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Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.

Despite availability of effective drugs for hypertension therapy, significant numbers of hypertensive patients fail to achieve recommended blood pressure levels on ≥3 antihypertensive drugs of different classes. These individuals have a high prevalence of adverse cardiovascular events and are defined as having resistant hypertension (RHT) although nonadherence to prescribed antihypertensive medications is common in patients with apparent RHT. Furthermore, apparent and true RHT often display increased sympathetic activity. Based on these findings, technology was developed to treat RHT by suppressing sympathetic activity with electrical stimulation of the carotid baroreflex and catheter-based renal denervation (RDN). Over the last 15 years, experimental and clinical studies have provided better understanding of the physiological mechanisms that account for blood pressure lowering with baroreflex activation and RDN and, in so doing, have provided insight into which patients in this heterogeneous hypertensive population are most likely to respond favorably to these device-based therapies. Experimental studies have also played a role in modifying device technology after early clinical trials failed to meet key endpoints for safety and efficacy. At the same time, these studies have exposed potential differences between baroreflex activation and RDN and common challenges that will likely impact antihypertensive treatment and clinical outcomes in patients with RHT. In this review, we emphasize physiological studies that provide mechanistic insights into blood pressure lowering with baroreflex activation and RDN in the context of progression of clinical studies, which are now at a critical point in determining their fate in RHT management.

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure.

Chronic kidney disease is prevalent among patients with resistant hypertension and activation of the sympathetic nervous system is common in both conditions. While renal nerve ablation lowers blood pressure (BP) in some resistant hypertensive patients, the influence of kidney disease on the antihypertensive response is largely unknown. Systemic hemodynamics and sympathetically-mediated low frequency oscillations of systolic BP were determined continuously by telemetry in rats before and after unilateral nephrectomy and surgical excision of the poles of the remaining kidney to reduce renal mass (RRM) ~ 80%. Before RRM, BP was not salt sensitive. However, placing rats with RRM on a high salt diet induced sustained increases in mean arterial pressure (Figure) and cardiac output while suppressing sympathetic activity. After denervation of the remnant kidney, sympathetic activity and heart rate increased, concomitant with reductions in BP and cardiac output. However, these acute responses waned over the 2 weeks of follow up. Subsequent central sympathetic inhibition with clonidine reduced sympathetic activity, heart rate and cardiac output, but not BP as peripheral resistance increased. Finally, when the low salt diet was restored, BP decreased back to normotensive levels. These results show that renal denervation does not chronically lower BP in this model of salt-sensitive hypertension associated with substantial nephron loss, but without active parenchymal disease, thus providing insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with advanced kidney disease.

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure (AP) and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation (BA) are often attributed to renal sympathoinhibition. However, BA also decreases heart rate (HR) and, surprisingly, robust blood pressure lowering occurs even after renal denervation. Accordingly, responses to BA were simulated under normal conditions and after blockade of changes in renal sympathetic nerve activity (fixed RSNA) and autonomic activity to the heart (fixed HR) using an established mathematical model of human physiology (HumMod). Three week responses to BA closely mimicked our actual experimental observations in dogs including a 40% decrease in plasma [norepinephrine] (and RSNA in the simulation). With RSNA and HR fixed at control levels, mean AP (MAP), HR, right atrial pressure (RAP) and plasma atrial natriuretic peptide (ANP) responses to BA were: Changes in autonomic activity to the heart during BA lead to bradycardia, increases in atrial pressure and ANP secretion. Increased ANP and suppression of RSNA enhance renal excretory function and normally account for most of the hypotensive response to BA. However, when suppression of RSNA is not possible, blood pressure lowering in response to BA is not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that BA effectively lowers blood pressure in subjects with previous renal denervation.

Chronic electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation has not been determined. As sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes ( 5, 40, 450 mmol/day, respectively) under control conditions and during a 7-day constant level of baroreflex activation. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mmHg) sodium intakes, but pressure increased 9 ±2 mmHg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng ANGI/mL/hr) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mmHg) and norepinephrine (20-40%) were lower at all salt intakes during baroreflex activation, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by baroreflex activation lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during baroreflex activation is independent of salt intake.

