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Renal Nerves and Long‐Term Control of Arterial Pressure

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ABSTRACT

The objective of this review is to provide an in‐depth evaluation of how renal nerves regulate renal and cardiovascular function with a focus on long‐term control of arterial pressure. We begin by reviewing the anatomy of renal nerves and then briefly discuss how the activity of renal nerves affects renal function. Current methods for measurement and quantification of efferent renal‐nerve activity (ERNA) in animals and humans are discussed. Acute regulation of ERNA by classical neural reflexes as well and hormonal inputs to the brain is reviewed. The role of renal nerves in long‐term control of arterial pressure in normotensive and hypertensive animals (and humans) is then reviewed with a focus on studies utilizing continuous long‐term monitoring of arterial pressure. This includes a review of the effect of renal‐nerve ablation on long‐term control of arterial pressure in experimental animals as well as humans with drug‐resistant hypertension. The extent to which changes in arterial pressure are due to ablation of renal afferent or efferent nerves are reviewed. We conclude by discussing the importance of renal nerves, relative to sympathetic activity to other vascular beds, in long‐term control of arterial pressure and hypertension and propose directions for future research in this field. © 2017 American Physiological Society. Compr Physiol 7:263‐320, 2017.

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Figure 1. Figure 1. (A) Basic anatomy of renal nerves: The cell body of afferent renal nerves (left pane in blue) is located in the dorsal root ganglion from the T8‐L4 spinal segments. Sensory endings are located primarily in the pelvic wall and project to the dorsal horn of the spinal cord. Efferent renal nerves (right panel in red) are comprised of a preganglionic neuron and a postganglionic neuron. The cell body of renal preganglionic neurons, located in the IML cell column of spinal segments T6‐L4, project to synapse on the cell body of postganglionic neuron located either in the paravertebral or prevertebral ganglia. (B) Schematic representation of the traditional method for recording renal‐nerve activity in multifiber preparation: A bipolar hook electrode is placed around the renal nerve and the voltage difference between the two electrodes is amplified, then rectified and finally integrated. Recording from an intact renal nerve includes both afferent (shown as the blue fiber) and efferent (shown as red fibers) renal‐nerve activity.
Figure 2. Figure 2. Theoretical concept to explain how the three functions regulated by efferent renal nerves may be independently controlled: (A) In this scenario, JG cells, renal tubules, and renal arterioles are regulated via target‐specific preganglionic and postganglionic nerves. Three possible relationships between the frequency of nerve discharge (Hz) and renin release, sodium reabsorption, and RVR are illustrated in the stimulus‐responses curves below. (B) In this scenario, a single renal postganglionic neuron branches to innervate all three targets, each with a different frequency threshold.
Figure 3. Figure 3. Generalized concept demonstrating the multiple neural and hormonal inputs that potentially regulate the activity of RSNA: The two key brain sites that regulate renal sympathetic preganglionic neurons are the RVLM and the PVN. Neural inputs modulate activity of the RVLM via input to the NTS, which ultimately inhibits RVLM neurons via polysynaptic pathway (shown as a dotted line). Hormonal inputs act via several circumventricular organs including the SFO, OVLT in the hypothalamus and the area postrema in the brain stem. MnPO; median preoptic nucleus.
Figure 4. Figure 4. (A) Simplified schematic of arterial baroreflex control of ERNA. Baroreceptor input to the NTS results in inhibition of sympathetic premotor neurons in the RVLM (and PVN) resulting in a inverse relationship between arterial pressure and ERNA. (B) The arterial baroreceptor reflex curve. The relationship between arterial pressure and ERNA can be quantified in several ways. The set point is defined as arterial pressure and ERNA under basal conditions and is shown as the black dot on the curve. The gain of the reflex is defined as the slope of the linear portion of the curve around the set point. The maximum and minimum levels of ERNA represent the upper and lower plateaus, respectively. (C) Schematic representation of the acute responses, over the course of minutes, of ERNA and arterial pressure (AP) to surgical interruption of arterial baroreceptor input to the brainstem by sinoaortic denervation (SAD): Since arterial baroreceptors provide a tonic sympathoinhibitory input to the RVLM, SAD results in an immediate increase in ERNA which drives an increase in AP.
Figure 5. Figure 5. First demonstration in a conscious animal preparation that vasopressin inhibits RSNA independent of the arterial baroreceptor reflex. Comparison of the responses of RSNA and heart rate (HR) to infusion of phenylephrine (filled circle) and vasopressin (open circle) demonstrate that, at “equipressor doses” RSNA a HR decrease to a much greater extent. Indeed, during vasopressin infusion RSNA decreased markedly within the 0 to 5 mmHg range. Figure reprinted, with permission, from .
Figure 6. Figure 6. Frequency histograms comparing the distribution of MAP in conscious normal and sinoaortic‐denervated dogs. Panel A shows the 24‐h distribution from a single dog before and after denervation. Panel B shows data from 10 normal dogs. Panel C shows data from 12 denervated dogs. Although the variability was much greater in denervated dogs, the 24‐h mean level of arterial pressure was not elevated compared to normal dogs. Reprinted, with permission, from .
Figure 7. Figure 7. Schematic representation of the interaction of the arterial baroreceptor reflex and the renal‐body‐fluid control system in the regulation of arterial pressure: Both systems are shown as having a “set‐point” and an output variable that is responsive to arterial pressure. For the arterial baroreceptor reflex, increases in arterial pressure result in inhibition of SNA, which acts to normalize arterial pressure. For the renal‐body‐fluid control system, increases in arterial pressure result in increased urine output, which decreases blood volume (BV) and arterial pressure.
Figure 8. Figure 8. Cardiovascular and fluid balance responses to sinoaortic denervation over a period of 7 days in conscious rats: Mean arterial pressure and heart rate were increased transiently but returned to normal within 5 to 7 days after denervation. Although sodium excretion was elevated, resulting in an overall negative sodium balance, the first day after denervation, this response was reversed beginning the day 2 after denervation resulting in sodium retention. These results demonstrate that the normalization of arterial pressure following sinoaortic denervation is not due to pressure natriuresis and diuresis as predicted by the renal‐body‐fluid control system. Reprinted, with permission, from .
Figure 9. Figure 9. Renal sympathetic activity and arterial pressure in conscious intact and sinoaortic denervated rabbits: The left panel shows tracings of integrated (top) and raw (middle) renal SNA as well as arterial blood pressure (bottom) in a sinoaortic denervated rabbit. The right panel shows the level of arterial pressure (solid lines) and renal SNA (dotted lines) in four denervated rabbits (top four panels) and two intact rabbits (bottom two panels). In contrast to the predicted increase in renal SNA, sinoaortic denervated rabbits had normal arterial pressure and renal SNA. Reprinted, with permission, from .
Figure 10. Figure 10. Theoretical framework for the “CNS‐MAP set point” hypothesis: It is proposed that, although arterial baroreceptors are critical for the short‐term regulation of sympathetic activity (and arterial pressure), a nonbaroreflex neural system dictates the long‐term level of arterial pressure. Reprinted, with permission, from .
Figure 11. Figure 11. Response of RSNA, MAP, and heart rate (HR) to 1 week of oral salt loading in conscious rabbits: Despite the predicted importance of renal sympathetic nerves in the regulation of sodium balance, RSNA did not change during the entire oral salt loading period. Reprinted, with permission, from .
Figure 12. Figure 12. The “hormonal‐sympathetic reflex” proposed in 1995 for long‐term control of arterial pressure: The arterial baroreceptor reflex is shown as an “adaptive” short‐term controller of renal and nonrenal sympathetic activity and arterial pressure. In contrast, long‐term control or sympathetic activity and arterial pressure is dependent on “nonadaptive” input to the brain from hormonal inputs such as AngII, which is sympathoexcitatory, and arginine vasopressin (AVP), which is sympathoinhibitory. Reprinted, with permission, from .
Figure 13. Figure 13. The brain receives multiple hormonal inputs that modulate sympathetic outflow: Hormones related to regulation of energy balance (left) and body‐fluid balance (right) have been shown to modulate central neural networks that control sympathetic outflow to several targets. Schematic illustrates how several hormonal inputs generate a sympathetic signature: The left panel shows the response of three different hormones (A, B, and C) to an input indicated by the dotted line. Hormone A increases, hormone B remains constant, and hormone C is decreased. The right panel shows the response of cardiac, renal, splanchnic, and skeletal muscle SNA to this state‐specific hormonal profile.
Figure 14. Figure 14. Response of RSNA to AngII infusion in conscious rabbits: 7 days of AngII infusion increased arterial pressure and decreased RSNA in baroreceptor intact rabbits (left panel). Analysis of baroreflex curves suggests that the reduction of renal nerve activity was mediated by the baroreceptor reflex. Reprinted, with permission, from .
Figure 15. Figure 15. Effect of sinoaortic denervation on the response of RSNA to AngII infusion in conscious rabbits: 7 days of AngII administration decreases RSNA in normal rabbits (gray line) but not sinoaortic denervated rabbits (black line). Prevention of the sympathoinhibitory response to AngII did not affect the response of arterial pressure. These results indicate that renal sympathetic nerves are not important in modulating the pressor response to AngII in conscious rabbits. Reprinted, with permission, from .
Figure 16. Figure 16. The hypertensive response to AngII is directly related to dietary salt intake in conscious rats: Values for 24 h MAP measured by radiotelemetry are shown in rats fed a low (0.1% NaCl), normal (0.4% NaCl), or high (2.0% NaCl) diet. AngII was infused for 14 days. Reprinted, with permission, from .
Figure 17. Figure 17. Direct measurement of renal and lumbar sympathetic activity during the pathogenesis of AngII‐salt hypertension in conscious rats: MAP, RSNA, lumbar SNA (LSNA), and heart rate (HR) were measured in chronically instrumented rats administered either vehicle (open circles) or AngII (closed circles). All rats consumed a high‐salt diet (2.0% NaCl) throughout the protocol. Reprinted, with permission, from ().
Figure 18. Figure 18. Schematic representation of the hypothetical mechanisms responsible for generation of the AngII‐salt sympathetic signature: AngII and salt (NaCl) act synergistically in the forebrain to drive an increase in splanchnic SNA (SSNA) resulting in an increase in splanchnic vascular resistance and a decrease in capacitance. Inset shows a viscerotropic organization of sympathetic premotor neurons in the rostral ventrolateral medulla with strength of baroreceptor input indicated by the thickness of the red line. The balance of descending excitatory drive from the paraventricular nucleus (PVN) and inhibitory input from baroreceptors results in the changes in SSNA, RSNA, and LSNA sympathetic activity shown. Reprinted, with permission, from .
Figure 19. Figure 19. Effect of low‐dose AngII plus salt treatment on renal sympathetic activity in conscious rabbits: Arterial blood pressure (BP), RSNA, heart rate (HR), and daily‐fluid consumption was measured in chronically instrumented rabbits. On group consumed a 0.9% saline solution received AngII beginning on day 0 (open circles). The other group drank water and received vehicle treatment beginning on day 0 (closed circles). RSNA was quantified as either as absolute voltage or percentage of maximum. Reprinted, with permission, from .
Figure 20. Figure 20. High‐fat feeding increases renal sympathetic activity in conscious rabbits: Changes from baseline in body weight, blood glucose, plasma insulin concentration, plasma leptin concentration, calorie intake, MAP, heart rate (HR), and RSNA (normalized units [nu]) of rabbits fed a normal diet (open circles) or high‐fat diet (HFD; closed circles). Reprinted, with permission, from ().
Figure 21. Figure 21. Renal denervation chronically lowers arterial pressure in normotensive rats: (A) The responses of mean arterial pressure and heart rate to high salt feeding in intact (open circles) and renal‐denervated (closed circles) rats. Dietary salt intake was increased from normal (0.4% NaCl) to high (4.0%) for 10 days and then returned to normal. (B) Same experimental groups protocol shown in (A) but salt intake was decreased from normal to low (0.04%) for 10 days and then returned to normal. Reprinted, with permission ().
Figure 22. Figure 22. Summary of the effect of renal denervation on arterial pressure in healthy normotensive rats: Bilateral denervation results in an ∼10‐mmHg decrease in arterial pressure. Unilateral denervation results in a 5‐mmHg decrease in arterial pressure. In rats that had been subjected to a unilateral nephrectomy, denervation of the remaining kidney decreased arterial pressure by 10 mmHg.
Figure 23. Figure 23. Relationship between RSNA, renal blood flow (RBF), and renal vascular conductance (RVC) in conscious rats: Arterial pressure and RBF were measured simultaneously and continuously in consciously instrumented normotensive rats. Values are expressed as the change from baseline over a variety of physiological states including REM and NREM sleep, moving and grooming. Both RBF and RVC were significantly correlated to spontaneous changes in RSNA. Printed, with permission, from .
Figure 24. Figure 24. Table commonly shown in many reviews summarizing the effect of renal denervation on experimental models of hypertension. Reference numbers related to original paper and not this review article. Reprinted, with permission, from .
Figure 25. Figure 25. Effect of catheter‐based renal‐nerve ablation in drug‐resistant hypertensives from the Symplicity HTN 1 trial: Shown are the changes in office systolic and diastolic blood pressure from 1 to 36 months after renal‐nerve ablation. Reprinted, with permission, from .
Figure 26. Figure 26. Effect of catheter‐based renal‐nerve ablation in drug‐resistant hypertensives from the Symplicity HTN 3 trial: Effect of renal denervation and sham denervation on office systolic blood pressure 6 months following the procedure. Reprinted, with permission, from .
Figure 27. Figure 27. Effect of catheter‐based renal denervation on renal norepinephrine spillover in drug‐resistant hypertensives: The ability of catheter‐based renal denervation to denervate the kidney was assessed by the reduction in norepinephrine spillover. Reprinted, with permission, from .
Figure 28. Figure 28. Potential mechanisms mediating the responses to renal denervation: Renal denervation effects renal and nonrenal functions as a result of ablation of both efferent and afferent renal nerves. Reprinted, with permission, from .
Figure 29. Figure 29. Effects of renal‐CAP on markers for renal efferent and afferent nerves: Shown on left is a typical immunohistochemical preparation showing staining markers of efferent (TH) and afferent (CGRP) renal‐nerve terminals. Quantification of these markers is shown in (A) and (B) of the right panel. Quantification of the content of norepinephrine and CGRP content is shown in (C) and (D) of the right panel. Reprinted, with permission, from .
Figure 30. Figure 30. Comparison of the effects of renal‐CAP treatment and surgical renal denervation on markers of afferent renal nerves: Panel (A) shows CGRP content as the percent of control from 10 to 50 days posttreatment (). Panel (B) shows the ratio of SP and CGRP between denervated and innervated kidneys (). The time course of the recovery of these markers was similar for both methods. Reprinted with permission from , .
Figure 31. Figure 31. Effect of renal‐CAP treatment on the cardiovascular responses to intrarenal administration of bradykinin: Increasing doses of bradykinin were administered via either the renal artery (left) or intravenously (right) to conscious rats. Intrarenal artery infusion increased MAP and heart rate (HR) in sham treated (filled circles) but not renal‐CAP‐treated (open circles) rats. Intravenous administration of bradykinin had no effect in either group. Reprinted, with permission, from .
Figure 32. Figure 32. Effect of renal‐CAP treatment on the responses of MAP and heart rate (HR) to increased salt intake. Reprinted, with permission, from .
Figure 33. Figure 33. Comparison of the effects of surgical renal denervation (RDNX) and renal‐CAP on the development of DOCA‐salt hypertension: Baseline MAP and heart rate (HR) are shown in panel (A). Panel (B) shows the changes in MAP and HR in response to DOCA‐salt in sham (closed circles), RDNX (gray circles), and renal‐CAP (open circles) groups. Reprinted, with permission, from .
Figure 34. Figure 34. Comparison of the effects of renal‐CAP and surgical renal denervation (RDNX) on salt‐induced hypertension in Dahl S rats: Measurements were made after three (early phase) or nine (late phase) weeks of high‐salt diet. Bar graphs show the level of MAP before sham (black), RDNX (gray), or renal‐CAP (white treatment). The salt‐induced change in MAP following treatment is shown in the line graphs. The red line is the difference between sham and RDNX treatment groups on each day. Adapted, with permission, from .
Figure 35. Figure 35. Summary of studies from our laboratory on the effect of RDNX on MAP in normotensive Sprague Dawley and hypertensive Dahl S rats: RDNX decreases MAP ∼10 mmHg in both groups. Data adapted, with permission, from .
Figure 36. Figure 36. Relationship between renal nerve fibers and immune cells: ED1‐positive macrophages (blue) are located in close vicinity to both TH‐positive (red) and CGRP‐positive (green) nerve fibers. Dendritic cells (blue), positively stained for DC11c, OX62, or OX6 (MHC class II), are closely apposed (arrows) to both TH (red) and CGRP (green) positive fibers (purple overlay of TH/OX62 in lower left panel; white triple overlay of OX6, TH, and CGRP in lower right panel; yellow overlay of TH and CGRP nerve fibers as a result of intermingling with the fiber bundles. Bars = 50 μm. Reprinted, with permission, from .
Figure 37. Figure 37. Working hypothesis for the relationship between renal nerves, renal inflammation, and hypertension: Renal efferent nerves (red) drive trafficking of immune cells into the kidney, which release inflammatory cytokines. Renal inflammation drives afferent renal nerves (blue), which then stimulate central sympathoexcitatory pathways in the brain. This results in conditions associated with elevated sympathetic activity such as hypertension, altered glucose metabolism, and arrhythmias.
Figure 38. Figure 38. Schematic representation of how the renocentric (red) and neurocentric (blue) mathematical models of cardiovascular control generate the hemodynamic profile of AngII‐salt hypertension: Both models operate on the same cardiovascular circuit shown in black. Reprinted, with permission, from .
Figure 39. Figure 39. Simulations of the hemodynamic profile and pressure‐natriuresis relationship of AngII‐salt hypertension generated by the renocentric (gray) and neurocentric (black) mathematical models: The response of arterial pressure (AP), cardiac output (CO), blood volume (BV), total peripheral resistance (TPR), splanchnic vascular resistance (Ras), renal vascular resistance (Rar) to increased sodium intake (NaI), and AngII are shown in the left panel. The relationship between arterial pressure and sodium (Na) excretion is shown in the right panel. Reprinted, with permission, from .
Figure 40. Figure 40. Summary of studies from our laboratory examining the effect of targeted sympathetic ablation on arterial pressure in normotensive rats: Adapted, with permission, from .
Figure 41. Figure 41. Effect of targeted sympathetic ablation on MAP and heart rate (HR) in Dahl S rats: Rats were placed on a high‐salt diet on day 5 and 3 weeks later subjected to sham (open circles), RDNX (black circles), celiac ganglionectomy (CGX; open triangles), or combined RDNX‐GGX. Reprinted, with permission, from .
Figure 42. Figure 42. Effect of carotid baroreceptor stimulation on MAP and heart rate in conscious dogs before (gray circles) and after (black circles) renal denervation: Renal denervation had no effect on the arterial pressure response to chronic activation of carotid baroreceptors. Reprinted, with permission, from .


