Background Although 98% of potassium (K+) resides intracellularly, current clinical diagnostics assess only extracellular K+ concentrations. Noninvasive imaging of tissue K+ distribution could provide novel insights into pathophysiologic processes in diseases such as primary aldosteronism (PA). PA is characterized by excessive aldosterone production, which leads to electrolyte imbalances, hypertension, and increased cardiovascular risk. Purpose To determine whether potassium 39 (39K) MRI combined with sodium 23 (23Na) MRI can help detect alterations in skeletal muscle K+ and Na+ distribution in participants with PA. Materials and Methods A prospective pre-post study in participants with PA and a cross-sectional case-control study in participants with PA and age- and sex-matched control participants were conducted between January 2019 and April 2024. Participants underwent 7-T 39K and 23Na MRI of the calf muscle before treatment and approximately 4 months after standard therapy (mineralocorticoid receptor antagonists or adrenalectomy). Control participants underwent a single scan. Apparent tissue K+ concentrations (aTPCs) and apparent tissue Na+ concentrations (aTSCs) were quantified; serum aldosterone and K+ were measured and correlated with imaging. Fifty-five male mice underwent sham surgery or deoxycorticosterone acetate-pellet implantation for translational chemical muscle K+ validation. Statistical tests included the Student t test or Mann-Whitney U test (between-group), Wilcoxon signed-rank test (within-participant), and Spearman correlation (two-sided α = .05). Results Forty-two participants were evaluated, including 21 participants with PA (mean age, 52 years ± 9 [SD]; 11 female participants) and 21 control participants (mean age, 53 years ± 9; 11 female participants). Participants with PA showed lower aTPC and higher aTSC than control participants (mean aTPC: 72.7 mmol/L ± 6.8 vs 79.1 mmol/L ± 10.0, P = .02; mean aTSC: 23.9 mmol/L ± 5.3 vs 19.0 mmol/L ± 3.0, P < .001). In within-participant comparisons, PA therapy increased aTPC (mean, 72.9 mmol/L ± 7.5 to 80.9 mmol/L ± 9.8; P = .001) but decreased aTSC (25.2 mmol/L ± 4.8 to 18.9 mmol/L ± 3.4; P < .001), with values approaching control participant values. Baseline aTPC did not correlate with serum K+ (r2 = .02, P = .54). Mouse muscle chemistry mirrored MRI-based K+ depletion. Conclusion Combined 39K and 23Na MRI enabled noninvasive detection of aldosterone-mediated tissue electrolyte shifts. ClinicalTrials.gov Identifier: NCT04251780 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Ellermann in this issue.

Cardiac vagal afferent neurons, located in the nodose ganglion, play a pivotal role in cardiopulmonary reflexes that link cardiac filling states to renal sympathetic outflow and the maintenance of circulatory homeostasis. Their excitability depends on a fine balance of depolarizing and repolarizing ion fluxes, yet the contribution of mechanosensitive (MS) ion channels to this regulation remains incompletely understood. While non-selective cation channels such as Piezo1/2 are established mediators of baroreceptor function, they are not directly responsible for repolarization. In contrast, mechanosensitive potassium channels are ideally suited to terminate action potentials and thereby shape afferent signaling from the heart. We, therefore, tested the hypothesis that MS potassium channels are functionally expressed in nodose ganglion neurons with cardiac projections. Using excised-patch recordings with stepwise suction, we identified two types of MS channels. One was inhibited by extracellular gadolinium (100 µM) and exhibited a higher unitary conductance, while the other was insensitive to gadolinium and showed a lower conductance. Both channel types were predominantly selective for K+ but also permeable to Na+, with a relative K+: Na+ permeability of ∼3.3–3.4. This mixed selectivity provides sufficient depolarization to activate voltage-gated Na+ channels and thereby initiate action potential firing. Our findings provide direct evidence for the presence of MS potassium channels in cardiac vagal afferent neurons and suggest that they may contribute critically to the mechanoelectric coupling and reflex control of cardiovascular function.