The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation—current therapies in patients with resistant hypertension, who are commonly obese—restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1–4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ≈70% reduction in renal mass. After control measurements, sodium intake was increased from ≈45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102±4 to 121±6 mm Hg and glomerular filtration rate from 40±2 to 45±2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103±6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139±21 to 81±9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43±2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons.

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electric activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat, whereas sodium intake was held constant. After 4 weeks on the high-fat diet, when body weight had increased ≈50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite an approximately 35% increase in glomerular filtration rate. The importance of increased tubular reabsorption to sodium retention was further reflected by ≈35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, glomerular filtration rate increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.

Following sinoaortic denervation, which eliminates arterial baroreceptor input into the brain, there are slowly developing adaptations that abolish initial sympathetic activation and hypertension. In comparison, electrical stimulation of the carotid sinus for 1 wk produces sustained reductions in sympathetic activity and arterial pressure. However, whether compensations occur subsequently to diminish these responses is unclear. Therefore, we determined whether there are important central and/or peripheral adaptations that diminish the sympathoinhibitory and blood pressure-lowering effects of more sustained carotid sinus stimulation. To this end, we measured whole body plasma norepinephrine spillover and α1-adrenergic vascular reactivity in six dogs over a 3-wk period of baroreflex activation. During the first week of baroreflex activation, there was an ∼45% decrease in plasma norepinephrine spillover, along with reductions in mean arterial pressure and heart rate of ∼20 mmHg and 15 beats/min, respectively; additionally, plasma renin activity did not increase. Most importantly, these responses during week 1 were largely sustained throughout the 3 wk of baroreflex activation. Acute pressor responses to α-adrenergic stimulation during ganglionic blockade were similar throughout the study, indicating no compensatory increases in adrenergic vascular reactivity. These findings indicate that the sympathoinhibition and lowering of blood pressure and heart rate induced by chronic activation of the carotid baroreflex are not diminished by adaptations in the brain and peripheral circulation. Furthermore, by providing evidence that baroreflexes have long-term effects on sympathetic activity and arterial pressure, they present a perspective that is opposite from studies of sinoaortic denervation.

1. Chronic electrical stimulation of the carotid sinuses has provided unique insight into the mechanisms that cause sustained reductions in blood pressure during chronic suppression of central sympathetic outflow. 2. Because renal denervation does not abolish the sustained fall in arterial pressure in response to baroreflex activation, this observation has seemingly challenged the concept that the kidneys play a critical role in the long-term control of arterial pressure during chronic changes in sympathetic activity. The aim of the present study was to use computer simulations to provide a more comprehensive understanding of physiological mechanisms that mediate sustained reductions in arterial pressure during prolonged baroreflex-mediated suppression of central sympathetic outflow. 3. Physiological responses to baroreflex activation under different conditions were simulated by an established mathematical model of human physiology (QHP2008; see Supporting Information (Appendix S1) provided in the online version of this article and/or http://groups.google.com/group/modelingworkshop). The model closely reproduced empirical data, providing important validation of its accuracy. 4. The simulations indicated that baroreflex-mediated suppression of renal sympathetic nerve activity does chronically increase renal excretory function but that, in addition, hormonal and haemodynamic mechanisms also contribute to this natriuretic response. The contribution of these redundant natriuretic mechanisms to the chronic lowering of blood pressure is of increased importance when suppression of renal adrenergic activity is prevented, such as after renal denervation. Activation of these redundant natriuretic mechanisms occurs at the expense of excessive fluid retention. 5. More broadly, the present study illustrates the value of numerical simulations in elucidating physiological mechanisms that are not obvious intuitively and, in some cases, not readily testable in experimental studies.

