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The kidneys are densely innervated with renal efferent and afferent nerves to communicate with the central nervous system. Innervation of major structural components of the kidneys, such as blood vessels, tubules, the pelvis, and glomeruli, forms a bidirectional neural network to relay sensory and sympathetic signals to and from the brain. Renal efferent nerves regulate renal blood flow, glomerular filtration rate, tubular reabsorption of sodium and water, as well as release of renin and prostaglandins, all of which contribute to cardiovascular and renal regulation. Renal afferent nerves complete the feedback loop central autonomic nuclei where the signals are integrated and modulate central sympathetic outflow; thus both types of nerves form integral parts of the self-regulated renorenal reflex loop. Renal sympathetic nerve activity (RSNA) is commonly increased in pathophysiological conditions such as hypertension and chronic- and end-stage renal disease. Increased RSNA raises blood pressure and can contribute to the deterioration of renal function. Attempts have been made to eliminate or interfere with this important link between the brain and the kidneys as a neuromodulatory treatment for these conditions. Catheter-based renal sympathetic denervation has been successfully applied in patients with resistant hypertension and was associated with significant falls in blood pressure and renal protection in most studies performed. The focus of this review is the neural contribution to the control of renal and cardiovascular hemodynamics and renal function in the setting of hypertension and chronic kidney disease, as well as the specific roles of renal efferent and afferent nerves in this scenario and their utility as a therapeutic target.

Patients diagnosed with heart failure have high rates of mortality and morbidity. Based on promising preclinical studies, vagal nerve stimulation has been trialled in these patients using whole nerve electrical stimulation, but the results have been mixed. This is, at least in part, due to an inability to selectively recruit the activity of specific fibres within the vagus with whole nerve electrical stimulation, as well as not knowing which the ‘therapeutic’ fibres are. This symposium review focuses on a population of cardiac‐projecting efferent vagal fibres with cell bodies located within the dorsal motor nucleus of the vagus nerve and a new method of selectively targeting these projections as a potential treatment in heart failure. What is the topic of this review? Selective efferent vagal stimulation in heart failure. What advances does it highlight? Selectively targeting a population of cardiac‐projecting efferent vagal fibres with cell bodies within the dorsal motor nucleus of the vagus using optogenetics slows the progression of heart failure in rats.

Recent work has demonstrated the feasibility of minimally-invasive implantation of electrodes into a cortical blood vessel. However, the effect of the dura and blood vessel on recording signal quality is not understood and may be a critical factor impacting implementation of a closed-loop endovascular neuromodulation system. The present work compares the performance and recording signal quality of a minimally-invasive endovascular neural interface with conventional subdural and epidural interfaces. We compared bandwidth, signal-to-noise ratio, and spatial resolution of recorded cortical signals using subdural, epidural and endovascular arrays four weeks after implantation in sheep. We show that the quality of the signals (bandwidth and signal-to-noise ratio) of the endovascular neural interface is not significantly different from conventional neural sensors. However, the spatial resolution depends on the array location and the frequency of recording. We also show that there is a direct correlation between the signal-noise-ratio and classification accuracy, and that decoding accuracy is comparable between electrode arrays. These results support the consideration for use of an endovascular neural interface in a clinical trial of a novel closed-loop neuromodulation technology.

Healthcare-associated infections (HAIs) pose significant risks, leading to increased morbidity, mortality, and costs, exacerbated by multi-drug-resistant microorganisms. This study aimed to evaluate pharmacological prophylaxis targeting sympathetic reflex control of immunity to mitigate systemic infections, offering a novel approach to combating HAIs. The study included animal experiments and a retrospective analysis of orthopedic surgery patients in Romagna, Italy. Young female pigs were intravenously inoculated with Escherichia coli ( E. coli ) and divided into two groups: propranolol-treated (non-selective β-blocker; 3 mg/kg; 3x/day orally) and vehicle-treated, starting two days before infection. Parameters such as bacteraemia, serum cytokines, biochemical profile, blood count, lactate, glycemia, and flow cytometry were assessed. Additionally, a retrospective analysis of 92,649 orthopedic surgery hospitalizations (2017–2022) examined the association of non-selective and selective β1-blockers with HAI development using conditional logistic regression. Propranolol-treated pigs exhibited a disinhibited immune response to systemic infection, clearing circulating bacteria much earlier than vehicle-treated animals. The retrospective analysis showed that patients on non-selective beta-blockers had a 71.7% reduced risk of developing HAIs, while those on selective β1-blockers had an 18% higher risk. These findings suggest that targeting sympathetic reflex control of immunity via pharmacological prophylaxis may reduce HAIs in surgical patients.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non‐anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and PO2 ${P_{{{\\mathrm{O}}_{\\mathrm{2}}}$ , and renal function were then monitored for up to 8 h post‐treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and PO2 ${P_{{{\\mathrm{O}}_{\\mathrm{2}}}$were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post‐treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue PO2 ${P_{{{\\mathrm{O}}_{\\mathrm{2}}}$fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide‐induced diuresis. What is the central question of this study? What are the effects of commonly used diuretics on renal cortical and medullary perfusion and oxygenation in non‐anaesthetised healthy sheep? What is the main finding and its importance? Diuretic agents do not increase renal tissue oxygen tension in non‐anaesthetised healthy sheep. On the contrary, rebound cortical tissue hypoxia can develop after furosemide‐induced diuresis has dissipated.