AIMS:Sodium-glucose co-transporter 2 inhibitors have become a cornerstone in managing chronic heart failure (CHF). While their acute impact on urinary glucose and sodium excretion is well-established, their mid- and long-term persistence of these effects remains uncertain. This study investigated fluid and sodium balance over 3 months in a randomized, placebo-controlled trial (NCT03128528). METHODS AND RESULTS:Overall, 74 patients with New York Heart Association class II-III CHF and an ejection fraction (EF) ≤49% were randomized (2:1) to empagliflozin 10 mg (n = 48) or placebo (n = 26). Sodium, potassium, glucose, urea, and urine were determined from standardized 24-h urine collections. Free water clearance (FWC) and plasma/urine osmolality were calculated. Body weight was measured, and dedicated sodium magnetic resonance imaging (23Na-magnetic resonance imaging) was performed to quantify skin and muscle sodium levels at baseline, at 1 month, and at 3 months. Patients (mean age 66.4 years; 84% male; EF 40%; baseline N-terminal pro-B-type natriuretic peptide 707.9 pg/ml) were followed up at 1 and 3 months. Empagliflozin significantly increased natriuresis at 1 month (p = 0.040), while natriuresis returned to baseline by 3 months. Skin sodium content decreased at 1 month (p = 0.039) and remained reduced at 3 months (p = 0.013), while muscle sodium was unchanged. Persistent glucosuria (p < 0.001) increased urine osmolality at 3 months (p = 0.003). Urine volume increased transiently at 1 month (p = 0.046) but normalized by 3 months. Empagliflozin-treated patients showed a reduction in FWC at 1 and 3 months (p < 0.001), with a compensatory rise in copeptin levels, indicating increased vasopressin activity (1 month: p = 0.020; 3 months: p = 0.001). CONCLUSIONS:Mid-range effects of empagliflozin in heart failure with reduced EF include transient natriuresis and sustained glucosuria, with compensatory reductions in FWC. Reductions in skin sodium content were maintained, and volume homeostasis in CHF patients stabilized after 3 months.

In autosomal dominant polycystic kidney disease (ADPKD) cysts can arise from all compartments of the nephron and collecting duct. Identification of the cellular origin would improve our understanding of cyst development and allow to target cyst growth in a more specific and potentially personalized way. However, no imaging technique is currently able to classify cysts according to their origin. Ex vivo data of cyst fluid suggested variations of Na+ concentration probably linked to cyst development. We hypothesized that cyst Na+ concentration can be measured by 23Na magnetic resonance imaging (23Na MRI) in vivo and that cysts of ADPKD patients can be characterized and distinguished by their Na+ concentration. We conducted 23Na MRI measurements combined with anatomical 1H MRI sequences of the kidney using an ultra-high-field 7Tesla MRI scanner (Siemens, Magnetom Terra.X, Erlangen, Germany). Initially, polycystic kidneys of four ADPKD patients (three on dialysis/one kidney transplant patient) were assessed ex vivo after nephrectomy. Correspondent cyst fluid was obtained by aspiration and electrolyte concentration was determined by ion selective electrodes. In a subsequent clinical study the established 23Na MRI methodology was applied in 18 ADPKD patients to investigate cyst Na+ concentration and distribution in vivo. Interleaved 23Na/1H MRI was performed with a nominal spatial resolutions of 6 mm 23Na/2 mm 1H and an acquisition time of 15 min. To verify our MRI methodology we compared 23Na MRI measurements of nephrectomized ADPKD kidneys with the directly determined Na+ concentration of fluid from prespecified cysts. Cyst Na+ concentration was either comparable to serum Na+ (136 ± 10 mmol/l, n = 14) or very low with 27 ± 22 mmol/l (n = 18). A close correlation was found between both measurement methods, and 23Na MRI was able to reliably distinguish between cysts with high and low Na+ concentrations (Fig. 1A). Based on these findings ADPKD patients (age: 47 ± 12 years, female/male: 7/11, eGFR 61 ± 35 ml/min/1.73 m2) were assessed with 1H and 23Na MRI. In all patients - regardless of kidney function, gender or age - cysts with low and high Na+ concentration could be identified. However, number, distribution and localization of the two distinct cyst types were highly variable. 1H/23Na images and image overlay of two representative patients are depicted in Fig. 1B. Renal cysts in ADPKD patients can be classified according to their Na+ concentration and 23Na MRI at 7Tesla is capable of visualizing these different cyst types in vivo. In future, 23Na MRI could be used to assess the effect of current and/or upcoming therapies on the progression of specific cysts, thereby evolving into a diagnostic tool to predict the course of the disease and therapy outcomes.