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%–50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

Prolonged electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure in normotensive dogs. The main goal of this study was to assess the influence of prolonged baroreflex activation on arterial pressure and neurohormonal responses in 6 dogs with obesity-induced hypertension. After control measurements, the diet was supplemented with cooked beef fat for 6 weeks, whereas sodium intake was held constant. After 4 weeks of the high-fat diet, there were increments in body weight from 25.8+/-0.7 to 38.6+/-1.0 kg, mean arterial pressure from 97+/-2 to 110+/-3 mm Hg, heart rate from 67+/-3 to 91+/-4 bpm, and plasma norepinephrine concentration from 141+/-35 to 280+/-52 pg/mL. Plasma glucose and insulin concentrations were elevated, but increases in plasma renin activity during the initial weeks of the high-fat diet were not sustained. During week 5, baroreflex activation resulted in sustained reductions in mean arterial pressure, heart rate, and plasma norepinephrine concentration; at the end of week 5, these values were 87+/-2 mm Hg, 77+/-4 bpm, and 166+/-45 pg/mL, respectively. These suppressed values returned to week 4 levels during a 7-day recovery period after baroreflex activation. There were no changes in plasma glucose or insulin concentrations, or plasma renin activity during prolonged baroreflex activation. These findings indicate that baroreflex activation can chronically suppress the sympathoexcitation associated with obesity and abolish the attendant hypertension while having no effect on hyperinsulinemia or hyperglycemia.

Recent studies indicate that suppression of renal sympathetic nerve activity and attendant increments in renal excretory function are sustained baroreflex-mediated responses in hypertensive animals. Given the central role of the kidneys in long-term regulation of arterial pressure, we hypothesized that the chronic blood pressure-lowering effects of the baroreflex are critically dependent on intact renal innervation. This hypothesis was tested in 6 dogs by bilaterally activating the carotid baroreflex electrically for 7 days before and after bilateral renal denervation. Before renal denervation, control values for mean arterial pressure and plasma norepinephrine concentration were 95+/-2 mm Hg and 96+/-12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13+/-1 mm Hg, and there was modest sodium retention. Daily sodium balance was subsequently restored, but reductions in mean arterial pressure were sustained throughout the 7 days of baroreflex activation. Activation of the baroreflex was associated with sustained decreases in plasma norepinephrine concentration ( approximately 50%) and plasma renin activity (30% to 40%). All of the values returned to control levels during a 7-day recovery period. Two weeks after renal denervation, control values for mean arterial pressure, plasma norepinephrine concentration, plasma renin activity, and sodium excretion were comparable to those measured when the renal nerves were intact. Moreover, after renal denervation, all of the responses to activation of the baroreflex were similar to those observed before renal denervation. These findings demonstrate that the presence of the renal nerves is not an obligate requirement for achieving long-term reductions in arterial pressure during prolonged activation of the baroreflex.

Recent technology for chronic electric activation of the carotid baroreflex and renal nerve ablation provide global and renal-specific suppression of sympathetic activity, respectively, but the conditions for favorable antihypertensive responses in resistant hypertension are unclear. Because inappropriately high plasma levels of aldosterone are prevalent in these patients, we investigated the effects of baroreflex activation and surgical renal denervation in dogs with hypertension induced by chronic infusion of aldosterone (12 μg/kg per day). Under control conditions, basal values for mean arterial pressure and plasma norepinephrine concentration were 100±3 mm Hg and 134±26 pg/mL, respectively. By day 7 of baroreflex activation, plasma norepinephrine was reduced by ≈40% and arterial pressure by 16±2 mm Hg. All values returned to control levels during the recovery period. Arterial pressure increased to 122±5 mm Hg concomitant with a rise in plasma aldosterone concentration from 4.3±0.4 to 70.0±6.4 ng/dL after 14 days of aldosterone infusion, with no significant effect on plasma norepinephrine. After 7 days of baroreflex activation at control stimulation parameters, the reduction in plasma norepinephrine was similar but the fall in arterial pressure (7±1 mm Hg) was diminished (≈55%) during aldosterone hypertension when compared with control conditions. Despite sustained suppression of sympathetic activity, baroreflex activation did not have central actions to inhibit either the stimulation of vasopressin secretion or drinking induced by increased plasma osmolality during chronic aldosterone infusion. Finally, renal denervation did not attenuate aldosterone hypertension. These findings suggest that aldosterone excess may portend diminished blood pressure lowering to global and especially renal-specific sympathoinhibition during device-based therapy.

