Renal Sympathetic Efferent Nerves Research Articles

Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation?

This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney's pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.

Renal denervation: a key approach to hypertension and cardiovascular disease.

Sympathetic activation plays a critical role in the development of hypertension and cardiovascular disease, including heart failure and arrhythmias. Renal nerves contribute to the regulation of blood pressure and fluid volume through renal sympathetic efferent nerves, and to the modulation of sympathetic outflow through renal sensory afferent nerves. Previous studies including ours suggest that selective afferent renal denervation with preservation of efferent renal nerves can significantly decrease central sympathetic outflow in animal models of hypertension with renal damage. In Dahl salt-sensitive rats fed high salt diet from an early age, a model of hypertensive heart failure, this central sympathoinhibition by afferent renal denervation may attenuate the development of heart failure without significant blood pressure reduction. Accumulating clinical evidence supports the efficacy of renal denervation as an antihypertensive treatment. However, it remains important to clarify the appropriate indications and predictors of responders to renal denervation in the treatment of hypertension. Several clinical studies suggest beneficial effects of renal denervation in patients with heart disease, with or without hypertension, although most were not sham-controlled. In particular, some clinical studies have demonstrated that renal denervation reduces the incidence of atrial fibrillation or cardiovascular events even without a significant antihypertensive effect. It is essential to accumulate more insightful data in patients undergoing renal denervation, to establish the efficacy of renal denervation in patients with cardiovascular disease in the clinical setting, and to elucidate the therapeutic mechanisms of renal denervation and the renal nerves-linked pathophysiology of cardiovascular disease in basic research. This review outlines the effects of renal denervation on sympathetic activity and organ damage in animal models of hypertension and hypertensive heart failure, including our own data. Beyond the antihypertensive effects, the beneficial effects of renal denervation on cardiovascular disease are also discussed based on clinical studies. Several animal and clinical studies suggest the cardioprotective effects of renal denervation even in the absence of significant blood pressure reduction, probably due to its sympathoinhibitory effects.

The Implementation of Renal Denervation in the Management of Resistant Hypertension Despite Use of Multitherapy Antihypertensives at Maximally Tolerated Doses: A Contemporary Literature Review.

Refractory hypertension is highly prevalent among the hypertensive population, and current clinical management has failed to provide optimal control for these individuals. This subtype of arterial hypertension is defined as a persistently elevated systolic blood pressure reading of 140 mmHg, or higher, despite multiple antihypertensive use at maximally tolerated dosing. These patients have an elevated risk of cardiovascular and renal complications, urging for the need of more effective therapeutic management. Renal sympathetic efferent nerves have been noted to play an important role in volume and blood pressure homeostasis. Before the implementation of oral antihypertensives, the use of surgical lumbar sympathectomy for the reduction of persistent hypertension was considered a life-saving approach. However, individuals were left with debilitating side effects, such as postural hypotension, syncope, and impotence. A new and minimally invasive technique has been proposed, where the kidneys undergo selective denervation in hopes of providing decreased cardiovascular morbidity and mortality for patients with resistant hypertension. Some studies demonstrated promising outcomes with a reduction in blood pressure, a decrease in medication reliance, and a potential long-lasting effect of the procedure with an overall improvement in cardiovascular health. Unfortunately, most of the available data was obtained from observational, uncontrolled studies with short-term follow-up, small sample sizes, and high variability in blood pressure measurement. Therefore, further evidence is needed to determine whether renal denervation provides long-term benefits for blood pressure control and improves outcomes for mortality and cardiovascular events in this patient population.

Abstract 17410: Catheter-based Radiofrequency Renal Denervation Decreases Renal Norepinephrine Spillover and Improves Cardiac Contractile Function in a Porcine Model of Ischemic Heart Failure