IntroductionTissue Na+ overload is present in patients receiving hemodialysis (HD) and is associated with cardiovascular mortality. Strategies to actively modify tissue Na+ amount in these patients by adjusting the HD regimen have not been evaluated.MethodsIn several substudies, including cross-sectional analyses (n = 75 patients on HD), a cohort study and a cross-over interventional study (n = 10 patients each), we assessed the impact of ultrafiltration (UF) volume, prolongation of dialysis treatment time, and modification of dialysate Na+ concentration on tissue Na+ content using 23Na magnetic resonance imaging (23Na-MRI).ResultsIn the cross-sectional analysis of our patients on HD, differences in dialysate sodium concentration ([Na+]) were associated with changes in tissue Na+ content, whereas neither UF volume nor HD treatment time affected tissue Na+ amount. Skin Na+ content was lower in 17 patients on HD, with dialysate [Na+] of <138 mmol/l compared to 58 patients dialyzing at ≥138 mmol/l (20.7 ± 7.3 vs. 26.0 ± 8.8 arbitrary units [a.u.], P < 0.05). In the cohort study, intraindividual prolongation of HD treatment time was not associated with a reduction in tissue Na+ content. Corresponding to the observational data, intraindividual modification of dialysate [Na+] from 138 to 142 to 135 mmol/l resulted in concordant changes in skin Na+ (24.3 ± 7.6 vs. 26.3 ± 8.0 vs. 20.8 ± 5.6 a.u, P < 0.05 each), whereas no significant change in muscle Na+ occurred.ConclusionSolely adjustment of dialysate [Na+] had a reproducible impact on tissue Na+ content. 23Na-MRI could be utilized to monitor the effectiveness of dialysate [Na+] modifications in randomized-controlled outcome trials.

Background: SGLT2 inhibitors may improve cardiac outcomes due to their osmotic-diureticpotential. We prospectively tested the hypothesis that vasopressin-driven urine concentration overrides the osmotic-diuretic driving force of dapagliflozin-induced glucosuria.Methods: DAPA-Shuttle1 was an investigator-initiated, mechanistic, single-center, randomized controlled trial at the National Heart Centre, Singapore. Eligible participants with heart failure NYHA classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10mg daily or placebo (1:1) for 4 weeks. Participants, investigators, and study personnel were masked to assignment throughout the trial. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels, solute free water clearance (FWC), and tissue Na+ content.Results: Between November 2019 and September 2021 forty participants were enrolled. Thirty three randomized, SGLT2 inhibitors naïve participants started the treatment intervention and completed the study, of which (placebo: n=14; dapagliflozin: n=15) provided accurate 24h urine collections (mean age 59±14 years, LVEF 31±9%). Dapagliflozin treatment increased glucosuria by 3.3 mmol/kg/d ([95%CI 2.51,4.04], p<0.0001) within 48h (early); this effect persisted after 4 weeks (late; 2.7 mmol/kg/d [95%CI 1.98,3.5], p<0.0001). Dapagliflozin treatment neither increased natriuresis (early: P=0.68; late: P=0.64), nor changed tissue Na+ content (early: P=0.62; late: P=0.90). Despite sustained glucosuria, urine volume did not significantly increase with dapagliflozin (mean difference early: +2.8 ml/kg/d [95%CI -1.97,7.48], P=0.25; late: +0.9ml/kg/d [95%CI -3.83,5.62], P=0.70). Dapagliflozin treatment increased plasma copeptin early (+5.5 pmol/L [95%CI 0.45,10.5], p<0.05) and late (+7.8 pmol/L [95%CI 2.77,12.81], p<0.01), leading to proportional reductions in FWC (early: -9.1 ml/kg/d [95%CI -14, -4.12], p<0.001; late: -11.0 ml/kg [95%CI -15.94, -6.07], p<0.0001) and increases in urine concentration (late: +134 mmol/L [95%CI 39.28, 229.12], p<0.01). This physiological-adaptive water conservation mechanism prevented a glucose-driven increase 70 in urine volume of approximately ≍10 ml/kg/d · 75 kg = 750 ml/d.Conclusions: SGLT2 inhibition with dapagliflozin caused relevant glucosuria, but adaptive physiological, vasopressin-driven water conservation virtually eliminated the expected osmotic diuretic potential of the drug. Therefore, the presented mechanistic-experimental evidence does not support the hypothesis that the beneficial effects of SGLT2 inhibitors in patients with heart failure are attributable to chronic cardiac decongestion. The DAPA-Shuttle1 study was an investigator-initiated trial funded by Astra Zeneca via the Externally sponsored scientific research program (ESR-18-13712). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BACKGROUND:Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES:The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS:DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS:Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS:Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