This article reviews the history and current status of an innovative nonpharmacological approach for the treatment of resistant hypertension - chronic electrical activation of the afferent limb of the carotid baroreflex. Recent studies in both normotensive and hypertensive canine models have unambiguously demonstrated sustained and clinically relevant reductions in arterial pressure and sympathetic activity in the course of prolonged baroreflex activation. Clinical trials designed to evaluate the efficacy and safety of this therapy in patients with resistant hypertension are now underway in both Europe and the USA.

In most patients with hypertension, arterial pressure is above the target level for control, even in those individuals taking multiple antihypertensive drugs. In this article, we review the history and current status of a nonpharmacologic approach for the treatment of hypertension--chronic electrical activation of the afferent limb of the carotid baroreflex. Recent studies in normotensive and hypertensive dogs have clearly demonstrated impressive and sustained reductions in arterial pressure and sympathetic activity during prolonged baroreflex activation. Clinical trials are now underway in Europe, and clinical investigation in the United States will begin this year to evaluate the efficacy of this therapy in patients with resistant hypertension.

The major goal of this study was to determine whether there is increased activation of medullary neurons that participate in the central baroreceptor reflex pathway in dogs with obesity-induced hypertension, a model of hypertension that is associated with increased sympathetic activity. We used Fos-like (Fos-Li) protein immunohistochemical methods to determine activation of neurons in the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). Dogs were fed either a regular diet or an identical diet with the addition of 0.5 to 0.9 kg of cooked beef fat. After approximately 6 weeks of the high fat diet, body weight (36.3+/-0.4 vs 21.5+/-0.5 kg), mean arterial pressure (105+/-4 vs 91+/-3 mm Hg), and heart rate (97+/-4 vs 70+/-3 bpm) were significantly greater in obese than in control dogs, respectively. There was little Fos-Li immunoreactivity in medullary neurons of control dogs but marked reactivity in obese dogs. Specifically, the number of Fos-Li-positive cells in the NTS and CVLM was 3 to 5 times greater in obese than in control dogs. Furthermore, despite sustained activation of these baroreceptor-sensitive neurons, there was a significantly greater number of Fos-Li positive cells in the RVLM of dogs fed the high fat diet. As baroreceptor suppression of sympathoexcitatory cells in the RVLM is mediated by activation of neurons in the NTS and CVLM, these results support recent findings indicating that baroreflex suppression of sympathetic activity is a long-term compensatory response in hypertension. However, sympathoexcitatory inputs onto RVLM neurons would appear to predominate over the inhibitory effects of the baroreflex in obesity hypertension.

Recent technical advances have led to the development of a medical device that can reliably activate the carotid baroreflex with an acceptable degree of safety. Because activation of the sympathetic nervous system plays an important role in the pathogenesis of hypertension and heart failure, the unique ability of this device to chronically suppress central sympathetic outflow in a controlled manner suggests potential value in the treatment of these conditions. This notion is supported by both clinical and experimental animal studies, and the major aim of this article is to elucidate the physiological mechanisms that account for the favorable effects of baroreflex activation therapy in patients with resistant hyper-tension and heart failure. Illumination of the neurohormonal, renal, and cardiac actions of baroreflex activation is likely to provide the means for better identification of those patients that are most likely to respond favorably to this device-based therapy.