Figure 1. (A) Basic anatomy of renal nerves: The cell body of afferent renal nerves (left pane in blue) is located in the dorsal root ganglion from the T8‐L4 spinal segments. Sensory endings are located primarily in the pelvic wall and project to the dorsal horn of the spinal cord. Efferent renal nerves (right panel in red) are comprised of a preganglionic neuron and a postganglionic neuron. The cell body of renal preganglionic neurons, located in the IML cell column of spinal segments T6‐L4, project to synapse on the cell body of postganglionic neuron located either in the paravertebral or prevertebral ganglia. (B) Schematic representation of the traditional method for recording renal‐nerve activity in multifiber preparation: A bipolar hook electrode is placed around the renal nerve and the voltage difference between the two electrodes is amplified, then rectified and finally integrated. Recording from an intact renal nerve includes both afferent (shown as the blue fiber) and efferent (shown as red fibers) renal‐nerve activity.


Figure 2. Theoretical concept to explain how the three functions regulated by efferent renal nerves may be independently controlled: (A) In this scenario, JG cells, renal tubules, and renal arterioles are regulated via target‐specific preganglionic and postganglionic nerves. Three possible relationships between the frequency of nerve discharge (Hz) and renin release, sodium reabsorption, and RVR are illustrated in the stimulus‐responses curves below. (B) In this scenario, a single renal postganglionic neuron branches to innervate all three targets, each with a different frequency threshold.


Figure 3. Generalized concept demonstrating the multiple neural and hormonal inputs that potentially regulate the activity of RSNA: The two key brain sites that regulate renal sympathetic preganglionic neurons are the RVLM and the PVN. Neural inputs modulate activity of the RVLM via input to the NTS, which ultimately inhibits RVLM neurons via polysynaptic pathway (shown as a dotted line). Hormonal inputs act via several circumventricular organs including the SFO, OVLT in the hypothalamus and the area postrema in the brain stem. MnPO; median preoptic nucleus.


Figure 4. (A) Simplified schematic of arterial baroreflex control of ERNA. Baroreceptor input to the NTS results in inhibition of sympathetic premotor neurons in the RVLM (and PVN) resulting in a inverse relationship between arterial pressure and ERNA. (B) The arterial baroreceptor reflex curve. The relationship between arterial pressure and ERNA can be quantified in several ways. The set point is defined as arterial pressure and ERNA under basal conditions and is shown as the black dot on the curve. The gain of the reflex is defined as the slope of the linear portion of the curve around the set point. The maximum and minimum levels of ERNA represent the upper and lower plateaus, respectively. (C) Schematic representation of the acute responses, over the course of minutes, of ERNA and arterial pressure (AP) to surgical interruption of arterial baroreceptor input to the brainstem by sinoaortic denervation (SAD): Since arterial baroreceptors provide a tonic sympathoinhibitory input to the RVLM, SAD results in an immediate increase in ERNA which drives an increase in AP.


Figure 5. First demonstration in a conscious animal preparation that vasopressin inhibits RSNA independent of the arterial baroreceptor reflex. Comparison of the responses of RSNA and heart rate (HR) to infusion of phenylephrine (filled circle) and vasopressin (open circle) demonstrate that, at “equipressor doses” RSNA a HR decrease to a much greater extent. Indeed, during vasopressin infusion RSNA decreased markedly within the 0 to 5 mmHg range. Figure reprinted, with permission, from .


Figure 6. Frequency histograms comparing the distribution of MAP in conscious normal and sinoaortic‐denervated dogs. Panel A shows the 24‐h distribution from a single dog before and after denervation. Panel B shows data from 10 normal dogs. Panel C shows data from 12 denervated dogs. Although the variability was much greater in denervated dogs, the 24‐h mean level of arterial pressure was not elevated compared to normal dogs. Reprinted, with permission, from .


Figure 7. Schematic representation of the interaction of the arterial baroreceptor reflex and the renal‐body‐fluid control system in the regulation of arterial pressure: Both systems are shown as having a “set‐point” and an output variable that is responsive to arterial pressure. For the arterial baroreceptor reflex, increases in arterial pressure result in inhibition of SNA, which acts to normalize arterial pressure. For the renal‐body‐fluid control system, increases in arterial pressure result in increased urine output, which decreases blood volume (BV) and arterial pressure.