Abstract Background Clinical magnetic resonance imaging (MRI) studies often use Cartesian gradient-echo (GRE) sequences with ~2-ms echo times (TEs) to monitor apparent total sodium concentration (aTSC). We compared Cartesian GRE and ultra-short echo time three-dimensional (3D) radial-readout sequences for measuring skeletal muscle aTSC. Methods We retrospectively evaluated 211 datasets from 112 volunteers aged 62.3 ± 12.1 years (mean ± standard deviation), acquired at 3 T from the lower leg. For 23Na MRI acquisitions, we used a two-dimensional Cartesian GRE sequence and a density-adapted 3D radial readout sequence with cuboid field-of-view (DA-3D-RAD-C). We calibrated the 23Na MR signal using reference tubes either with or without agarose and subsequently performed a relaxation correction. Additionally, we employed a six-echo 1H GRE sequence and a multi-echo spin-echo sequence to calculate proton density fat fraction (PDFF) and water T2. Paired Wilcoxon signed-rank test, Cohen dz for paired samples, and Spearman correlation were used. Results Relaxation correction effectively reduced the differences in muscle aTSC between the two acquisition and calibration methods (DA-3D-RAD-C using NaCl/agarose references: 20.05 versus 19.14 mM; dz = 0.395; Cartesian GRE using NaCl/agarose references: 19.50 versus 18.82 mM; dz = 0.427). Both aTSC of the DA-3D-RAD-C and Cartesian GRE acquisitions showed a small but significant correlation with PDFF as well as with water T2. Conclusions Different 23Na MRI acquisition and calibration approaches affect aTSC values. Applying relaxation correction is advised to minimize the impact of sequence parameters on quantification, and considering additional fat correction is advisable for patients with increased fat fractions. Relevance statement This study highlights relaxation correction’s role in improving sodium MRI accuracy, paving the way for better disease assessment and comparability of measured sodium signal in patients. Key points • Differences in MRI acquisition methods hamper the comparability of sodium MRI measurements. • Measured sodium values depend on used MRI sequences and calibration method. • Relaxation correction during postprocessing mitigates these discrepancies. • Thus, relaxation correction enhances accuracy of sodium MRI, aiding its clinical use. Graphical Abstract

Patients with treatment resistant hypertension (TRH) are known to have elevated sodium (Na) content in muscle and skin. Renal denervation (RDN) emerged as an adjacent therapeutic option in this group of patients. This analysis aimed at evaluating whether tissue Na content predicts blood pressure (BP) response after RDN in patients with TRH. Radiofrequency-device based RDN was performed in 58 patients with uncontrolled TRH. Office and 24-h ambulatory BP were measured at baseline and after 6 months. To assess tissue Na content Na magnetic resonance imaging (Na-MRI) was performed at baseline prior to RDN. We splitted the study cohort into responders and non-responders based on the median of systolic 24-h ambulatory blood pressure (ABP) reduction after 6 months and evaluated the association between BP response to RDN and tissue Na content in skin and muscle. The study was registered at http://www.clinicaltrials.gov (NCT01687725). Six months after RDN 24-h ABP decreased by −8.6/−4.7 mmHg. BP-Responders were characterized by the following parameters: low tissue sodium content in the skin ( p = 0.040), female gender ( p = 0.027), intake of aldosterone antagonists ( p = 0.032), high baseline 24-h night-time heart rate ( p = 0.045) and high LDL cholesterol ( p < 0.001). These results remained significant after adjustment for baseline 24-h systolic BP. Similar results were obtained when the median of day-time and night-time ABP reduction after 6 months were used as cut-off criteria for defining BP response to RDN. We conclude that in addition to clinical factors including baseline 24-h ABP Na-MRI may assist to select patients with uncontrolled TRH for RDN treatment.