Background: Catheter-based radiofrequency (RF) renal denervation (RD) has been shown to decrease renal norepinephrine (NE) spillover in animal models and humans with hypertension. Nevertheless, the effect of RD on renal NE spillover in systolic heart failure (HF) is unknown. Methods: Ischemic HF model was created in 16 porcine by inducing myocardial infarction (MI) via coronary embolization of the left circumflex artery followed by rapid ventricular pacing for 4 weeks (MI+HF). Of these, 8 porcine underwent bilateral RD using the EnligHTN System (St. Jude Medical) and the remaining 8 served as control. All animals were given daily oral metoprolol ZOK (50 mg) plus ramipril (2.5 mg). Serum NE levels at different sites and index of cardiac contractility (dP/dt max /IP) were measured at baseline, immediately after MI (post-MI), at MI+HF and at 10 weeks follow-up. Renal arteries were then prepared for histological analysis. Results: RD significantly increased the dP/dt max /IP as compared with the control group (P<0.05, Figure 1a). RD also decreased the arterial and coronary sinus NE (P<0.05), and renal NE spillover (-54%, P=0.06) at 10 weeks as compared with MI+HF (Figures 1b & 1c). Histological examination showed significant reduction of renal sympathetic efferent nerves (tyrosine hydroxylase+) at proximal, middle and distal portions of the renal artery after RD as compared with the control group (-65%, P<0.05, Figure 1d). Conclusions: In a porcine model of ischemic HF, bilateral RD using catheter-based RF effectively destroys renal nerves to decrease renal NE spillover, and improves LV contractile function compared with medical therapy alone.

The Pathophysiological Basis of Renal Nerve Ablation for the Treatment of Hypertension

Renal sympathetic innervation plays an important role in blood pressure regulation. Gradual activation of renal sympathetic efferent nerves enhances renin release, promotes sodium and water re-absorption, and reduces renal blood flow and glomerular filtration rate. On the other hand, activation of renal afferent sympathetic nerves induced by renal injury results in central sympathetic activation. This reciprocal relationship between the kidneys and the brain is involved in the pathogenesis of hypertension and other disease conditions characterized by sympathetic overactivity. Renal sympathetic nerve ablation has been recently introduced for the treatment of resistant hypertension. This review aims to provide the pathophysiological basis of renal nerve ablation for the attenuation of sympathetic overactivity.

The Role of Renal Denervation in the Treatment of Heart Failure

The heart and kidney interact in terms of hemodynamics and neurohumoral regulatory mechanisms, and this helps to maintain circulatory homeostasis under normal conditions. However, the normal regulatory mechanisms become inappropriate in the setting of congestive heart failure (CHF), and significant renal dysfunction often develops in CHF patients. Activation of renal sympathetic efferent nerves causes renin release, sodium and water retention, and reduced renal blood flow, all hallmarks of the renal manifestations of CHF. An increase in plasma levels of angiotensin II that is mediated in part by renal sympathetic activation has an effect on the central nervous system to further increase global sympathetic tone. Renal sympathetic activity can be assessed clinically by renal norepinephrine spillover, and an increase in renal norepinephrine spillover in CHF predicts reduced survival. In addition to efferent sympathetic activation, activation of renal sensory nerves in CHF may cause a reflex increase in sympathetic tone that contributes to elevated peripheral vascular resistance and vascular remodeling as well as left ventricular remodeling and dysfunction. In animal models of heart failure, surgical renal denervation has been shown to improve both renal and ventricular function. Although surgical renal denervation has long been known to lower blood pressure and improve survival in patients with hypertension, the invasive nature of this approach and its associated complications has limited its appeal. However, a novel catheter-based device has recently been introduced that specifically interrupts both efferent and afferent renal nerves, and there is significant interest in the use of this device to treat both hypertension and CHF. Several ongoing clinical trials are investigating the safety and efficacy of renal denervation in patients with CHF.

Changes in blood pressure induced by electrical stimulation of the femur in anesthetized rats

The effects of electrical stimulation of the femur, on blood pressure, were examined in anesthetized rats. Two small holes, 3–4 mm apart, were manually drilled into the femur down to the bone marrow. Following this, two stainless-steel electrodes were inserted into the holes, and an electrical square wave current was passed between the electrodes. In central nervous system-intact rats, electrical stimulation of the femur at 5 and 10 mA at 20 Hz for 20 s produced an intensity-dependent decrease in mean arterial blood pressure. This response was abolished by severance of the femoral and sciatic nerves ipsilateral to the stimulation. Furthermore, the renal sympathetic efferent nerve activities (as a representative index of vasoconstrictor activities) decreased following the electrical stimulation of the femur. However, in acutely-spinalized rats (spinalized at the cervical level) the same stimulation increased renal sympathetic efferent nerve activities and mean arterial blood pressure. It was concluded that high-intensity electrical stimulation of the femur reflexively affected blood pressure. It can be inferred that the osteal high-threshold receptors and/or fibers are involved in the afferent nerve pathway, and the efferent nerve pathway is the sympathetic vasoconstrictor nerve. The excitatory response properties at the propriospinal level are modified into an inhibitory response by supraspinal structures.