Figure 8. Cardiovascular and fluid balance responses to sinoaortic denervation over a period of 7 days in conscious rats: Mean arterial pressure and heart rate were increased transiently but returned to normal within 5 to 7 days after denervation. Although sodium excretion was elevated, resulting in an overall negative sodium balance, the first day after denervation, this response was reversed beginning the day 2 after denervation resulting in sodium retention. These results demonstrate that the normalization of arterial pressure following sinoaortic denervation is not due to pressure natriuresis and diuresis as predicted by the renal‐body‐fluid control system. Reprinted, with permission, from .


Figure 9. Renal sympathetic activity and arterial pressure in conscious intact and sinoaortic denervated rabbits: The left panel shows tracings of integrated (top) and raw (middle) renal SNA as well as arterial blood pressure (bottom) in a sinoaortic denervated rabbit. The right panel shows the level of arterial pressure (solid lines) and renal SNA (dotted lines) in four denervated rabbits (top four panels) and two intact rabbits (bottom two panels). In contrast to the predicted increase in renal SNA, sinoaortic denervated rabbits had normal arterial pressure and renal SNA. Reprinted, with permission, from .


Figure 10. Theoretical framework for the “CNS‐MAP set point” hypothesis: It is proposed that, although arterial baroreceptors are critical for the short‐term regulation of sympathetic activity (and arterial pressure), a nonbaroreflex neural system dictates the long‐term level of arterial pressure. Reprinted, with permission, from .


Figure 11. Response of RSNA, MAP, and heart rate (HR) to 1 week of oral salt loading in conscious rabbits: Despite the predicted importance of renal sympathetic nerves in the regulation of sodium balance, RSNA did not change during the entire oral salt loading period. Reprinted, with permission, from .


Figure 12. The “hormonal‐sympathetic reflex” proposed in 1995 for long‐term control of arterial pressure: The arterial baroreceptor reflex is shown as an “adaptive” short‐term controller of renal and nonrenal sympathetic activity and arterial pressure. In contrast, long‐term control or sympathetic activity and arterial pressure is dependent on “nonadaptive” input to the brain from hormonal inputs such as AngII, which is sympathoexcitatory, and arginine vasopressin (AVP), which is sympathoinhibitory. Reprinted, with permission, from .


Figure 13. The brain receives multiple hormonal inputs that modulate sympathetic outflow: Hormones related to regulation of energy balance (left) and body‐fluid balance (right) have been shown to modulate central neural networks that control sympathetic outflow to several targets. Schematic illustrates how several hormonal inputs generate a sympathetic signature: The left panel shows the response of three different hormones (A, B, and C) to an input indicated by the dotted line. Hormone A increases, hormone B remains constant, and hormone C is decreased. The right panel shows the response of cardiac, renal, splanchnic, and skeletal muscle SNA to this state‐specific hormonal profile.


Figure 14. Response of RSNA to AngII infusion in conscious rabbits: 7 days of AngII infusion increased arterial pressure and decreased RSNA in baroreceptor intact rabbits (left panel). Analysis of baroreflex curves suggests that the reduction of renal nerve activity was mediated by the baroreceptor reflex. Reprinted, with permission, from .


Figure 15. Effect of sinoaortic denervation on the response of RSNA to AngII infusion in conscious rabbits: 7 days of AngII administration decreases RSNA in normal rabbits (gray line) but not sinoaortic denervated rabbits (black line). Prevention of the sympathoinhibitory response to AngII did not affect the response of arterial pressure. These results indicate that renal sympathetic nerves are not important in modulating the pressor response to AngII in conscious rabbits. Reprinted, with permission, from .


Figure 16. The hypertensive response to AngII is directly related to dietary salt intake in conscious rats: Values for 24 h MAP measured by radiotelemetry are shown in rats fed a low (0.1% NaCl), normal (0.4% NaCl), or high (2.0% NaCl) diet. AngII was infused for 14 days. Reprinted, with permission, from .


Figure 17. Direct measurement of renal and lumbar sympathetic activity during the pathogenesis of AngII‐salt hypertension in conscious rats: MAP, RSNA, lumbar SNA (LSNA), and heart rate (HR) were measured in chronically instrumented rats administered either vehicle (open circles) or AngII (closed circles). All rats consumed a high‐salt diet (2.0% NaCl) throughout the protocol. Reprinted, with permission, from ().


Figure 18. Schematic representation of the hypothetical mechanisms responsible for generation of the AngII‐salt sympathetic signature: AngII and salt (NaCl) act synergistically in the forebrain to drive an increase in splanchnic SNA (SSNA) resulting in an increase in splanchnic vascular resistance and a decrease in capacitance. Inset shows a viscerotropic organization of sympathetic premotor neurons in the rostral ventrolateral medulla with strength of baroreceptor input indicated by the thickness of the red line. The balance of descending excitatory drive from the paraventricular nucleus (PVN) and inhibitory input from baroreceptors results in the changes in SSNA, RSNA, and LSNA sympathetic activity shown. Reprinted, with permission, from .


Figure 19. Effect of low‐dose AngII plus salt treatment on renal sympathetic activity in conscious rabbits: Arterial blood pressure (BP), RSNA, heart rate (HR), and daily‐fluid consumption was measured in chronically instrumented rabbits. On group consumed a 0.9% saline solution received AngII beginning on day 0 (open circles). The other group drank water and received vehicle treatment beginning on day 0 (closed circles). RSNA was quantified as either as absolute voltage or percentage of maximum. Reprinted, with permission, from .


Figure 20. High‐fat feeding increases renal sympathetic activity in conscious rabbits: Changes from baseline in body weight, blood glucose, plasma insulin concentration, plasma leptin concentration, calorie intake, MAP, heart rate (HR), and RSNA (normalized units [nu]) of rabbits fed a normal diet (open circles) or high‐fat diet (HFD; closed circles). Reprinted, with permission, from ().


Figure 21. Renal denervation chronically lowers arterial pressure in normotensive rats: (A) The responses of mean arterial pressure and heart rate to high salt feeding in intact (open circles) and renal‐denervated (closed circles) rats. Dietary salt intake was increased from normal (0.4% NaCl) to high (4.0%) for 10 days and then returned to normal. (B) Same experimental groups protocol shown in (A) but salt intake was decreased from normal to low (0.04%) for 10 days and then returned to normal. Reprinted, with permission ().


Figure 22. Summary of the effect of renal denervation on arterial pressure in healthy normotensive rats: Bilateral denervation results in an ∼10‐mmHg decrease in arterial pressure. Unilateral denervation results in a 5‐mmHg decrease in arterial pressure. In rats that had been subjected to a unilateral nephrectomy, denervation of the remaining kidney decreased arterial pressure by 10 mmHg.


Figure 23. Relationship between RSNA, renal blood flow (RBF), and renal vascular conductance (RVC) in conscious rats: Arterial pressure and RBF were measured simultaneously and continuously in consciously instrumented normotensive rats. Values are expressed as the change from baseline over a variety of physiological states including REM and NREM sleep, moving and grooming. Both RBF and RVC were significantly correlated to spontaneous changes in RSNA. Printed, with permission, from .


Figure 24. Table commonly shown in many reviews summarizing the effect of renal denervation on experimental models of hypertension. Reference numbers related to original paper and not this review article. Reprinted, with permission, from .


Figure 25. Effect of catheter‐based renal‐nerve ablation in drug‐resistant hypertensives from the Symplicity HTN 1 trial: Shown are the changes in office systolic and diastolic blood pressure from 1 to 36 months after renal‐nerve ablation. Reprinted, with permission, from .


Figure 26. Effect of catheter‐based renal‐nerve ablation in drug‐resistant hypertensives from the Symplicity HTN 3 trial: Effect of renal denervation and sham denervation on office systolic blood pressure 6 months following the procedure. Reprinted, with permission, from .


Figure 27. Effect of catheter‐based renal denervation on renal norepinephrine spillover in drug‐resistant hypertensives: The ability of catheter‐based renal denervation to denervate the kidney was assessed by the reduction in norepinephrine spillover. Reprinted, with permission, from .


Figure 28. Potential mechanisms mediating the responses to renal denervation: Renal denervation effects renal and nonrenal functions as a result of ablation of both efferent and afferent renal nerves. Reprinted, with permission, from .


Figure 29. Effects of renal‐CAP on markers for renal efferent and afferent nerves: Shown on left is a typical immunohistochemical preparation showing staining markers of efferent (TH) and afferent (CGRP) renal‐nerve terminals. Quantification of these markers is shown in (A) and (B) of the right panel. Quantification of the content of norepinephrine and CGRP content is shown in (C) and (D) of the right panel. Reprinted, with permission, from .


Figure 30. Comparison of the effects of renal‐CAP treatment and surgical renal denervation on markers of afferent renal nerves: Panel (A) shows CGRP content as the percent of control from 10 to 50 days posttreatment (). Panel (B) shows the ratio of SP and CGRP between denervated and innervated kidneys (). The time course of the recovery of these markers was similar for both methods. Reprinted with permission from , .


Figure 31. Effect of renal‐CAP treatment on the cardiovascular responses to intrarenal administration of bradykinin: Increasing doses of bradykinin were administered via either the renal artery (left) or intravenously (right) to conscious rats. Intrarenal artery infusion increased MAP and heart rate (HR) in sham treated (filled circles) but not renal‐CAP‐treated (open circles) rats. Intravenous administration of bradykinin had no effect in either group. Reprinted, with permission, from .


Figure 32. Effect of renal‐CAP treatment on the responses of MAP and heart rate (HR) to increased salt intake. Reprinted, with permission, from .


Figure 33. Comparison of the effects of surgical renal denervation (RDNX) and renal‐CAP on the development of DOCA‐salt hypertension: Baseline MAP and heart rate (HR) are shown in panel (A). Panel (B) shows the changes in MAP and HR in response to DOCA‐salt in sham (closed circles), RDNX (gray circles), and renal‐CAP (open circles) groups. Reprinted, with permission, from .


Figure 34. Comparison of the effects of renal‐CAP and surgical renal denervation (RDNX) on salt‐induced hypertension in Dahl S rats: Measurements were made after three (early phase) or nine (late phase) weeks of high‐salt diet. Bar graphs show the level of MAP before sham (black), RDNX (gray), or renal‐CAP (white treatment). The salt‐induced change in MAP following treatment is shown in the line graphs. The red line is the difference between sham and RDNX treatment groups on each day. Adapted, with permission, from .


Figure 35. Summary of studies from our laboratory on the effect of RDNX on MAP in normotensive Sprague Dawley and hypertensive Dahl S rats: RDNX decreases MAP ∼10 mmHg in both groups. Data adapted, with permission, from .


Figure 36. Relationship between renal nerve fibers and immune cells: ED1‐positive macrophages (blue) are located in close vicinity to both TH‐positive (red) and CGRP‐positive (green) nerve fibers. Dendritic cells (blue), positively stained for DC11c, OX62, or OX6 (MHC class II), are closely apposed (arrows) to both TH (red) and CGRP (green) positive fibers (purple overlay of TH/OX62 in lower left panel; white triple overlay of OX6, TH, and CGRP in lower right panel; yellow overlay of TH and CGRP nerve fibers as a result of intermingling with the fiber bundles. Bars = 50 μm. Reprinted, with permission, from .


Figure 37. Working hypothesis for the relationship between renal nerves, renal inflammation, and hypertension: Renal efferent nerves (red) drive trafficking of immune cells into the kidney, which release inflammatory cytokines. Renal inflammation drives afferent renal nerves (blue), which then stimulate central sympathoexcitatory pathways in the brain. This results in conditions associated with elevated sympathetic activity such as hypertension, altered glucose metabolism, and arrhythmias.


Figure 38. Schematic representation of how the renocentric (red) and neurocentric (blue) mathematical models of cardiovascular control generate the hemodynamic profile of AngII‐salt hypertension: Both models operate on the same cardiovascular circuit shown in black. Reprinted, with permission, from .


