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Renal Nerves and Long‐Term Control of Arterial Pressure

John W. Osborn, Jason D. Foss

10.1002/cphy.c150047

Source: Volume 7, Issue 2, April 2017

Published online: March 2017

Full Article on Wiley Online Library



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 255.
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 50.
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 205.
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 165.
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 209.
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 172.
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 31.
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 20.
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 19.
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 210.
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 (279).
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 210.
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 90.
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 (10).
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 (110).
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 281.
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 55.
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 149.
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 122.
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 63.
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 228.
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 79.
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 (79). Panel (B) shows the ratio of SP and CGRP between denervated and innervated kidneys (189). The time course of the recovery of these markers was similar for both methods. Reprinted with permission from 79, 189.
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 79.
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 79.
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 79.
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 78.
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 76,78,110,113,257.
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 256.
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 14.
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 14.
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 110,257,282.
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 76.
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 157.


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 255.


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 50.


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 205.


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 165.


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 209.


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 172.


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 31.


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 20.


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 19.


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 210.


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 (279).


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 210.


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 90.


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 (10).


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 (110).


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 281.


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 55.


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 149.


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 122.


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 63.


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 228.


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 79.


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 (79). Panel (B) shows the ratio of SP and CGRP between denervated and innervated kidneys (189). The time course of the recovery of these markers was similar for both methods. Reprinted with permission from 79, 189.


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 79.


Figure 32. Effect of renal‐CAP treatment on the responses of MAP and heart rate (HR) to increased salt intake. Reprinted, with permission, from 79.


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 79.


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 78.


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 76,78,110,113,257.


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 256.


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 14.


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 14.


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 110,257,282.


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 76.


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 157.
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Article Title: Renal Nerves and Long‐Term Control of Arterial Pressure
 

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