To determine whether the sympathetic nervous system contributes to the hypertension induced by pathophysiological increments in plasma angiotensin II (Ang II) concentration, we determined the neurally induced changes in renal excretory function during chronic intravenous infusion of Ang II. Studies were carried out in five conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from the denervated and innervated kidneys. After control measurements, Ang II was infused for 5 days at a rate of 4.8 pmol/kg per minute (5 ng/kg per minute); this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure (MAP) and for the ratio of denervated to innervated kidneys (DEN/INN) for urinary sodium, potassium, and creatinine excretion were 93+/-5 mm Hg, 1.17+/-0.09, 1.10+/-0.10, and 1.00+/-0.02, respectively. As expected, Ang II infusion caused sodium retention for several days before sodium balance was achieved at an elevated MAP (day 5=124+/-4 mm Hg). Moreover, by day 2 of Ang II-induced hypertension, there were significant reductions in the DEN/INN for sodium and potassium, which persisted for the 5 days of Ang II infusion; on day 5, the DEN/INN values for sodium and potassium were 0.71+/-0.10 and 0.91+/-0.12, respectively. In contrast, the DEN/INN for creatinine was unchanged from control levels during Ang II infusion, and measurements of renal hemodynamics indicated comparable reductions in glomerular filtration rate (approximately 13%) and renal plasma flow (approximately 25%) during Ang II infusion. This indicates that the renal nerves promoted sodium and potassium excretion during Ang II-induced hypertension by inhibiting tubular reabsorption of these electrolytes. Thus, this study provides no support for the hypothesis that increased renal sympathetic nerve activity impairs sodium excretion and contributes to Ang II-induced hypertension.

To determine whether the sympathetic nervous system contributes to the hypertension induced by long-term suppression of nitric oxide synthesis, we determined the neurally induced changes in renal excretory function during chronic administration of N g -nitro- l -arginine methyl ester (L-NAME). Studies were carried out in six conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into two hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. Animals were studied during acute (100 minutes) and chronic (5 days) intravenous infusion of L-NAME at 37.1 nmol/kg per minute (10 μg/kg per minute). During the first 100 minutes of L-NAME, there were no significant changes in mean arterial pressure (control: 96±3 mm Hg), but heart rate fell from 66±6 to 55±7 beats per minute. Changes in glomerular filtration rate were not significant, but renal plasma flow and urinary sodium excretion decreased to ≈75% and 50% of control values, respectively; however, these changes were comparable in both kidneys. In association with these responses, plasma concentrations of norepinephrine (control: 887±130 pmol/L or 150±22 pg/mL) and epinephrine (control: 691±192 pmol/L or 108±30 pg/mL) tended to decrease. In contrast to the acute responses, mean arterial pressure increased from 92±3 to 106±3 mm Hg and heart rate decreased from 72±4 to 57±5 beats per minute by day 5 of L-NAME infusion, while renal plasma flow and glomerular filtration rate were not significantly different from control values. Most importantly, there were no significant differences in urinary sodium excretion between innervated (control: 31±2 mmol/d) and denervated (control 33±2 mmol/d) kidneys during chronic L-NAME infusion or during the recovery period. These results indicate that the renal sympathetic nerves do not play an important role in promoting sodium retention during either acute or chronic inhibition of nitric oxide synthesis in conscious dogs. Thus, increased renal sympathetic nerve activity does not contribute significantly to L-NAME-induced hypertension.

Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electrical stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. However, a major goal of this article is to summarize experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term blood pressure lowering of arterial pressure with baroreflex activation. In so doing, the mechanistic insight from these studies may help to identify subsets of this heterogeneous population that stand to benefit the most. In this regard, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this article focuses on the mechanisms that link baroreflex-induced reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure. Despite the encouraging findings from recent clinical trials, more basic research and additional clinical trials are needed to better define the benefit of baroreflex activation therapy in resistant hypertension and in other states of sympathetic activation such as heart failure and advanced renal disease.

Abundant evidence supports a role of the sympathetic nervous system in the pathogenesis of obesity-related hypertension. However, the nature and temporal progression of mechanisms underlying this sympathetically mediated hypertension are incompletely understood. Recent technological advances allowing direct recordings of renal sympathetic nerve activity (RSNA) in conscious animals, together with direct suppression of RSNA by renal denervation and reflex-mediated global sympathetic inhibition in experimental animals and human subjects have been especially valuable in elucidating these mechanisms. These studies strongly support the concept that increased RSNA is the critical mechanism by which increased central sympathetic outflow initiates and maintains reductions in renal excretory function, causing obesity hypertension. Potential determinants of renal sympathoexcitation and the differential mechanisms mediating the effects of renal-specific versus reflex-mediated, global sympathetic inhibition on renal hemodynamics and cardiac autonomic function are discussed. These differential mechanisms may impact the efficacy of current device-based approaches for hypertension therapy.

