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Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p p

Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8–37reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.

Sympathetic nerve activity is a hallmark of hypertension in end-stage renal disease (ESRD). An initial proof-of-concept study implies that renal denervation (RDN) is feasible and safe in RDN, but overall data are limited. In this single-centre prospective pilot study six patients with ESRD and treatment resistant hypertension were consecutively included. Ambulatory blood pressure (ABP) was measured before and 6 months after RDN (Symplictiy Flex™, Medtronic Inc., Santa Rosa, CA). Moreover, haemodialysis parameters which may affect BP reduction were monitored closely. In all patients bilateral RDN was successful done, without documentation of peri- or postprocedural complications. There was a significant reduction in 24-h ABP by 20 ± 17/15 ± 12 mmHg 6 months after RDN (systolic: 163 ± 16 versus 143 ± 9 mmHg, p = 0.043; diastolic: 96 ± 9 versus 81 ± 15 mmHg, p = 0.043), with similar results for day-, and nighttime values, respectively. Antihypertensive medication was kept stable as well as there was no change in haemodialysis parameters during follow-up. In addition, ultrafiltration/week (1.4 ± 1.4 versus 2.2 ± 1.4 l, p = 0.08) as well as hematocrit (measured at baseline and 6 months after RDN) (33.7 ± 4.3 versus 33.1 ± 3.9%, p = 0.715) revealed no change in volume status. Our single-centre pilot study not only supports current data on renal safety of RDN even in small arteries of patients with ESRD, but also enhances the knowledge towards an effective ABP reduction in this type of hypertensive patients.

We demonstrated earlier that renal afferent pathways combine very likely “classical” neural signal transduction to the central nervous system and a substance P (SP)–dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 ± 5.1 to 21.6 ± 1.5 mV s (*p + dendritic cells (DCs). An enhanced frequency of CD11c+NK1R+ cell, NK-1 receptor+ macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c+NK1R+ cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.

Data on the blood pressure (BP)-lowering effect of renal denervation (RDN) in moderate treatment-resistant hypertension (TRH) are limited. Moreover, change of adherence to medication, as one potential confounder of BP response, has never been analyzed rigorously in this group of patients. We analyzed the effect of RDN on BP in patients with moderate TRH who were retrospectively found to be completely adherent to their antihypertensive medication.Our study cohort comprised 40 patients with moderate TRH [office BP ≥ 140/90 but160/100 mmHg and 24-h ambulatory BP monitoring (ABPM) ≥130/80 mmHg] who underwent catheter-based RDN. Further major inclusion criterion was complete adherence to their medication (≥80% intake of their prescribed antihypertensive drugs) at baseline (assessed by retrospective toxicological analysis).Six months after RDN, office BP was reduced by -10/-6 mmHg (SBP: 149 ± 6 vs. 139 ± 15 mmHg; DBP: 81 ± 12 vs. 75 ± 10 mmHg; both P 0.001) and 24-h ABPM by -7/-4 mmHg (SBP: 150 ± 14 vs. 143 ± 16 mmHg, P = 0.005; DBP: 82 ± 10 vs. 78 ± 9 mmHg, P = 0.009). Number of prescribed antihypertensive medication [6.0 (5.0-6.0) vs. 5.5 (5.0-6.0), P = 0.013] and adherence rate (95.2 ± 7.6 vs. 91.7 ± 13.9%, P = 0.065) was slightly reduced 6 months after RDN, both likely to underestimate the true BP reduction.Thus, our data indicate that even after given full respect to drug adherence as potential confounder of BP response after RDN, both office and 24-h ABPM were substantially reduced in patients with moderate TRH.

Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively ( P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation ( P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk ( P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.

Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e.

Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Navs). Dorsal root ganglion (DRG) neurons from rats (Th11-L2) were recorded by the current-clamp technique and distinguished as “tonic” or “phasic.” In voltage-clamp recordings, Navs were characterized by their tetrodotoxoxin (TTX) sensitivity, and their molecular identity was revealed by RT-PCR. The firing pattern of 66 DRG neurons (41 renal and 25 nonrenal) was investigated. Renal neurons exhibited more often a tonic firing pattern (56.1 vs. 12%). Tonic neurons showed a more positive threshold (−21.75 ± 1.43 vs.−29.33 ± 1.63 mV; P < 0.05), a higher overshoot (56.74 [53.6–60.96] vs. 46.79 mV [38.63–54.75]; P < 0.05) and longer action potential duration (4.61 [4.15–5.85] vs. 3.35 ms [2.12–5.67]; P < 0.05). These findings point to an increased presence of the TTX-resistant Navs 1.8 and 1.9. Furthermore, tonic neurons exhibited a relatively higher portion of TTX-resistant sodium currents. Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Navs.