Figure 39. Simulations of the hemodynamic profile and pressure‐natriuresis relationship of AngII‐salt hypertension generated by the renocentric (gray) and neurocentric (black) mathematical models: The response of arterial pressure (AP), cardiac output (CO), blood volume (BV), total peripheral resistance (TPR), splanchnic vascular resistance (Ras), renal vascular resistance (Rar) to increased sodium intake (NaI), and AngII are shown in the left panel. The relationship between arterial pressure and sodium (Na) excretion is shown in the right panel. Reprinted, with permission, from .


Figure 40. Summary of studies from our laboratory examining the effect of targeted sympathetic ablation on arterial pressure in normotensive rats: Adapted, with permission, from .


Figure 41. Effect of targeted sympathetic ablation on MAP and heart rate (HR) in Dahl S rats: Rats were placed on a high‐salt diet on day 5 and 3 weeks later subjected to sham (open circles), RDNX (black circles), celiac ganglionectomy (CGX; open triangles), or combined RDNX‐GGX. Reprinted, with permission, from .


Figure 42. Effect of carotid baroreceptor stimulation on MAP and heart rate in conscious dogs before (gray circles) and after (black circles) renal denervation: Renal denervation had no effect on the arterial pressure response to chronic activation of carotid baroreceptors. Reprinted, with permission, from .
References
 1.Abate N, Mansour YH, Tuncel M, Arbique D, Chavoshan B, Kizilbash A, Howell‐Stampley T, Vongpatanasin W, Victor RG. Overweight and sympathetic activity in black Americans. Hypertension 38: 379‐383, 2001.
 2.Abrams JM, Engeland WC, Osborn JW. Effect of intracerebroventricular benzamil on cardiovascular and central autonomic responses to DOCA‐salt treatment. Am J Physiol 299: R1500‐R1510, 2010.
 3.Abrams JM, Osborn JW. A role for benzamil‐sensitive proteins of the central nervous system in the pathogenesis of salt‐dependent hypertension. Clin Exp Pharmacol Physiol 35: 687‐694, 2008.
 4.Alexander N. Plasma volumes and hematocrits in rats with chronic sinoaortic denervation hypertension. Am J Physiol 236: H92‐H95, 1979.
 5.Alper RH, Jacob HJ, Brody MJ. Regulation of arterilal pressure lability in rats with chronic sinoaortic deafferentation. Am J Physiol 253: H466‐H474, 1987.
 6.Ammons WS. Spinoreticular cell responses to intrarenal injections of bradykinin. Am J Physiol 255: R994‐R1001, 1988.
 7.Ammons WS. Spinoreticular cell responses to renal venous and ureteral occlusion. Am J Physiol 254: R268‐R276, 1988.
 8.Ammons WS. Electrophysiological characteristics of primate spinothalamic neurons with renal and somatic inputs. J Neurophysiol 61: 1121‐1130, 1989.
 9.Ammons WS. Bowditch Lecture. Renal afferent inputs to ascending spinal pathways. Am J Physiol 262: R165‐R176, 1992.
 10.Armitage JA, Burke SL, Prior LJ, Barzel B, Eikelis N, Lim K, Head GA. Rapid onset of renal sympathetic nerve activation in rabbits fed a high‐fat diet. Hypertension 60: 163‐171, 2012.
 11.Ashton N, Clarke CG, Eddy DE, Swift FV. Mechanisms involved in the activation of ischemically sensitive, afferent renal nerve mediated reflex increases in hind‐limb vascular resistance in the anesthetized rabbit. Can J Physiol Pharmacol 72: 637‐643, 1994.
 12.Asirvatham-Jeyaraj N, Fiege JK, Han R, Foss J, Banek CT, Burbach BJ, Razzoli M, Bartolomucci A, Shimizu Y, Panoskaltsis-Mortari A, Osborn JW. Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension 68: 929‐936, 2016.
 13.Atherton DS, Deep NL, Mendelsohn FO. Micro‐anatomy of the renal sympathetic nervous system: A human postmortem histologic study. Clin Anat 25: 628‐633, 2012.
 14.Averina V, Othmer H, Fink GD, Osborn JW. A mathematical model of salt‐sensitive hypertension: The neurogenic hypothesis. J Physiol (Lond) 593: 3065‐3076, 2015.
 15.Averina VA, Othmer HG, Fink GD, Osborn JW. A new conceptual paradigm for the hemodynamics of salt‐sensitive hypertension: A mathematical modeling approach. J Physiol 590(23): 5975‐5992, 2012.
 16.Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, Midulla M, Mounier‐Vehier C, Courand PY, Lantelme P, Denolle T, Dourmap‐Collas C, Trillaud H, Pereira H, Plouin PF, Chatellier G, Renal Denervation for Hypertension (DENERHTN) investigators. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): A multicentre, open‐label, randomised controlled trial. Lancet 385(9981): 1957‐1965: 2015.
 17.Badoer E, Ng CW, De Matteo R. Glutamatergic input in the PVN is important in renal nerve response to elevations in osmolality. Am J Physiol 285: F640‐F650, 2003.
 18.Barrett C, Navakatikyan M, Malpas S. Long‐term control of renal blood flow: What is the role of the renal nerves? Am J Physiol Regulatory Integrative Comp Physiol 280: R1534‐R1545, 2001.
 19.Barrett CJ, Guild SJ, Ramchandra R, Malpas SC. Baroreceptor denervation prevents sympathoinhibition during angiotensin II‐induced hypertension. Hypertension 46: 168‐172, 2005.
 20.Barrett CJ, Ramchandra R, Guild SJ, Lala A, Budgett DM, Malpas SC. What sets the long‐term level of renal sympathetic nerve activity. A role for angiotensin II and baroreflexes? Circ Res 92: 1339‐1336, 2003.
 21.Beard DA, Pettersen KH, Carlson BE, Omholt SW, Bugenhagen SM. A computational analysis of the long‐term regulation of arterial pressure. F1000Res 2: 208, 2013.
 22.Berecek KH, Barron KW, Webb RL, Brody M. Vasopressin‐central nervous system interactions in the development of DOCA hypertension. Hypertension 4: II‐131‐II‐137, 1982.
 23.Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha‐Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN‐3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370: 1393‐1401, 2014.
 24.Bilgutay AM, Lillehei CW. Treatment of hypertension with an implantable electronic device. JAMA 191: 649‐653, 1965.
 25.Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease. Nephrol Dial Transplant 19: 1354‐1357, 2004.
 26.Blaustein MP, Leenen FH, Chen L, Golovina VA, Hanlyn JM, Pallone TL, Van Huysse JW, Zhang J, Wier WG. How NaCl raises blood pressure: A new paradigm for the pathogenesis of salt‐dependent hypertension. Am J Physiol 302: H1031‐H1049, 2012.
 27.Brennan AM, Mantzoros CS. Drug insight: The role of leptin in human physiology and pathophysiology‐emerging clinical applications. Nat Clin Pract Endocrinol Metab 2: 318‐327, 2006.
 28.Brinkmann J, Heusser K, Schmidt BM, Menne J, Klein G, Bauersachs J, Haller H, Sweep FC, Diedrich A, Jordan J, Tank J. Catheter‐based renal nerve ablation and centrally generated sympathetic activity in difficult‐to‐control hypertensive patients: Prospective case series. Hypertension 60: 1485‐1490, 2012.
 29.Briones AM, Nguyen DCA, Callera GE, Yogi A, Burger D, He Y, Correa JW, Gagnon AM, Gomez‐Sanchez CE, Gomez‐Sanchez EP, Sorisky A, Ooi TC, Ruzicka M, Burns KD, Touyz RM. Adipocytes produce aldosterone through calcineurin‐dependent signaling pathways: Implications in diabetes mellitus‐associated obesity and vascular dysfunction. Hypertension 59: 1069‐1078, 2012.
 30.Brooks VL, Haywood JR, Johnson AK. Translation of salt retention to central activation of the sympathetic nervous system in hypertension. Clin Exp Pharmacol Physiol 32: 426‐432, 2005.
 31.Brooks VL, Osborn JW. Hormonal‐sympathetic interactions in long‐term regulation of arterial pressure: An hypothesis. Am J Physiol 268: R1343‐R1358, 1995.
 32.Brooks VL, Qi Y, O'Donaughy TL. Increased osmolality of conscious water‐deprived rats supports arterial pressure and sympathetic activity via a brain action. Am J Physiol Regul Integr Comp Physiol 288: R1248‐R1255, 2005.
 33.Brooks VL, Qi Y, O'Donaughy TL. Increased osmolality of conscious water‐deprived rats supports arterial pressure and sympathetic activity via a brain action. Am J Physiol Regul Integr Comp Physiol 288: R1248‐R1255, 2005.
 34.Burke SL, Head GA. Method for in vivo calibration of renal sympathetic nerve activity in rabbits. J Neurosci Methods 127: 63‐74, 2003.
 35.Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension 25: 878‐882, 1995.
 36.Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal‐disease in the renal ablation model of chronic‐renal‐failure in the rat. Am J Kidney Dis 26: 861‐865, 1995.
 37.Cano G, Card JP, Sved AF. Dual viral transneuronal tracing of central autonomic circuits involved in the innervation of the two kidneys in rat. J Comp Neurol 471: 462‐481, 2004.
 38.Carlson S, Osborn JW, Wyss JM. Hepatic denervation produces chronic hypertension in Wistar‐Kyoto rats. Hypertension 32: 46‐51, 1998.
 39.Carlson SH, Beitz A, Osborn JW. Intragastric hypertonic saline increases vasopressin and central Fos immunoreactivity in conscious rats. Am J Physiol 272: R750‐R758, 1997.
 40.Cassaglia SM, Hermes SM, Aicher SA, Brooks VL. Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats. J Physiol 589: 1643‐1662, 2011.
 41.Caverson MM, Ciriello J. Effect of stimulation of afferent renal nerves on plasma levels of vasopressin. Am J Physiol 252: R801‐R807, 1987.
 42.Chen QH, Toney GM. AT1 receptor blockade in the hypothalamic PVN reduces central hyperosmolality‐induced renal sympathoexcitation. Am J Physiol 281: R1844‐R1853, 2001.
 43.Cherniack NS, Altose MD. Central chemoreceptors. In: Crystal RG, West JB, Weibel ER, Barnes PJ, editors. The Lung: Scientific Foundations. Philadelphia New York: Lippincott‐Raven, 1997, p. 1767‐1776.
 44.Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 15: 1063‐1067, 2012.
 45.Ciriello J, de Oliveira CV. Renal afferents and hypertension. Curr Hypertens Rep 4: 136‐142, 2002.
 46.Colindres RE, Spielman WS, Moss NG, Harrington WW, Gottschalk CW. Functional evidence for renorenal reflexes in the rat. Am J Physiol 239: F265‐F270, 1980.
 47.Coote JH, Yang Z, Pyner S, Deering J. Control of sympathetic outflows by the hypothalamic paraventricular nucleus. Clin Exp Pharm and Phys 25: 461‐463, 1998.
 48.Coote JH. Cardiovascular function of the paraventricular nucleus of the hypothalamus. Biol Signals 4: 142‐149, 1995.
 49.Cowley AW, Jr. Vasopressin and cardiovascular regulation. In: Guyton AC, Hall JE, editors. Cardiovascular Physiology IV: International Review of Physiology. Baltimore: University Park Press, 1982, p. 189‐242.
 50.Cowley AW, Jr, Liard JF, Guyton AC. Role of the baroreceptor reflex in daily control of arterial blood pressure and other variable in dogs. Circ Res 32: 564‐576, 1973.