The purpose of this study was to determine whether high plasma levels of atrial natriuretic peptide (ANP) in compensated heart failure are important in the maintenance of sodium balance. This was achieved by subjecting eight dogs to bilateral atrial appendectomy (APX) to blunt the ANP response to pacing-induced heart failure. Five intact dogs served as controls. In controls, 14 days of left ventricular pacing at 240 beats/min produced a sustained fall in cardiac output and mean arterial pressure of approximately 40 and 20%, respectively; compared with cardiac output, reductions in renal blood flow (up to approximately 25%) were less pronounced and even smaller decrements in GFR occurred (up to 9%). Despite these changes and a threefold elevation in plasma norepinephrine concentration, plasma renin activity (PRA) did not increase and sodium balance was achieved during the second week of pacing in association with a six- to eightfold rise in plasma levels of ANP. Similar responses occurred in four dogs in which APX was relatively ineffective in blunting the ANP response to pacing. In marked contrast, there were substantial increments in PRA and in plasma norepinephrine concentration, and marked sodium and water retention during the last week of pacing in four dogs with APX and severely deficient ANP. These results indicate that ANP plays a critical role in promoting sodium excretion in the early stages of cardiac dysfunction.

Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electrical stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. However, a major goal of this article is to summarize experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term blood pressure lowering of arterial pressure with baroreflex activation. In so doing, the mechanistic insight from these studies may help to identify subsets of this heterogeneous population that stand to benefit the most. In this regard, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this article focuses on the mechanisms that link baroreflex-induced reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure. Despite the encouraging findings from recent clinical trials, more basic research and additional clinical trials are needed to better define the benefit of baroreflex activation therapy in resistant hypertension and in other states of sympathetic activation such as heart failure and advanced renal disease.

There is considerable evidence that the sympathetic nervous system plays an important role in the pathogenesis of hypertension.1–3 However, the factors that chronically influence sympathetic activity and the precise mechanisms that mediate neurally induced hypertension are unclear. Topics of long-standing interest, but of considerable uncertainty, relate to the potential impact of the renin-angiotensin system and baroreflexes on sympathetic activity in hypertension. Numerous studies have demonstrated that baroreflex function is impaired in hypertension and that angiotensin II (Ang II) acutely stimulates the sympathetic nervous system.3–6 Despite this wealth of information, it is still unclear whether baroreflex dysfunction and elevated plasma levels of Ang II lead to chronic increases in sympathetic activity that promote hypertension. This uncertainty, in large part, has been due to technical limitations that prevent determination of long-term changes in sympathetic activity, particularly sympathetic activity to the kidneys (as discussed below). In this regard, the study by Barrett et al7 in this issue of Circulation Research is especially important for two reasons. First, it establishes a novel experimental technique for directly monitoring renal sympathetic nerve activity, 24 hours per day. Thus, for the first time, an experimental tool has been developed for assessing the critical neural signal from the brain to the kidneys that leads to long-term changes in body fluid volumes and arterial pressure. Second, by clearly establishing the time-dependent changes in renal sympathetic nerve activity during the induction of Ang II hypertension, this study brings to focus the complex interactions between Ang II and the sympathetic nervous system that are important in the long-term regulation of arterial pressure. Clearly, these interactions cannot be predicted from acute studies. Indeed, the most important finding in this study—that renal sympathetic nerve activity is chronically suppressed in Ang II hypertension—is diametrically opposite to what one might predict from …

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17±1 mmHg) and plasma (norepinephrine; ≈35%), with no change in plasma renin activity. Despite low pressure, sodium balance was achieved because of decreased tubular reabsorption, because glomerular filtration rate and renal blood flow decreased 10% to 20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mmHg, but with substantial increases in norepinephrine and plasma renin activity and no change in glomerular filtration rate. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation, and pressure decreased even further (by 11±2 mmHg). Moreover, during amlodipine administration, the fall in glomerular filtration rate with baroreflex activation was abolished. These findings suggest that the chronic blood pressure–lowering effects of baroreflex activation are attributed, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption before the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced glomerular filtration rate, a response abolished by amlodipine, which dilates the preglomerular vasculature.