Nitric oxide in the kidney.

bastron and kaloyanides([2][1]) had already investigated the effects of sodium nitroprusside in the isolated kidney 8 years before the postulate of an endothelium-derived relaxing factor was made by Furchgott and Zawadzki ([14][2]). More recent studies aim at the importance of nitric oxide (NO) for

Centrally mediated effect of 17beta-estradiol on parasympathetic tone in male rats.

The following experiments were conducted to determine if peripherally administered estrogen has an effect on central autonomic tone and whether this change in tone results in an alteration in cardiovascular reflex control. Male Sprague-Dawley rats were anesthetized with thiobutabarbitol sodium (50 mg/kg) and instrumented to record blood pressure, heart rate, and vagal parasympathetic or renal sympathetic efferent nerve activity. Additional rats were instrumented to test the sensitivity of the cardiac baroreflex using intravenous injections of phenylephrine hydrochloride (0.025, 0.05, 0.1 mg/kg) or sodium nitroprusside (0. 0025, 0.005, 0.01 mg/kg) and plotting the cardiovascular responses. Intravenous injection of estrogen (10(-4), 10(-2), and 10(-1) mg/kg) produced a significant increase in vagal efferent activity and in baroreflex sensitivity. The bilateral microinjection of an estrogen receptor antagonist, ICI-182,780 (1 pM, 50 nl/side) into the nucleus ambiguus blocked both the estrogen-induced increase in vagal efferent activity and baroreflex sensitivity. These results demonstrate that in male rats estrogen acts centrally to enhance baroreflex sensitivity by increasing parasympathetic efferent tone.

Effects of CGRP on baroreflex control of heart rate and renal sympathetic nerve activity in rabbits.

We examined the effects of intravenous infusion of calcitonin gene-related peptide (CGRP) and sodium nitroprusside (SNP) on baroreceptor afferent nerve activity, renal sympathetic efferent nerve activity (RSNA), and heart rate in alpha-chloralose-anesthetized rabbits. Baroreceptor afferent nerve activity was measured from aortic nerves during CGRP- and SNP-induced hypotension. Decreases in aortic nerve activity in response to decreases in mean arterial pressure were not different during CGRP and SNP infusion. Progressive infusion of CGRP (12-120 pmol.kg-1.min-1) increased RNSA by 83 +/- 14 (mean +/- SE), 175 +/- 26, 246 +/- 36, and 343 +/- 41%, and heart rate by 8 +/- 2, 24 +/- 3, 37 +/- 4, and 47 +/- 6 beats/min during falls of blood pressure of 5, 10, 15, and 20 mmHg, respectively. These increases in RSNA and heart rate produced by CGRP were significantly greater than those produced by SNP. The alterations in heart rate and RSNA with CGRP were reversed by restoring blood pressure with phenylephrine HCl. In rabbits with sinoaortic and vagal deafferentation, the responses of heart rate and RSNA to a fall of blood pressure were abolished during both CGRP and SNP infusion. Therefore, it is suggested that the facilitated responses of heart rate and RSNA during CGRP infusion occurred by way of the arterial baroreflex arc.

Effect of sympathetic sensitization of baroreceptors on renal nerve activity.

The role of sympathetic efferent innervation of the carotid sinus on the regulation of baroreceptor sensitivity was examined in thiopental-sodium anesthetized dogs (5 mg X kg-1 X h-1 infusion). Baroreflex sensitivity was defined as the slope of renal sympathetic efferent nerve activity vs. carotid sinus pressure in an isolated, perfused carotid sinus. Slopes were obtained before and after sinus sympathectomy performed by section of the cervical sympathetic trunk. There was no significant differences between baroreflex decreases in renal sympathetic activity due to increases in carotid sinus pressure before and after sympathectomy, but the responses to decreases in carotid sinus pressure after sympathectomy were significantly greater than control. Base-line level of renal sympathetic activity, obtained at a constant perfusion pressure of 115 mmHg, abruptly increased by 11% in response to sinus sympathectomy. The response of baroreceptors to sympathomimetic stimulation was examined by recording carotid baroreceptor afferent nerve activity during ramp changes in carotid sinus pressure after addition of epinephrine (10(-8) to 10(-6) M) to the perfusate of the sympathetically denervated sinus. The slopes of the sinus nerve activity vs. carotid sinus pressure were used as direct indexes of baroreceptor sensitivity. Lower levels of epinephrine (10(-8), 10(-7) M) increased the sensitivity of the baroreceptors and reduced renal nerve activity back toward presympathectomy levels. A higher dose of epinephrine (10(-6) M) did not significantly increase baroreceptor sensitivity. The results of this study suggest that sinus sympathetic fibers produce a tonic sensitization of the baroreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic efferent nerve activity in conscious and isoflurane-anesthetized dogs.