 51.Cowley AW, Jr, Liard JF, Skelton MM, Quillen EWJ, Osborn JWJ, Webb RL. Vasopressin‐Neural interactions in the control of cardiovascular function. In: Schrier RW, editor. Vasopressin. New York: Raven Press, 1985.
 52.Crile G. The clinical results of celiac ganglionectomy in the treatment of essential hypertension. Ann Surg 107: 909‐916, 1938.
 53.Day TA, Ciriello J. Afferent renal nerve stimulation excites supraoptic vasopressin neurons. Am J Physiol 249: R368‐R371, 1985.
 54.DiBona GF. The functions of the renal nerves. Rev Physiol Biochem Pharmacol 94: 76‐181, 1982.
 55.DiBona GF. Physiology in perspective: The wisdon of the body. Neural control of the kidney. Am J Physiol 289: R633‐R641, 2005.
 56.DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 77: 75‐197, 1997.
 57.Dickinson CJ. Neurogenic hypertension revisited. Clin Sci 60: 471‐477, 1981.
 58.do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JH. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57: 918‐926, 2011.
 59.Dubinion JH, do Carmo JH, Adi A, Hamza S, da Silva AA, Hall JH. Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin. Hypertension 61: 1066‐1074, 2013.
 60.Ely DL, Weigand J. Stress and high sodium effects on blood pressure and brain catecholamines in spontaneoulsy hypertensive rats. Clin Exper Hyper Theory and Practice A5(9): 1559‐1587, 1983.
 61.Esler M. Clinical application of noradrenaline spillover methodology: Delineation of regional human sympathetic nervous responses. Pharmacol Toxicol 73: 243‐253, 1993.
 62.Esler M. Sympathetic activity in experimental and human hypertension. In: Bulpitt CJ, editor. Pathophysiology of Hypertension. Amsterdam: Elsevier Science, 1997, p. 628‐673.
 63.Esler M. Illusions of truths in the Symplicity HTN‐3 trial: Generic design strengths but neuroscience failings. J Am Soc Hypertension 8: 593‐598, 2014.
 64.Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment‐resistant hypertension (The Symplicity HTN‐2 Trial): A randomised controlled trial. Lancet 376: 1903‐1909, 2010.
 65.Esler M, Lambert G, Jennings G. Regional norepinephrine turnover in human hypertension. Clin Exp Hyperten A 11: 75‐89, 1989.
 66.Evans RG, Bie P. The role of the kidney in the pathogenesis of hypertension: Towards a neo‐Guytonian pardigm? Am J Physiol 2015.
 67.Faber JE, Brody MJ. Afferent renal nerve‐dependent hypertension following acute renal artery stenosis in the conscious rat. Circ Res 57: 676‐688, 1985.
 68.Ferguson AV. The area postrema: A cardiovascular control centre at the blood brain interface. Can J Physiol Pharmacol 69: 1026‐1034, 1991.
 69.Ferguson AV. Neurophysiological analysis of mechanisms for subfornical organ and area postrema involvement in autonomic control. Prog Brain Res 91: 413‐421, 1992.
 70.Ferguson AV, Bains JS. Actions of angiotensin in the subfornical organ and area postrema: Implications for long‐term control of autonomic output. Clin Exp Pharmacol Physiol 24: 96‐101, 1997.
 71.Ferguson M, Bell C. Ultrastructural localization and characterization of sensory nerves in the rat kidney. J Comp Neurol 274: 9‐16, 1988.
 72.Ferguson AV, Donevan SD, Papas S, Smith PM. Circumventricular structures: CNS sensors of circulating peptides and autonomic control centres. Endocrinol Exp 24: 19‐27, 1990.
 73.Fink GD. Arthur C. Corcoran Memorial Lecture. Sympathetic activity, vascular capacitance, and long‐term regulation of arterial pressure. Hypertension 53: 307‐312, 2009.
 74.Fitzgerald M. Capsaicin and sensory neurones: A review. Pain 15: 109‐130, 1983.
 75.Foss JD, Engeland WC, Osborn JW. Effect of selective afferent renal denervation by periaxonal application of capsaicin on salt sensitivity of arterial pressure. Hypertension 60: A197, 2012.
 76.Foss JD, Fink GD, Osborn JW. Reversal of genetic salt‐sensitive hypertension by targeted sympathetic ablation. Hypertension 61: 806‐811, 2013.
 77.Foss JD, Fink GD, Osborn JW. Differential role of afferent and efferent renal nerves in the maintenance of early‐ and late‐phase Dahl S hypertension. Am J Physiol 310: R262‐R267, 2016.
 78.Foss JD, Wainford RD, Engeland WC, Fink GD, Osborn JW. A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Physiol 308: R112‐R122, 2015.
 79.Freis ED, Smithwick RH. The effect of lumbodorsal splanchnicectomy on the blood volume and thiocyanate space of patients with essential hypertension. Am J Med Sci 214: 363‐367, 1947.
 80.Friberg P, Meredith I, Jennings G, Lambert G, Fazio V, Esler M. Evidence for increased renal norepinephrine overflow during sodium restriction in humans. Hypertension 16: 121‐130, 1990.
 81.Frithiof R, Xing T, McKinley MJ, May CN, Ramchandra R. Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney. Am J Physiol 306: R567‐R575, 2014.
 82.Fukuda Y, Sato A, Suzuki A, Trzebski A. Autonomic nerve and cardiovascular responses to changing blood oxygen and carbon dioxide levels in the rat. J Auton Nerv Syst 28: 61‐74, 1989.
 83.Garrison RJ, Kannel WB, Stokes JI, Castelli WP. Incidence and precursors of hypertension in young adults: The Framingham Offspring Study. Prev Med 16: 235‐251, 1987.
 84.Genovesi S, Pieruzzi F, Wijnmaalen P, Centonza L, Golin R, Zanchetti A, Stella A. Renal afferents signaling diuretic activity in the cat. Circ Res 73: 906‐913, 1993.
 85.Grassi G, Esler M. The sympathetic nervous system in renovascular hypertension: Lead actor or bit player? (Editorial Comment). J Hypertens 1071‐1073, 2002.
 86.Greenberg SG, Enders C, Osborn JL. Renal nerves affect rate of achieving sodium balance in spontaneously hypertensive rats. Hypertension 22: 1‐8, 1993.
 87.Grimson KS, Orgain ES, Anderson B, D'Angelo GJ. Total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy for hypertension. Ann Surg 138: 532‐547, 1953.
 88.Guild SJ, Barrett CJ, McBryde FD, Van Vliet BN, Head GA, Burke SL, Malpas SC. Quantifying sympathetic nerve activity; problems and pitfalls, the need for standardization. Exp Physiol 2009.
 89.Guild SJ, McBryde FD, Malpas SC, Barrett CJ. High dietary salt and angiotensin II chronically increase renal sympathetic nerve activity: A direct telemetry study. Hypertension 59: 614‐620, 2012.
 90.Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 7: 335‐346, 2006.
 91.Guyton AC. Circulatory Physiology III: Arterial Pressure and Hypertension. Philadelphia: W.B. Saunders Co., 1980.
 92.Guyton AC. Hypertension: A neural disease? Archives Neurol 45: 178‐179, 1988.
 93.Guyton AC. Dominant role of the kidneys and accessory role of whole‐body autoregulation in the pathogenesis of hypertension. Am J Hypertens 2: 575‐585, 1989.
 94.Guyton AC, Coleman TG, Cowley AW, Jr, Manning RD, Jr, Norman RA, Jr, Ferguson JD. A systems analysis approach to understanding long‐range arterial blood pressure control and hypertension. Circ Res 35: 159‐169, 1974.
 95.Guyton AC, Coleman TG, Cowley AW, Jr, Scheel KW, Manning RD, Jr, Norman RA, Jr. Arterial pressure regulation: Overriding dominance of the kidneys in long‐term regulation and in hypertension. Am J Med 52: 584‐594, 1972.
 96.Hackenthal E, Paul M, Ganten D, Taugner R. Morphology, physiology, and molecular biology of renin secretion. Physiol Rev 70: 1067‐1116, 1990.
 97.Harlan SM, Morgan DA, Agassandian K, Guo DF, Cassell MD, Sigmund CD, Mark AL, Rahmouni K. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin‐induced sympathetic activation. Circ Res 108: 808‐812, 2011.
 98.Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, Vinh A, Weyand CM. Inflammation, immunity, and hypertension. Hypertension 57: 132‐140, 2011.
 99.Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH, Rahn KH. Sympathetic nerve activity in end‐stage renal disease. Circulation 106: 1974‐1979, 2002.
 100.Head GA, Gueguen C, Marques FZ, Jackson KL, Eikelis N, Stevenson ER, Lambert GW, Charchar FJ, Davern PJ. Effect of renal denervation on blood pressure and microRNA 181A in hypertensive Schlager mice. J Hypertension 33: e76, 2015.
 101.Hendel M, Collister JP. Renal denervation attenuates long‐term hypertensive effects of angiotensin II in the rat. Clin Exp Pharm Phys 33: 1225‐1230, 2006.
 102.Hering D, Lambert EA, Marusic P, Walton AS, Krum H, Lambert GW, Esler MD, Schlaich MP. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension 61: 457‐464, 2013.
 103.Holzer P. Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43: 143‐201, 1991.
 104.Hosomi H, Morita H. Hepatorenal and hepatointestinal reflexes in sodium homeostasis. News Physiol Sci 11: 103‐107, 1996.
 105.Huang BS, Leenen FH. Sympathoexcitatory and pressor responses to increased brain sodium and ouabain are mediated via brain Ang II. Am J Physiol 270: H275‐H280, 1996.
 106.Huang Y, Wang DH. Role of renin‐angiotensin‐aldosterone system in salt‐sensitive hypertension induced by sensory denervation. Am J Physiol Heart Circ Physiol 281: H2143‐H2149, 2001.
 107.Iliescu R, Yanes LL, Bell W, Dwyer TM, Baltaru OC, Reckelhoff JF. Role of renal nerves in blood pressure in male and female SHR. Am J Physiol (Reg Int Comp) 290: R341‐R344, 2006.
 108.Ishiki K, Morita H, Hosomi H. Reflex control of renal nerve activity originating from the osmoreceptors in the hepato‐portal region. J Auton Nerv Syst 36: 139‐148, 1991.
 109.Jacob F, Ariza P, Osborn JW. Renal denervation chronically lowers arterial pressure independent of dietary sodium intake in normal rats. Am J Physiol‐Heart C 284: H2302‐H2310, 2003.
 110.Jacob F, Clark LA, Guzman PA, Osborn JW. Role of renal nerves in development of hypertension in DOCA‐salt model in rats: A telemetric approach. Am J Physiol 289: H1519‐H1528, 2005.
 111.Jacob F, Clark LA, Guzman PA, Osborn JW. Role of renal nerves in development of hypertension in DOCA‐salt model in rats: A telemetric approach. Am J Physiol Heart Circ Physiol 289: H1519‐H1529, 2005.
 112.Jacob F, LaBine B, Ariza P, Katz S, Osborn JW. Renal denervation causes chronic hypotension in rats: Role of beta(1)‐adrenoceptor activity. Clin Exp Pharmacol and Physiol 32: 255‐262, 2005.
 113.Janssen BJ, van Essen H, Vervoort‐Peters LH, Struyker‐Boudier HA, Smits JF. Role of afferent nerves in spontaneous hypertension in rats. Hypertension 13: 327‐333, 1989.
 114.Janssen BJ, van Essen H, Vervoort‐Peters LH, Thijssen HH, Derkx FH, Struyker‐Boudier HA, Smits JF. Effects of complete renal denervation and selective afferent renal denervation on the hypertension induced by intrarenal norepinephrine infusion in conscious rats. J Hypertens 7: 447‐455, 1989.