See related article, pp 614–620 There has been a long-standing interest in the possibility that activation of the sympathetic nervous system may contribute to the hypertension induced by angiotensin II (Ang II). This hypothesis is commonly assessed by chronically infusing Ang II and using various tests to determine the sympathetic component to the increase in arterial pressure. Despite a multitude of studies, it is still unclear whether the sympathetic nervous system plays an important role in mediating this form of hypertension. Why the uncertainty? This is largely because of the varied and often times ambiguous experimental approaches to address this issue. More specifically, the uncertainty arises from studies using different animals, different sites of Ang II administration (central, intravenous, and subcutaneous), different rates of Ang II infusion, and different time courses of study. In addition, in most studies, measures of Ang II levels have not been made, making it difficult to determine whether reported effects are physiological, pathophysiological, or pharmacological. In addition, precise measures of sympathetic activity must be made before specific inferences regarding its role in Ang II hypertension can be made. Beyond these considerations, there are additional limitations that impede a clear resolution of this topic. The kidneys play a primary role in mediating long-term changes in arterial pressure, and, therefore, neurogenic mechanisms of hypertension must in some way impair renal excretory function. Because the renal nerves provide an obvious link between alterations in central sympathetic outflow and renal excretory function (Figure), an understanding of the role of neurogenic mechanisms in the maintenance of hypertension depends on measurement of renal sympathetic nerve activity (RSNA) and assessment of the influence of this sympathetic outflow on steady-state levels of arterial pressure. Unfortunately, technical limitations often preclude these chronic determinations. In this regard, the Circulatory Control Laboratory at the University of …

Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electric stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. The main goal of this article, however, is to summarize the preclinical studies that have provided insight into the mechanisms that account for the chronic blood pressure–lowering effects of carotid baroreflex activation. Some of the mechanisms identified were predictable and confirmed by experimentation. Others have been surprising and controversial, and resolution will require further investigation. Although feasibility studies have been promising, firm conclusions regarding the value of this device-based therapy for the treatment of resistant hypertension awaits the results of current multicenter trials.

Previous studies suggest that prolonged electric activation of the baroreflex may reduce arterial pressure more than chronic blockade of α 1 - and β 1,2 -adrenergic receptors. To determine whether central inhibition of sympathetic outflow has appreciable effects to chronically reduce arterial pressure by actions distinct from well-established mechanisms, we hypothesized that chronic baroreflex activation would lower arterial pressure substantially even during complete α 1 - and β 1,2 -adrenergic receptor blockade. This hypothesis was tested in 6 dogs during adrenergic blockade (AB; 18 days) with and without electric activation of the carotid baroreflex (7 days). During chronic AB alone, there was a sustained decrease in the mean arterial pressure of 21±2 mm Hg (control: 95±4 mm Hg) and an ≈3-fold increase in plasma norepinephrine concentration (control: 138±6 pg/mL), likely attributed to baroreceptor unloading. In comparison, during AB plus prolonged baroreflex activation, plasma norepinephrine concentration decreased to control levels, and mean arterial pressure fell an additional 10±1 mm Hg. Because of differences in plasma norepinephrine concentration, we also tested the acute blood pressure–lowering effects of MK-467, a peripherally acting α 2 -antagonist. After administration of MK-467, there was a significantly greater fall in arterial pressure during AB (15±3 mm Hg) than during AB plus prolonged baroreflex activation (7±3 mm Hg). These findings suggest that reflex-induced increases in sympathetic activity attenuate reductions in arterial pressure during chronic AB and that inhibition of central sympathetic outflow by prolonged baroreflex activation lowers arterial pressure further by previously undefined mechanisms, possibly by diminishing attendant activation of postjunctional α 2 -adrenergic receptors.