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection.

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 μg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD.

To measure renal blood flow (RBF) and renal function during recovery from experimental septic acute kidney injury (AKI). Controlled experimental study. Nine merino ewes. University physiology laboratory. We recorded systemic and renal hemodynamics during a 96-h observation period (control) via implanted transit-time flow probes. We then compared this period with 96[Symbol: see text]h of septic AKI (48 h of Escherichia coli infusion) and subsequent recovery (48 h of observation after stopping E. coli). Compared with the control period, E. coli infusion induced hyperdynamic sepsis (increased cardiac output and decreased blood pressure) and septic AKI (serum creatinine 65.4 +/- 8.7 vs. 139.9 +/- 33.0 micromol/l; creatinine clearance 73.8 +/- 12.2 vs. 40.2 +/- 17.2 ml/min; p < 0.05) with a mortality of 22%. RBF increased (278.8 +/- 33.9 vs. 547.9 +/- 124.8 ml/min; p < 0.05) as did renal vascular conductance (RVC). During recovery, we observed a decrease in RVC and RBF with all values returning to control levels. Indices of tubular function [fractional excretion of sodium (FENa) and urea (FEUn) and urinary sodium concentration (UNa)], which had been affected by sepsis, returned to control values after 18 h of recovery, as did serum creatinine. Infusion of E. coli induced a hyperdynamic circulatory state with hyperemic AKI. Recovery was associated with relative renal vasoconstriction and reduction in RBF and RVC back to control levels. Indices of tubular function normalized more rapidly than changes in RBF.

Background Cardiopulmonary bypass (CPB) is integral to the conduct of cardiac surgery but is associated with postoperative acute kidney injury (AKI). Dexmedetomidine, an α₂-adrenoceptor agonist with anti-inflammatory and sympatholytic properties, has putative renoprotective effects. In a recent meta-analysis, dexmedetomidine during CPB reduced AKI; conversely, a large, randomised trial reported an increase in postoperative AKI. Further, we found increased renal tubular injury in sheep receiving dexmedetomidine during CPB. Here, we aimed to determine whether dexmedetomidine during CPB induces changes in renal vascular reactivity or endothelial integrity that could explain focal renal tubular injury. Methods Fourteen instrumented Merino ewes underwent 2 h of non-pulsatile CPB (flow 70 mL/kg/min; MAP 65–75 mmHg; cooled by 3 °C) under standardised propofol–fentanyl–sevoflurane anaesthesia. Animals were randomly allocated to dexmedetomidine (0.4–0.8 µg/kg/h, n  = 7) or fluid-matched saline ( n  = 7) from induction of anesthesia to end-CPB. Arterial pressure, renal blood flow, cortical and medullary perfusion and PO₂ were measured in vivo ( n  = 7/group). Post-CPB, renal interlobar arteries were isolated for wire myography. Due to standardisation failures, in vitro analyses of dose–response curves for phenylephrine were performed in n  = 6 per group, while endothelial-dependent and independent relaxation responses were performed in n  = 7 per group. Endothelial histology of CPB arteries was compared with arteries from a separate cohort of healthy Merino ewes ( n  = 7). Results In vitro functional investigations demonstrated that interlobar arteries from dexmedetomidine-treated sheep exhibited a 2.3-fold increase in phenylephrine sensitivity ( p EC₅₀ 5.82 ± 0.27 vs. 5.45 ± 0.23; p  = 0.034), with unchanged maximal contraction. Endothelium-dependent and independent relaxations were similar between groups, though inhibitor studies indicated a shift towards cyclooxygenase-mediated dilation under dexmedetomidine. Histology revealed intact endothelial architecture and no damage to endothelial integrity in all groups. Conclusions Perioperative dexmedetomidine during CPB enhanced α₁-adrenergic vasoconstrictor sensitivity in renal interlobar arteries without disrupting endothelial integrity or compromising renal blood flow or intrarenal perfusion. The enhanced vasoreactivity may contribute to focal renal ischaemia and tubular injury during CPB, which cannot be detected by in vivo measurements of global and regional kidney perfusion and oxygenation. Further investigation is warranted to elucidate the pathways through which dexmedetomidine contributes to renal tubular injury during CPB.