 115.Johns EJ. An investigation into the type of beta‐adrenoceptor mediating sympathetically activated renin release in the cat. Br J Pharmacol 73: 749‐754, 1981.
 116.Johns EJ, Kopp UC, Dibona GF. Neural control of renal function. Compr Physiol 1: 731‐767, 2011.
 117.Johnson AK, Loewy AD. Circumventricular organs and their role in visceral functions. In: Loewy AD, Spyer KM, editors. Central Regulation of Autonomic Functions. New York Oxford: Oxford University Press, 1990, p. 247‐267.
 118.Kandlikar SS, Fink GD. Mild DOCA‐salt hypertension: Sympathetic system and role of renal nerves. Am J Physiol Heart Circ Physiol 300: H1781‐H1787, 2011.
 119.Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, Flack JM, Katzen BT, Lea J, Lee DP, Leon MB, Ma A, Massaro J, Mauri L, Oparil S, O'Neill WW, Patel MR, Rocha‐Singh K, Sobotka P, Svetkey L, Townsend RR, Bakris GL. Predictors of blood pressure response in the SYMPLICITY HTN‐3 Trial. Eur Heart J 36: 219‐227, 2015.
 120.Kandzari DE, Bhatt DL, Sobotka PA, O'Neill WW, Esler M, Flack JM, Katzen BT, Leon MB, Massaro JM, Negoita M, Oparil S, Rocha‐Singh K, Straley C, Townsend RR, Bakris G. Catheter‐based renal denervation for resistant hypertension: Rationale and design of the SYMPLICITY HTN‐3 Trial. Clin Cardiol 35: 528‐535, 2012.
 121.Katayama T, Kataoka SD, Katoaka K, Hasegawa Y, Kolbuchi N, Toyama K, Uekawa K, Mingiie M, Nakagawa T, Maeda M, Ogawa H, Kim‐Mitsuyama S. Long‐term renal denervation normalizes disrupted blood pressure circadian rhythm and ameliorates cardiovascular injury in a rat model of metabolic syndrome. J Am Heart Assoc 2: e000197, 2013.
 122.Katholi RE. Renal nerves in the pathogenesis of hypertension in experimental animals and humans. Am J Physiol 245: F1‐F14, 1983.
 123.Katholi RE, McCann WP, Woods WT. Intrarenal adenosine produces hypertension via renal nerves in the one‐kidney, one clip rat. Hypertension 7: I88‐I93, 1985.
 124.Katholi RE, Whitlow PL, Hageman GR, Woods WT. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J Hypertens 2: 349‐359, 1984.
 125.Katholi RE, Whitlow PL, Winternitz SR, Oparil S. Importance of the renal nerves in established two‐kidney, one clip Goldblatt hypertension. Hypertension 4: 166‐174, 1982.
 126.Katholi RE, Winternitz SR, Oparil S. Role of the renal nerves in the pathogenesis of one‐kidney renal hypertension in the rat. Hypertension 3: 404‐409, 1981.
 127.Kawano Y, Ferrario CM. Neurohormonal characteristics of cardiovascular response due to intraventricular hypertonic NaCl. Am J Physiol 247 (HCP 16): H422‐H428, 1984.
 128.Kawano Y, Sudo RT, Ferrario CM. Effects of chronic intraventricular sodium on blood pressure and fluid balance. Hypertension 17: 28‐35, 1991.
 129.Kawano Y, Yoshida K, Kawamura M, Yoshimi H, Ashida T, Abe H, Imanishi M, Kimura G, Kokima S, Kuramochi M. Sodium and noradrenaline in cerebrospinal fluid and blood in salt‐sensitive and non‐salt‐sensitive essential hypertension. Clin Exp Pharm and Phys 19: 235‐241, 1992.
 130.Kenney MJ, Mosher LJ. Translational physiology and SND recordings in humans and rats: A glimpse of the recent past with an eye on the future. Auton Neurosci 176: 5‐10, 2013.
 131.Kim J, Padanilam BJ. Renal nerves drive interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 24: 229‐242, 2013.
 132.King AJ, Fink GD. Whole body norepinephrine kinetics in AngII‐salt hypertension in the rat. Am J Physiol Regul Integr Comp Physiol 294: R1262‐R1267, 2008.
 133.King AJ, Osborn JW, Fink GD. Splanchnic circulation is a critical neural target in angiotensin II salt hypertension in rats. Hypertension 50: 547‐556, 2007.
 134.Knuepfer MM, Akeyson EW, Schramm LP. Spinal projections of renal afferent nerves in the rat. Brain Res 446: 17‐25, 1988.
 135.Knuepfer MM, Schramm LP. Properties of renobulbar afferent fibers in rats. Am J Physiol 248: R113‐R119, 1985.
 136.Knuepfer MM, Schramm LP. The conduction velocities and spinal projections of single renal afferent fibers in the rat. Brain Res 435: 167‐173, 1987.
 137.Koepke JP, DiBona GF. High sodium intake enhances renal nerve and antinatriuretic responses to stress in spontaneously hypertensive rats. Hypertension 7: 357‐363, 1985.
 138.Kopp UC. Neural control of renal function. In: Integrated Systems Physiology: From Molecule to Function to Disease. San Rafael: Morgan and Claypool Life Sciences, 2011.
 139.Kopp UC. Role of renal sensory nerves in physiological and pathophysiological conditions. Am J Physiol 308: R79‐R95, 2015.
 140.Kopp UC, Cicha MZ, Nakamura K, Nusing RM, Smith LA, Hokfelt T. Activation of EP4 receptors contributes to prostaglandin E2‐mediated stimulation of renal sensory nerves. Am J Physiol Renal Physiol 287: F1269‐F1282, 2004.
 141.Kopp UC, Cicha MZ, Smith LA. Dietary sodium loading increases arterial pressure in afferent renal‐denervated rats. Hypertension 42: 968‐973, 2003.
 142.Kopp UC, Smith LA, Pence AL. Na(+)‐K(+)‐ATPase inhibition sensitizes renal mechanoreceptors activated by increases in renal pelvic pressure. Am J Physiol 267: R1109‐R1117, 1994.
 143.Kottke FJ, Kubicek WG, Visscher MB. The production of arterial hypertension by chronic renal artery‐nerve stimulation. Am J Physiol 145: 38‐47, 1945.
 144.Krieger JE, Cowley AW, Jr. Prevention of salt angiotensin II hypertension by servo control of body water. Am J Physiol 258: H994‐H1002, 1990.
 145.Krieger JE, Liard J‐F, Cowley AW, Jr. Hemodynamics, fluid volume, and hormonal responses to chronic high‐salt intake in dogs. Am J Physiol Heart Circ Physiol 259: H1629‐H1636, 1990.
 146.Krieger JE, Roman RJ, Cowley AW, Jr. Hemodynamics and blood volume in angiotensin II salt‐dependent hypertension in dogs. Am J Physiol 257: H1402‐H1412, 1989.
 147.Krum H, Schlaich M, Sobotka P, Bohm M, Mahfoud F, Rocha‐Singh K, Katholi RE, Esler M. Percutaneous renal denervation in patients with treatment‐resistant hypertension: Final 3‐year report of the Symplicity HTN‐1 study. Lancet 383: 622‐629, 2014.
 148.Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter‐based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof‐of‐principle cohort study. Lancet 373: 1275‐1281, 2009.
 149.Kuhn TS. The Structure of Scientific Revolutions. Chicago: The University of Chicago Press, 1962.
 150.Kuo DC, Nadelhaft I, Hisamitsu T, de Groat WC. Segmental distribution and central projections of renal afferent fibers in the cat studied by transganglionic transport of horseradish peroxidase. J Comp Neurol 216: 162‐174, 1983.
 151.Kurtz TW, Dominiczak AF, DiCarlo SE, Pravenec M, Morris RC Jr. Molecular‐based mechanisms of Medelian forms of salt‐dependent hypertension: Questioning the prevailing theory. Hypertension 65: 932‐941, 2015.
 152.Lappe RW, Webb RL, Brody MJ. Selective destruction of renal afferent versus efferent nerves in rats. Am J Physiol 249: R634‐R637, 1985.
 153.Liard J‐F. Renal denervation delays blood pressure increase in the spontaneously hypertensive rat. Experientia 15(3): 339‐340, 1977.
 154.Lohmeier TE, Hildebrandt DA, Dwyer TM, Barrett AM, Irwin MAR, Kieval RS. Renal denervation does not abolish sustained baroreflex‐mediated reductions in arterial pressure. Hypertension 49: 373‐379, 2007.
 155.Lohmeier TE, Iliescu R. The baroreflex as a long‐term controller of arterial pressure. Physiology 30: 148‐158, 2015.
 156.Lohmeier TE, Iliescu R, Liu B, Henegar JR, Maric‐Bilkan C, Irwin ED. Systemic and renal‐specific sympathoinhibition in obesity hypertension. Hypertension 59: 331‐338, 2012.
 157.Ma G, Ho SY. Hemodynamic effects of renal interoceptor and afferent nerve stimulation in rabbit. Sheng li xue bao: [Acta physiologica Sinica] 42: 262‐268, 1990.
 158.Ma G, Ho SY. Observation on the afferent nerve activity induced by stimulation of renal receptors in the rabbits. Sheng li xue bao: [Acta physiologica Sinica] 42: 269‐276, 1990.
 159.Ma MC, Huang HS, Wu MS, Chien CT, Chen CF. Impaired renal sensory responses after renal ischemia in the rat. J Am Soc Nephrol 13: 1872‐1883, 2002.
 160.Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, Sobotka PA, Krum H, Esler M, Böhm M. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension. Circulation 123: 1940‐1946, 2011.
 161.Malpas S. What sets the long‐term level of sympathetic nerve activity: Is there a role for arterial baroreceptors? Am J Physiol Regul Integr Comp Physiol 286(1): R1‐R12, 2004.
 162.Malpas S. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90: 513‐557, 2010.
 163.Malpas S, Ramchandra R, Guild S, Budgett D, Barrett C. Baroreflex mechanisms regulating mean level of SNA differ from those regulating the timing and entrainment of the sympathetic discharges in rabbits. Am J Physiol Regul Integr Comp Physiol 291: R400, 2006.
 164.Maranon R, Lima R, Spradley FT, do Carmo JM, Zhang H, Smith AD, Bui E, Thomas RL, Moulana M, Hall JE, Granger JP, Reckelhoff JF. Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin‐4 receptor in the elevated blood pressure in hyperandrogenemic female rats. Am J Physiol 308: R708‐R713, 2015.
 165.Marfurt CF, Echtenkamp SF. Sensory innervation of the rat kidney and ureter as revealed by the anterograde transport of wheat germ agglutinin‐horseradish peroxidase (WGA‐HRP) from dorsal root ganglia. J Comp Neurol 311: 389‐404, 1991.
 166.Mark AL, Rahmouni K, Correia M, Haynes WG. A leptin‐sympathetic‐leptin feedback loop: Potential implications for regulation of arterial pressure and body fat. Acta Physiol Scand 177: 345‐349, 2003.
 167.Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand C, Gordon FJ, Harrison DG. Central and peripheral mechanisms of T‐lymphocyte activation and vascular inflammation produced by angiotensin II‐induced hypertension. Circ Res 107: 263‐270, 2010.
 168.Mathis KW, Venegas‐Pont M, Flynn ER, Williams JM, Maric‐Bilkan C, Dwyer TM, Ryan MJ. Hypertension in an experimental model of systemic lupus erythematosus occurs independently of renal nerves. Am J Physiol 305: R711‐R719, 2013.
 169.McBryde FD, Guild SJ, Barrett CJ, Osborn JW, Malpas SC. Angiotensin II‐based hypertension and the sympathetic nervous system: The role of dose and increased dietary salt in rabbits. Exp Physiol 92: 831‐840, 2007.
 170.McBryde FD, Malpas S, Guild SJ, Barrett C. A high salt diet does not influence renal sympathetic nerve activity: A direct telemetric investigation. Am J Physiol 297: R396‐R402, 2009.
 171.McKinley MJ, Clarke IJ, Oldfield BJ. Circumventricular organs. In: The Human Nervous System. USA: Elsevier Academic Press, 2004, p. 562‐591.