Recent technological advances have made the activation of the afferent limb of the baroreflex a viable therapeutic approach for lowering blood pressure. Experimental studies demonstrate sustained reductions in blood pressure in response to electrical baroreflex activation and initial results from clinical trials using device-based therapy for drug-resistant hypertension are promising. Although theoretically obvious at first glance, the mechanisms involved in the blood pressure lowering effect of baroreflex activation elude precise quantification, and experiments designed to investigate them invariably challenge preconceived notions and even dogmas. This paper is a brief overview of our current understanding of these mechanisms.

Recent findings in chronically instrumented animals challenge the classic concept that baroreflexes do not play a role in the chronic regulation of arterial pressure. As alterations in renal excretory function are of paramount importance in the chronic regulation of arterial pressure, several of these recent studies have focused on the long-term interactions between the baroreflex and the kidneys during chronic perturbations in arterial pressure and body fluid volumes. An emerging body of evidence indicates that the baroreflex is chronically activated in several experimental models of hypertension, but in most cases, the duration of these studies has not exceeded 2 wk. Although these studies suggest that the baroreflex may play a compensatory role in attenuating the severity of the hypertension, possibly even in primary hypertension with uncertain causes of sympathetic activation, there has been only limited assessment of the quantitative importance of this interaction in the regulation of arterial pressure. In experimental models of secondary hypertension, baroreflex suppression of renal sympathetic nerve activity is sustained and chronically promotes sodium excretion. This raises the possibility that the renal nerves may be the critical efferent link for baroreceptor-induced suppression of central sympathetic output through which long-term compensatory reductions in arterial pressure are produced. This contention is supported by strong theoretical evidence but must be corroborated by experimental studies. Finally, although it is now clear that pressure-induced increases in baroreflex activity persist for longer periods of time than previously suggested, studies using new tools and novel approaches and extending beyond 2 wk of hypertension are needed to elucidate the true role of the baroreflex in the pathogenesis of clinical hypertension.

The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93+/-3 mm Hg and 64+/-4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75+/-4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAP=72+/-5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rate=51+/-3 bpm). Prolonged baroreflex activation was also associated with approximately 35% reduction in plasma norepinephrine concentration (control=87+/-15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response.

hemorrhage and heart failure are conditions characterized by reduced cardiac output and arterial pressure. In both conditions, neurohormonal mechanisms are evoked in an attempt to restore arterial pressure to normal levels. However, the relative importance of the various neurohormonal mechanisms in

The major goal of this study was to determine whether there is increased activation of medullary neurons that participate in the central baroreceptor reflex pathway in dogs with obesity-induced hypertension, a model of hypertension that is associated with increased sympathetic activity. We used Fos-like (Fos-Li) protein immunohistochemical methods to determine activation of neurons in the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). Dogs were fed either a regular diet or an identical diet with the addition of 0.5 to 0.9 kg of cooked beef fat. After approximately 6 weeks of the high fat diet, body weight (36.3+/-0.4 vs 21.5+/-0.5 kg), mean arterial pressure (105+/-4 vs 91+/-3 mm Hg), and heart rate (97+/-4 vs 70+/-3 bpm) were significantly greater in obese than in control dogs, respectively. There was little Fos-Li immunoreactivity in medullary neurons of control dogs but marked reactivity in obese dogs. Specifically, the number of Fos-Li-positive cells in the NTS and CVLM was 3 to 5 times greater in obese than in control dogs. Furthermore, despite sustained activation of these baroreceptor-sensitive neurons, there was a significantly greater number of Fos-Li positive cells in the RVLM of dogs fed the high fat diet. As baroreceptor suppression of sympathoexcitatory cells in the RVLM is mediated by activation of neurons in the NTS and CVLM, these results support recent findings indicating that baroreflex suppression of sympathetic activity is a long-term compensatory response in hypertension. However, sympathoexcitatory inputs onto RVLM neurons would appear to predominate over the inhibitory effects of the baroreflex in obesity hypertension.