The hypotension accompanying isoflurane suggests that the anesthetic produces an attenuation of sympathetic tone. Previous studies examining the effects of isoflurane on sympathetic efferent nerve activity have required concomitant use of a basal anesthetic or decerebration, both of which independently alter sympathetic activity. This study was performed to examine the effects of isoflurane on sympathetic efferent nerve activity in the absence of basal anesthetic or decerebration. Five mongrel dogs were anesthetized with 4% isoflurane by mask. Platinum electrodes chronically were implanted around a renal nerve adjacent to the renal artery in order to measure renal sympathetic efferent nerve activity in the conscious and anesthetized animal. After 5-24 h for recovery, renal nerve activity and arterial pressure (via an implanted femoral artery cannula) were measured in the conscious, resting animal (control); during induction (4% isoflurane) and intubation; in the anesthetized animal (1.5% and 2.5% isoflurane); and during recovery and extubation. Isoflurane produced a significant dose-dependent depression of arterial blood pressure but did not significantly change heart rate from control. Renal sympathetic efferent nerve activity at 1.5% isoflurane was not significantly different from that in conscious animals, but nerve activity at 2.5% isoflurane was depressed significantly from both control and 1.5% isoflurane. Both intubation and extubation were accompanied by an increase in sympathetic nerve activity. Isoflurane appeared to directly depress sympathetic activity at both levels of anesthesia, but the direct depression of activity at 1.5% isoflurane seemed to be countered by reflex increases in sympathetic tone due to the hypotension accompanying the anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Splenic afferents and some of their reflex responses.

Afferent nerve activity was recorded from the distal ends of cut splenic nerves in pentobarbital- (35 mg/kg) anesthetized mongrel dogs (15-20 kg). Increases in splenic venous pressure (SVP) produced either by manual compression of discrete portions of the spleen or splenic contraction produced by injection of epinephrine (100 micrograms) into the splenic artery or vein of an occluded spleen produced significant increases in SVP and splenic afferent nerve activity. Increases in splenic afferent nerve activity were linearly related to increases in SVP. Histological sections of nerves from which afferent recordings were obtained demonstrated that all afferents were unmyelinated C-fibers. Electrical stimulation of the cut central end of splenic nerves resulted in marked reflex increases in both renal and cardiopulmonary sympathetic efferent nerve activity that remained elevated throughout the stimulation period. Reflex increase in cardiopulmonary sympathetic efferent nerve activity was associated with increases in right (22-45%) and left (11-19%) ventricular contractile force measured with Brodie-Walton strain gauge transducers, in heart rate (5-15 beats/min), and in blood pressure (5-10 mmHg). This study is the first to demonstrate both the existence of low-pressure baroreceptors in the spleen and that these splenic afferents can reflexly alter cardiopulmonary and renal sympathetic efferent nerve activity, heart rate, ventricular contractile force, and systemic blood pressure.

Reflex responses of single renal sympathetic fibres to stimulation of atrial receptors and carotid baro- and chemoreceptors.

Recordings were made of the discharge of single fibres from renal sympathetic efferent nerves in the anaesthetized dog. Stimulation of left atrial receptors by distension of small balloons at the junctions of the pulmonary veins and the left atrium resulted in a reduction in the discharge of one group of these single fibres and no change in the discharge of a second group of fibres. Bilateral occlusion of the common carotid arteries resulted in an increase in the discharge of all single fibres tested. All fibres tested which responded to stimulation of atrial receptors also responded to carotid occlusion. These results provide evidence for convergence of the central pathways from atrial receptors and baroreceptors on individual sympathetic efferent neurones.