 172.McKinley MJ, Johnson AK. The physiological regulation of thirst and fluid intake. News Physiol Sci 19: 1‐6, 2004.
 173.McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, Uschakov A, Oldfield BJ. The Sensory Circumventricular Organs of the Mammalian Brain. Berlin: Springer, 2003, p. 1‐126.
 174.Miki K, Hayashida Y, Sagawa S, Shiraki K. Renal sympathetic nerve activity and natriuresis during water immersion in conscious dogs. Am J Physiol 256: R299‐R305, 1989.
 175.Miki K, Kosho A, Hayashida Y. Method for continuous measurements of renal sympathetic nerve activity and cardiovascular function during exercise in rats. Exp Physiol 87(1): 33‐39, 2002.
 176.Miki K, Oda M, Kamijyo N, Kawahara K, Yoshimoto M. Lumbar sympathetic nerve activity and hindquarter blood flow during REM sleep in rats. J Physiol 557: 261‐271, 2004.
 177.Miki K, Yoshimoto M. Differential effects of behaviour on sympathetic outflow during sleep and exercise. Exp Physiol 90: 155‐158, 2005.
 178.Miki K, Yoshimoto M, Tanimizu M. Acute shifts of baroreflex control of renal sympathetic nerve activity induced by treadmill exercise in rats. J Physiol 548: 313‐322, 2003.
 179.Moldovanova I, Schroeder C, Jacob G, Hiemke C, Diedrich A, Luft FC, Jordan J. Hormonal influences on cardiovascular norepinephrine transporter responses in healthy women. Hypertension 51: 1203‐1209, 2008.
 180.Morita H, Ishiki K, Hosomi H. Effects of hepatic NaCl receptor stimulation on renal nerve activity in conscious rabbits. Neurosci Lett 123: 1‐3, 1991.
 181.Morita H, Matsuda T, Furuya F, Khanchowdhury MR, Hosomi H. Hepatorenal reflex plays an important role in natriuresis after high‐NaCl food intake in conscious dogs. Circ Res 72: 552‐559, 1993.
 182.Morita H, Yamashita Y, Nishida Y, Tokuda M, Hatase O, Hosomi H. Fos induction in rat brain neurons after stimulation of the hepatoportal Na‐sensitive mechanism. Am J Physiol 272: R913‐R923, 1997.
 183.Morrison SF. Differential control of sympathetic outflow. Am J Physiol 281: R683‐R696, 2001.
 184.Morrissey DM, Brookes VS, Cooke WT. Sympathectomy in the treatment of hypertension: Review of 122 cases. Lancet 1: 403‐408, 1953.
 185.Moss NG. Electrophysiology of afferent renal nerves. Fed Proc 44: 2828‐2833, 1985.
 186.Mueller PJ, Mischel NA, Scislo TJ. Differential activation of adrenal, renal, and lumbar sympathetic nerves following stimulation of the rostral ventrolateral medulla of the rat. Am J Physiol 300: R1230‐R1240, 2011.
 187.Mulder J, Hokfelt T, Knuepfer M, Kopp UC. Renal sensory and sympathetic nerves reinnervate the kidney in a similar time‐dependent fashion after renal denervation in rats. Am J Physiol 304: R675‐R682, 2013.
 188.Muller EF, Petersen WF. Ueber den Anteil des vegetativen Nervensystems an den Infections‐schaden der Nierengefasse. Ferhandl d Deutsch Gesellsch Int Med 44: 419, 1932.
 189.Muntzel MS, Anderson EA, Johnson AK, Mark AL. Mechanisms of insulin action on sympathetic nerve activity. Clin Exp Hypertens 17: 39‐50, 1995.
 190.Muntzel MS, Morgan DA, Mark AL, Johnson AK. Intracerebroventricular insulin produces nonuniform regional increases in sympathetic activity. Am J Physiol 267: R1350‐R1355, 1994.
 191.Nakagawa T, Hasegawa Y, Uekawa K, Ma M, Katayama T, Sueta D, Toyama K, Kataoka K, Koibuchi N, Maeda M, Kuratsu J, Kim‐Mitsuyama S. Renal denervation prevents stroke and brain injury via attenuation of oxidative stress in hypertensive rats. J Am Heart Assoc 2: e000375, 2013.
 192.Nakamura K, Cowley AW, Jr. Sequential changes of cerebrospinal fluid sodium during the development of hypertension in Dahl rats. Hypertension 13: 243‐249, 1989.
 193.Neumann J, Ligtenberg G, Klein II, Koomans HA, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: Pathogenesis, clinical relevance, and treatment. Kidney Int 65: 1568‐1576, 2004.
 194.Niijima A. Observation on the localization of mechanoreceptors in the kidney and afferent nerve fibres in the renal nerves in the rabbit. J Physiol 245: 81‐90, 1975.
 195.Nishida Y, Sugimoto I, Morita H, Murakami H, Hosomi H, Bishop VS. Suppression of renal sympathetic nerve activity during portal vein infusion of hypertonic saline. Am J Physiol 274: R97‐R103, 1998.
 196.Nishida Y, Tandai‐Hiruma M, Kemuriyama T, Hagisawa K. Long‐term blood pressure control: Is there a set point in the brain? J Physiol Sci 62: 147‐161, 2012.
 197.Norman RA, Jr, Murphy WR, Dzielak DJ, Khraibi AA, Carroll RG. Role of the renal nerves in one‐kidney, one clip hypertension in rats. Hypertension 6: 622‐626, 1984.
 198.O'Donaughy TL, Brooks VL. Deoxycorticosterone acetate‐salt rats: Hypertension and sympathoexcitation driven by increased NaCl levels. Hypertension 47: 680‐685, 2006.
 199.O'Donaughy TL, Qi Y, Brooks VL. Central action of increased osmolality to support blood pressure in deoxycorticosterone acetate‐salt rats. Hypertension 48: 658‐663, 2006.
 200.Osborn J. Hypothesis: Set points and long‐term control of arterial pressure. A theoretical argument for a long‐term arterial pressure control system in the brain rather than the kidney. Clin Exp Pharmacol Physiol 32: 384‐393, 2005.
 201.Osborn JW, Averina VA, Fink GD. Current computational models do not reveal the importance of the nervous system in long‐term control of arterial pressure. Exp Physiol 94: 381‐397, 2009.
 202.Osborn J, Camara A. Renal neurogenic mediation of Intracerebroventricular angiotensin II hypertension in rats raised on high sodium chloride diet. Hypertension 30 (Part 1): 331‐336, 1997.
 203.Osborn JW, England SK. Normalization of arterial pressure after barodenervation: Role of pressure natriuresis. Am J Physiol 259: R1172‐R1180, 1990.
 204.Osborn JW, Fink GD. Region specific changes in sympathetic nerve activity in AngII‐salt hypertension. Exp Physiol 95: 61‐68, 2010.
 205.Osborn JW, Fink GD, Kuroki MT. Neural mechanisms of angiotensin II‐salt hypertension: Implications for therapies targeting neural control of the splanchnic circulation. Curr Hypertens Rep 13: 221‐228, 2011.
 206.Osborn JW, Fink GD, Sved AF, Toney GM, Raizada MK. Circulating angiotensin II and dietary salt: Converging signals for neurogenic hypertension. Curr Hypertens Rep 9: 228‐235, 2007.
 207.Osborn J, Jacob F, Guzman P. A neural set point for the long‐term control of arterial pressure: Beyond the arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 288(4): R846‐R855, 2005.
 208.Osborn JW, Kuroki M. Sympathetic signatures of cardiovascular disease: A blueprint for development of targeted sympathetic ablation therapies. Hypertension 59: 545‐547, 2012.
 209.Osborn JW, Olson DM, Guzman P, Toney GM, Fink GD. The neurogenic phase of angiotensin II‐salt hypertension is prevented by chronic intracerebroventricular administration of benzamil. Physiol Rep 26: e00245, 2014.
 210.Osborn JL, Roman RJ, Ewens JD. Renal nerves and the development of Dahl salt‐sensitive hypertension. Hypertension 11: 523‐528, 1988.
 211.Page IH, Heuer GJ. The effect of renal denervation on the level of arterial blood pressure and renal function in essential hypertension. J Clin Invest 14: 27‐30, 1934.
 212.Page IH, Heuer GJ. The effect of renal denervation on patients suffering from nephritis. J Clin Invest 14: 443‐458, 1935.
 213.Pan JY, Bishop VS, Ball NA, Haywood JR. Inability of dorsal spinal rhizotomy to prevent renal wrap hypertension in rats. Hypertension 7: 722‐728, 1985.
 214.Papademetriou V, Tsioufis CP, Sinhal A, Chew DP, Meredith IT, Malaiapan Y, Worthley MI, Worthley SG. Catheter‐based renal denervation for resistant hypertension: 12 month results of the EnligHTN I first‐in‐human study using a multielectrode ablation system. Hypertension 64: 565‐572, 2014.
 215.Papin E, Ambard L. Resection of the nerves of the kidney for nephralgia and small hydronephroses. J Urology 11: 337, 1924.
 216.Paton JF, Dickinson CJ, Mitchell G. Harvey Cushing and the regulation of blood pressure in the giraffe, rat and man: Introducing “Cushing's mechanism.” Exp Physiol 94: 11‐17, 2009.
 217.Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—Linking immunity and metabolism. Nat Rev Endocrinol 8: 743‐754, 2012.
 218.Pedrino GR, Rosa DA, Korim WS, Cravo SL. Renal sympathoexcitation induced by hypernatremia: Involvement of A1 noradrenergic neurons. Auton Neurosci 142: 55‐63, 2008.
 219.Persson PB. History of arterial baroreceptor reflexes. In: Persson PB, Kirchheim HR, editors. Baroreceptor Reflexes. Heidelberg: Springer‐Verlag, 1991, pp. 1‐8.
 220.Rahmouni K. Obesity‐associated hypertension: Recent progress in deciphering the pathogenesis. Hypertension 64: 215‐221, 2014.
 221.Rosas‐Arellano M, Solano‐Flores L, Ciriello J. Co‐localization of estrogen and angiotensin receptors within subfornical organ neurons. Brain Res 837: 254‐262, 1999.
 222.Rosas‐Arellano MP, Solano‐Flores LP, Ciriello J. c‐Fos induction in spinal cord neurons after renal arterial or venous occlusion. Am J Physiol 276: R120‐R127, 1999.
 223.Rumantir MS, Vaz M, Jennings GL, Esler M. Neural mechanisms in human obesity‐related hypertension. J Hypertens 17: 1125‐1133, 1999.
 224.Schiffrin EL. Inflammation, immunity and development of essential hypertension. J Hypertens 32: 228‐229, 2014.
 225.Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler M. Renal sympathetic‐nerve ablation for uncontrolled hypertension. N Engl J Med 361: 932‐934, 2009.
 226.Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler M. Renal denervation as a therapeutic approach for hypertension: Novel implications for an old concept. Hypertension 54: 1195‐1201, 2009.
 227.Schmidlin O, Forman A, Sebastian A, Morris RC. Sodium‐selective salt sensitivity: Its occurrence in blacks. Hypertension 50: 1085‐1092, 2007.
 228.Schramm LP, Strack AM, Platt KB, Loewy AD. Peripheral and central pathways regulating the kidney: A study using pseudorabies virus. Brain Res 616: 251‐262, 1993.
 229.Shi P, Stocker SD, Toney GM. Organum vasculosum laminae terminalis contributes to increased sympathetic nerve activity induced by central osmolality. Am J Physiol 293: R2279‐R2289, 2007.
 230.Shweta A, Denton KM, Kett MM, Bertram JF, Lambert GW, Anderson WP. Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney. J Hypertension 23: 851‐859, 2005.
 231.Simon JK, Kasting NW, Ciriello J. Afferent renal nerve effects on plasma vasopressin and oxytocin in conscious rats. Am J Physiol 256: R1240‐R1244, 1989.