Introduction: Our previous work showed that the sensory innervation of the kidney in rats has a peculiarity containing predominantly (more than 50%) highly active tonic neurons to electrical stimulation. In a previous publication demonstrated an increased mRNA expression of the TTX-resistant sodium channel Nav1.8 in renal sensory neurons. Hence, we tested the hypothesis that tonic firing pattern is related to the specific expression of Na v 1.8 on the cell surface of neurons with renal sensoric axons in the dorsal root ganglia (DRG Th12-L2). Material and methods: Harvested dorsal root ganglion neurons (DRG Th11-L2) from male Sprague Dawley (SD) with renal afferents were investigated in primary neuronal cell culture using current clamp mode to assess action potential generation during current injection and to characterize neurons as tonic highly active and phasic less active neurons using a Nav1.8 blocker (A-803467) before and after stimulation. Further, renal DRG neurons from a Nav1.8 knock out mouse (C57BL6J-Scn10atm1Jwo) were investigated in a current clamp mode. C57BL6 mice were used as controls. Results: At a concentration of 0.3μM the maximum AP firing frequency of tonic neurons was blocked from 13+/- 1.1 APs/600ms to 7.6+/-1.4 APs/600ms under superfusion with a Nav1.8 blocker. No blocker effects were seen at a concentration of 0.1 μM and due to superfusion with the solvent methanol alone. The firing pattern of renal neurons in the C57BL6 mouse was similar to that in the SD rat with a dominance of the tonic highly active neurons. In a Nav1.8 knock out mouse (C57BL6J-Scn10atm1Jwo) in the population of neurons with dendrites from the kidney only a single cell out of 70 showed tonic firing behavior (control vs Nav1.8 KO mouse, z-test, p<0.05). Conclusion: Under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings in this study support the significance of the TTX-resistant sodium channel Nav1.8 for the specific tonic firing pattern of neurons with renal projections. That might be of importance for pharmacological interventions to influence renal nerve activity, which likely plays a crucial role in the regulation of blood pressure and control of cardiovascular function.

Introduction: Previous work of ours suggests that pathologically decreased sensitivity of renal afferent neurons (reduced number of highly active tonic neurons) due to high salt diet is normalized 1 wk after renal denervation (DNX). Now we tested the hypothesis that normalized sensitivity of renal neurons persists after DNX even through regrowth of afferent axons after 12 wk. This morphological regrowth of afferent nerves 12wk after renal DNX (postDNX) was shown by us previously. Material and methods: 6 male Sprague Dawley (SD) rats were put on high salt diet (HS; 8% NaCl) for 10 days. In another group of 12 rats on high salt diet (HS) left kidneys were denervated (postDNX) 12 weeks prior to examination. Rats on standard diet were used as controls. Harvested dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated in primary neuronal cell culture using current clamp mode to assess action potential generation during current injection and to characterize neurons as tonic highly active and phasic less active neurons. Results: In renal neurons from rats on HS the relation of tonic to phasic neurons shifted towards less active phasic units (62% tonic neurons in controls [n=72 out of 114] vs. 42% [n=37 out of 86] on HS, (p<0.05, z-test)). Denervation of the left kidney in rats on high salt diet (HS-DNX) led to a recovery of afferent renal DRG neurons after 1 wk; (40% tonic neurons [n=32 out of 80] on HS vs. 72% tonic neurons [n=58 out of 81] on HS+DNX)(p<0.05, z-test)). Even 12 weeks after renal denervation this regained electrophysiological property of tonic firing persisted (43% tonic neurons [n=35 out of 82] on HS vs. 69% tonic neurons [n=46 of 67]on HS-postDNX, p<0.05, z-test)). Conclusion: The reduced proportion of highly active tonic neurons increased 1 wk after renal denervation to control levels. Even 12 weeks after renal denervation, this effect of renal denervation persisted, and the sensitivity of renal neurons to electrical stimuli did not change despite high-salt diet. Hence, the positive effects of renal denervation persisted even through the regrowth of renal afferent axons to the kidney.

Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6

Objective: Afferent renal nerve pathways likely play a role in salt sensitive hypertension. We recently reported that high salt diet (HS) impairs these afferent renal pathways in rats. Now we tested the hypothesis that during HS a decrease in sensitivity of renal afferent neurons is prevented by the SGLT2 inhibitor empagiflozin. Design and method: Respective groups of rats were put on HS containing 8% NaCl or a normal diet. Two groups (HS, controls) received empagiflozin 20 mg/kg BW/day orally. Renal neurons were retrogradely labeled with DiI. In culture, labeled dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated electrophysiologically using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active ( less than 5 action potentials, AP) and phasic less active neurons (more than 5 AP upon stimulation). Results: In neurons from rats on HS, the relation of tonic highly active neurons to less active phasic neurons shifted consistently towards phasic units (63,8% tonic neurons in controls vs. 42%* on HS, *p < 0.05, z-test). However, continuous treatment with empagiflozin preserved the proportion of tonic neurons as in controls (67,9% on HS with concomitant administration of empagiflozin). In controls, empagiflozin did not affect the proportion of tonic to phasic neurons (63,8% tonic neurons in controls vs. 67,9% on HS & empagliflozin, p = 0.7, z-test). Blood pressure and heart rate were not altered by HS and/or treatment with any chosen dose of empagiflozin. Conclusions: In rats, chronically elevated sodium intake (8% NaCl) reduced the sensitivity and stimulability of renal afferent DRG neurons. Under these circumstances, concomitant treatment with the SGLT2 inhibitor empagiflozin preserved the function of renal afferent DRG neurons. SGLT 2 inhibitors may help to treat dysfunction of renal innervation in cardiovascular disease.

Introduction: In experimental myocardial infarction with reduced ejection fraction causing overt congestive heart failure, the control of renal sympathetic nerve activity (RSNA) by the cardio-renal baroreflex was impaired. The afferent vagal nerve activity under these experimental conditions had a lower frequency at saturation than that in controls. Hence, by investigating respective first neurons in the nodose ganglion (NG), we wanted to test the hypothesis that after myocardial infarction with still-preserved ejection fraction, the cardiac afferent nerve pathway is also already impaired.Material and methods: A myocardial infarction was induced by coronary artery ligature. After 21 days, nodose ganglion neurons with cardiac afferents from rats with myocardial infarction were cultured. A current clamp was used to characterize neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., <5 APs upon current injection. Cardiac ejection fraction was measured using echocardiography; RSNA was recorded to evaluate the sensitivity of the cardiopulmonary baroreflex. Renal and cardiac histology was studied for inflammation and fibrosis markers.Results: A total of 192 neurons were investigated. In rats, after myocardial infarction, the number of neurons with a tonic response pattern increased compared to that in the controls (infarction vs. control: 78.6% vs. 48.5%; z-test, *p < 0.05), with augmented production of APs (23.7 ± 2.86 vs. 15.5 ± 1.86 APs/600 ms; mean ± SEM, t-test, *p < 0.05). The baseline activity of RSNA was subtly increased, and its control by the cardiopulmonary baroreflex was impaired following myocardial infarction: the fibrosis marker collagen I augmented in the renal interstitium.Discussion: After myocardial infarction with still-preserved ejection fraction, a complex impairment of the afferent limb of the cardio-renal baroreflex caused dysregulation of renal sympathetic nerve activity with signs of renal fibrosis.