation modulates renal hemodynamics early during development. Renal nerve stimulation during alpha-adrenoceptor blockade produces renal vasodilation in fetal and newborn animals but not in adults. Unlike the effect of renal nerves on fetal renal hemodynamics which is observed in the young fetus, the role of renal sympathetic nerves in modulating fluid and electrolyte homeostasis seems to develop during late gestation. Recent studies have also shown that renal nerves play an important role in regulating renin secretion during the transition from fetal to newborn life. For example, renal denervation during fetal life suppressed the physiological rise in plasma renin activity associated with delivery and decreased renal renin mRNA levels after birth. Taken together, these studies suggest that renal nerves influence fetal renal development and that the influence of renal sympathetic innervation on renal hemodynamics and function changes with maturation.

Role of renal sympathetic nerves in lambs during the transition from fetal to newborn life.

To determine the role of renal sympathetic nerves in influencing renal function during the transition from fetal to newborn life, studies were carried out in conscious, chronically instrumented fetal sheep with either bilateral renal denervation (n = 11) or intact renal nerves (n = 12), 3-6 d after surgery. Endocrine, renal, and cardiovascular parameters were measured before and after delivery of lambs by cesarean section. Blood pressure and heart rate were similar in intact and denervated fetuses, and increased after delivery in both groups. There was also a transient diuresis and natriuresis, in the immediate postnatal period, the response being significantly greater in denervated than intact lambs (P less than 0.05). By 24 h postnatally, fluid and electrolyte excretions were similar in both groups, and significantly less than fetal levels. In the absence of renal nerves, the normal rise in plasma renin activity at birth was attenuated. These data provide evidence that renal sympathetic nerves play an important role during the transition from fetal to newborn life, and support the premise that birth is associated with sympathetic activation.

Role of renal sympathetic nerves in response of the ovine fetus to volume expansion

To investigate the role of renal sympathetic nerves in the fetal response to hypervolemia, studies were carried out in conscious, chronically instrumented fetal sheep aged 137-142 days of gestation. Bilateral renal denervation (n = 9) or sham surgery (n = 8) was carried out under halothane anesthesia 3-6 days before experiments. Bilateral renal denervation did not alter basal fetal renal hemodynamics, glomerular filtration rate (GFR), or Na+ excretion. Volume expansion with 6% Dextran 70 (18 ml/kg) was associated with a fall in fetal hematocrit, a sustained increase in mean arterial blood pressure, and a sustained diuresis and natriuresis. There was no significant change in GFR during fetal hypervolemia from control levels of 4.51 +/- 0.74 ml/min (intact) and 4.43 +/- 0.43 ml/min (denervated). Atrial natriuretic factor increased from 144 +/- 34 to 464 +/- 134 pg/ml, and plasma renin activity decreased from 5.15 +/- 1.7 to 3.04 +/- 1.0 ng.ml-1.h-1 in intact animals, within 30 min of completion of the dextran infusion. Similar changes occurred in denervated fetuses. Plasma aldosterone levels remained constant in intact and denervated fetuses during hypervolemia at control levels of 40.8 +/- 5.4 and 59.3 +/- 8.4 pg/ml, respectively. These findings suggest that renal sympathetic nerves do not influence basal renal hemodynamics or function and do not appear to play an important role in the natriuretic response to volume expansion during fetal life. This can be explained by a low tonic renal nerve activity before birth.