 232.Smithwick RH. Surgical treatment of hypertension. Am J Med 4: 744‐759, 1948.
 233.Smithwick RH. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc 152: 1501‐1504, 1953.
 234.Smits JF, Brody MJ. Activation of afferent renal nerves by intrarenal bradykinin in conscious rats. Am J Physiol 247: R1003‐R1008, 1984.
 235.Solano‐Flores LP, Rosas‐Arellano MP, Ciriello J. Fos induction in central structures after afferent renal nerve stimulation. Brain Res 753: 102‐119, 1997.
 236.Srinivasan K. Biological activities of red pepper (capsicum annuum) and its pungent principle capsaicin: A review. Crit Rev Food Sci Nutr 56(9):1488‐1500, 2015.
 237.Sripairojthikoon W, Wyss JM. Cells of origin of the sympathetic renal innervation in rat. Am J Physiol 252: F957‐F963, 1987.
 238.Steinberg JS, Pokushalov E, Mittal S. Renal denervation for arrhythmias: Hope or hype? Curr Cardiol Rep 15: 392, 2013.
 239.Stella A, Weaver L, Golin R, Genovesi S, Zanchetti A. Cardiovascular effects of afferent renal nerve stimulation. Clin Exp Hypertens A 9 (Suppl 1): 97‐111, 1987.
 240.Stocker SD, Hunwick KJ, Toney GM. Hypothalamic paraventricular nucleus differentially supports lumbar and renal sympathetic outflow in water‐deprived rats. J Physiol 563: 249‐263, 2005.
 241.Stocker SD, Keith KJ, Toney GM. Acute inhibition of the hypothalamic paraventricular nucleus decreases renal sympathetic nerve activity and arterial pressure in water‐deprived rats. Am J Physiol 286: R1844‐R1853, 2004.
 242.Stocker SD, Muntzel MS. Recording sympathetic activity chronically in rats: Surgery techniques, assessment of nerve activity, and quantification. Am J Physiol 305: H1407‐H1416, 2013.
 243.Strack AM, Sawyer WB, Hughes JH, Platt KB, Loewy AD. A general pattern of CNS innervation of the sympathetic outflow demonstrated by transneuronal pseudorabies viral infections. Brain Res 491: 156‐162, 1989.
 244.Symplicity HTNI. Catheter‐based renal sympathetic denervation for resistant hypertension: Durability of blood pressure reduction out to 24 months. Hypertension 57: 911‐917, 2011.
 245.Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 51: 159‐212, 1999.
 246.Thoren P, Ricksten SE. Recordings of renal and splanchnic sympathetic nervous activity in normotensive and spontaneously hypertensive rats. Clin Sci 57: 197S‐199S, 1979.
 247.Thrasher T. Baroreceptors, baroreceptor unloading, and the long‐term control of blood pressure. Am J Physiol Regul Integr Comp Physiol 288: 819‐827, 2005.
 248.Tobey J, Fry H, Mizejewski C, Fink G, Weaver L. Differential sympathetic responses initiated by angiotensin and sodium chloride. Am J Physiol Regul Integr Comp Physiol 245: 60‐68, 1983.
 249.Toney GM, Stocker SD. Hyperosmotic activation of CNS sympathetic drive: Implications for cardiovascular disease. J Physiol 588: 3375‐3384, 2010.
 250.Ulrich‐Lai YM, Arnhold MM, Engeland WC. Adrenal splanchnic innervation contributes to the diurnal rhythm of plasma corticosterone in rats by modulating adrenal sensitivity to ACTH. Am J Physiol Regul Integr Comp Physiol 290: R1128‐R1135, 2006.
 251.Ulrich‐Lai YM, Fraticelli AI, Engeland WC. Capsaicin‐sensitive nerve fibers: A potential extra‐ACTH mechanism participating in adrenal regeneration in rats. Microsc Res Tech 61: 252‐258, 2003.
 252.Ulrich‐Lai YM, Marek DJ, Engeland WC. Capsaicin‐sensitive adrenal sensory fibers participate in compensatory adrenal growth in rats. Am J Physiol Regul Integr Comp Physiol 283: R877‐R884, 2002.
 253.Undesser KP, Hassar EM, Haywood JR, Johnson AK, Bishop VS. Interactions of vasopressin with the area postrema in arterial baroreflex function in conscious rabbits. Circ Res 56: 410‐417, 1985.
 254.Veelken R, Vogel E‐V, Hilgers KF, Amann K, Hartner A, Sass G, Neuhuber WL, Tiegs G. Autonomic renal denervation ameliorates experimental glomerulonephritis. J Am Soc Nephrol 19: 1371‐1378, 2008.
 255.Veitenheimer BJ, Engeland WC, Guzman PA, Fink GD, Osborn JW. Effect of global and regional sympathetic blockade on arterial pressure during water deprivation in conscious rats. Am J Physiol Heart Circ Physiol 303: H1022‐H1034, 2012.
 256.Verheye S, Ormiston J, Bergmann M, Sievert H, Schwindt A, Werner H, Vogel B, Colombo A. Twelve month results of the Rapid Renal Sympathetic Denervation for Resistant Hypertension Using the OneShot Ablation System (RAPID) study. EuroIntervention 10: 1221‐1229, 2014.
 257.Wallin BG. Human sympathetic nerve activity and blood pressure regulation. Clin Exp Hypertens A 11 (Suppl 1): 91‐101, 1989.
 258.Wallin BG. Microneurographic assessment of sympathetic nerve traffic. Suppl Clin Neurophysiol 57: 345‐351, 2004.
 259.Wallin BG, Charkoudian N. Sympathetic neural control of integrated cardiovascular function: Insights from measurment of human sympathetic nerve activity. Muscle Nerve 36: 595‐614, 2007.
 260.Wang Y, Chen AF, Wang DH. ET(A) receptor blockade prevents renal dysfunction in salt‐sensitive hypertension induced by sensory denervation. Am J Physiol Heart Circ Physiol 289: H2005‐H2011, 2005.
 261.Wang Q, Fan XP, Chen Z, Zhao QH, Chen SQ, Wan ZH. Role of afferent renal nerves in 2K2C Goldblatt hypertension. Sheng li xue bao: [Acta physiologica Sinica] 47: 366‐372, 1995.
 262.Wang DH, Li J, Qiu J. Salt‐sensitive hypertension induced by sensory denervation: Introduction of a new model. Hypertension 32: 649‐653, 1998.
 263.Wang H, Wang DH, Galligan JJ. P2Y2 receptors mediate ATP‐induced resensitization of TRPV1 expressed by kidney projecting sensory neurons. Am J Physiol Regul Integr Comp Physiol 298: R1634‐R1641, 2010.
 264.Wang DH, Wu W, Lookingland KJ. Degeneration of capsaicin‐sensitive sensory nerves leads to increased salt sensitivity through enhancement of sympathoexcitatory response. Hypertension 37: 440‐443, 2001.
 265.Warner HR. The frequency‐dependent nature of blood pressure regulation by the carotid sinus studied with an electric analog. Circ Res 6: 35‐40, 1958.
 266.Wehrwein EA, Barman SM. Highlights in basic autonomic neurosciences: Is an increase in sympathetic nerve activity involved in the development and maintenance of hypertension? Auton Neurosci Basic Clin 180: 1‐4, 2014.
 267.Weiss ML, Chowdhury SI. The renal afferent pathways in the rat: A pseudorabies virus study. Brain Res 812: 227‐241, 1998.
 268.Whitelaw GP, Smithwick RH. Lumbodorsal splanchnicectomy in the treatment of essential hypertension. J Med Assoc Ga 47: 492‐497, 1958.
 269.Witkowski A, Prejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, Michalowska I, Kabat M, Warchol E, Januszewicz M, Narkiewicz K, Somers VK, Sobotka PA, Januszewicz A. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 58: 559‐565, 2011.
 270.Wyss JM, Aboukarsh N, Oparil S. Sensory denervation of the kidney attenuates renovascular hypertension in the rat. Am J Physiol 250: H82‐H86, 1986.
 271.Wyss JM, Donovan MK. A direct projection from the kidney to the brainstem. Brain Res 298: 130‐134, 1984.
 272.Wyss JM, Oparil S, Sripairojthikoon W. Neuronal control of the kidney: Contribution to hypertension. Can J Physiol Pharmacol 70: 759‐770, 1992.
 273.Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi T, Loperena R, Foss JD, Chen W, Osborn JW, Itani HA, Harrison DG. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II‐induced hypertension. Circ Res 117(6): 547‐557, 2015.
 274.Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi T, Loperena R, Foss JD, Mernaugh RL, Chen W, Roberts J, Osborn JW, Itani HA, Harrison DG. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II‐induced hypertension. Circ Res 117: 547‐557, 2015.
 275.Yang W‐Y, Staessen JA. Hypertension: Renal denervation‐promising data from the DENERHTN trial. Nat Rev Nephrol 11: 258‐260, 2015.
 276.Yiannikouris F, Gupte M, Putnam K, Thatcher S, Charnigh R, Rateri DL, Daugherty A, Cassis LA. Adipocyte deficiency of angiotensinogen prevents obesity induced hypertension in male rats. Hypertension 60: 1524‐1530, 2012.
 277.Yoshimoto M, Miki K, Fink GD, King A, Osborn JW. Chronic angiotensin II infusion causes differential responses in regional sympathetic nerve activity in rats. Hypertension 55: 644‐651, 2010.
 278.Yoshimoto M, Miki K, King A, Fink G, Osborn JW. Differential responses of renal and muscle sympathetic nerve activity to chronic angiotensin II administration in rats consuming a high‐salt diet. Hypertension 52: e64, 2008.
 279.Yoshimoto M, Sakagami T, Nagura S, Miki K. Relationship between renal sympathetic nerve activity and renal blood flow during natural behavior in rats. Am J Physiol Regul Integr Comp Physiol 286: R881‐R887, 2004.
 280.Yoshimoto M, Wehrwein EA, Novotny M, Swain GM, Kreulen DL, Osborn JW. Effect of stellate ganglionectomy on basal cardiovascular function and responses to beta‐1 adrenoceptor blockade in the rat. Am J Physiol Heart Circ Physiol 295: H2447‐H2454, 2008.
 281.Young CN, Morgan DA, Butler SD, Mark AL, Davisson RL. The brain subfornical organ mediates leptin‐induced increases in renal sympathetic nerve activity but not its metabolic effects. Hypertension 61: 737‐744, 2013.
 282.Zanchetti A, Stella A, Golin R, Genovesi S. Neural control of the kidney–Are there reno‐renal reflexes? Clin Exp Hypertens A 6: 275‐286, 1984.
 283.Zanutto BS, Frias BC, Valentinuzzi ME. Blood pressure long term regulation: A neural network model of the set point development. Biomed Eng Online 10: 54, 2011.
 284.Zanutto BS, Valentinuzzi ME, Segura ET. Neural set point for the control of arterial pressure: Role of the nucleus tractus solitarius. Biomed Eng Online 9: 4, 2010.
 285.Zhang W, Victor RG. Calcineurin inhibitors cause renal afferent activation in rats: A novel mechanism of cyclosporine‐induced hypertension. Am J Hypertens 13: 999‐1004, 2000.
 286.Zhu Y, Xie C, Wang DH. TRPV1‐mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. Am J Nephrol 27: 530‐537, 2007.
 287.Zicha J, Dobesova Z, Vokurkova M, Rauchova H, Hojna S, Kadlecova M, Behuliak M, Vaneckova I, Kunes J. Age‐dependent salt hypertension in Dahl rats: Fifty years of research. Physiol Res 61 (Suppl 1): S35‐S87, 2012.
 288.Zubcevic J, Waki H, Raizada MK, Paton JF. Autonomic‐immune‐vascular interactions: An emerging concept for neurogenic hypertension. Hypertension 57: 1026‐1033, 2011.

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How to Cite

John W. Osborn, Jason D. Foss. Renal Nerves and Long‐Term Control of Arterial Pressure. Compr Physiol 2017, 7: 263-320. doi: 10.1002/cphy.c150047