Peptidergic afferent renal nerves (PARN) have been linked to kidney damage in hypertension and nephritis. Neither the receptors nor the signals controlling local release of neurokinines [calcitonin gene-related peptide (CGRP) and substance P (SP)] and signal transmission to the brain are well-understood. We tested the hypothesis that PARN, compared with nonrenal afferents (Non-RN), are more sensitive to acidic stimulation via transient receptor potential vanilloid type 1 (TRPV1) channels and exhibit a distinctive firing pattern. PARN were distinguished from Non-RN by fluorescent labeling (DiI) and studied by in vitro patch-clamp techniques in dorsal root ganglion neurons (DRG; T11-L2). Acid-induced currents or firing due to current injection or acidic superfusion were studied in 252 neurons, harvested from 12 Sprague-Dawley rats. PARN showed higher acid-induced currents than Non-RN (transient: 15.9 ± 5.1 vs. 0.4 ± 0.2* pA/pF at pH 6; sustained: 20.0 ± 4.5 vs. 6.2 ± 1.2* pA/pF at pH 5; * P < 0.05). The TRPV1 antagonist capsazepine inhibited sustained, amiloride-transient currents. Forty-eight percent of PARN were classified as tonic neurons (TN = sustained firing during current injection), and 52% were phasic (PN = transient firing). Non-RN were rarely tonic (15%), but more frequently phasic (85%), than PARN ( P < 0.001). TN were more frequently acid-sensitive than PN (50–70 vs. 2–20%, P < 0.01). Furthermore, renal PN were more frequently acid-sensitive than nonrenal PN (20 vs. 2%, P < 0.01). Confocal microscopy revealed innervation of renal vessels, tubules, and glomeruli by CGRP- and partly SP-positive fibers coexpressing TRPV1. Our data show that PARN are represented by a very distinct population of small-to-medium sized DRG neurons exhibiting more frequently tonic firing and TRPV1-mediated acid sensitivity. These very distinct DRG neurons might play a pivotal role in renal physiology and disease.

In contrast to other sympathetic outflow tracts, renal sympathetic nerve activity (RSNA) decreases in response to hypotensive hemorrhage. The functional significance of this “paradox” is not known. We tested the hypothesis that RSNA modulates renal perfusion and thus erythropoietin (EPO) release after transient hypotensive hemorrhage in anesthetized rats. Plasma EPO was measured before and after 30 min of transient hypotensive hemorrhage (i.e., −40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 min thereafter in sham-denervated rats, and after renal denervation (DNX) or bilateral cervical vagotomy (VX) to abolish/blunt the RSNA decrease mediated by a cardiopulmonary reflex. RSNA, renal Doppler flow, renal vascular resistance (RVR), resistance index, and oxygen delivery/uptake (Do2/V̇o2) were measured. RSNA decreased in intact animals (−40 ± 5% from baseline, P < 0.05). This was blunted by VX. With intact nerves, EPO level did not increase. In DNX rats, EPO was increased at minute 120 (49 ± 3 vs. 74 ± 2 mU/ml; P < 0.05), in VX rats this (47 ± 2 vs. 62 ± 4 mU/ml; P < 0.05) was less pronounced. Do2 in DNX rats was lower compared with intact and VX rats (0.25 ± 0.04 vs. 0.51 ± 0.06 and 0.54 ± 0.05 ml O2/min; P < 0.05) due to lower Doppler flow and increased RVR. RVR and Do2 were similar in intact and VX rats, but resistance index differed between all groups (0.70 ± 0.02 vs. 0.78 ± 0.02 vs. 0.85 ± 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. V̇o2 was unaffected by VX and DNX. Renal sympathoinhibition during hypotensive hemorrhage might help to preserve sufficient oxygenation of renal tissue by modulation of hemodynamic mechanisms that act to adapt renal oxygen availability to demand.

Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension.We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) ≥ 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement ≥ 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at http://www.clinicaltrials.gov (ID: NCT01442883).Mean baseline BP was 156 ± 12/82 ± 13 mmHg, despite treatment with 6.2 ± 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 ± 20 (P 0.001)/8 ± 14 mmHg (P = 0.005) and average 24-h ambulatory BP by 9 ± 14 (P = 0.009)/4 ± 7 mmHg (P = 0.019). Before RDN, eGFR declined by -4.8 ± 3.8 ml/min per 1.73 m per year, and after RDN eGFR improved by +1.5 ± 10 ml/min per 1.73 m at 12 months (P = 0.009).Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.

Stimulation of renal sympathetic nerves causes reduced renal blood flow. To elucidate whether renal denervation (RDN) affects renal perfusion, we analysed renal blood flow of parenchymal areas perfused by arteries that were non-treated versus treated with RDN. In a pilot study 8 patients with treatment-resistant hypertension that had multiple renal arteries in either kidney were included. All patients underwent catheter-based RDN using the Symplicity FlexTM RDN System of the main renal arteries, but not of accessory renal arteries. Renal perfusion was measured noninvasively by magnetic resonance imaging on a 1.5-T scanner with arterial spin labelling before (day-1), after (day + 1) and again after 3 months (3 M) of RDN. Renal parenchyma was divided into areas that were perfused by renal arteries which were treated with RDN versus those areas perfused by accessory renal arteries not treated with RDN. Hence, every patient could serve at its own control with respect to changes of renal blood flow in the same kidney. In addition renal function was assessed by eGFR according CKD-Epi formula. There was an acute increase of renal perfusion in areas supplied by arteries not undergoing RDN (day-1: 242.3 [229.2-263.2] vs. day + 1: 260.0 [243.5-296.6] ml/min/100 g, p = 0.008), which returned to baseline values after 3 M (257.0 [240.5-277.8] ml/min/100 g, p = 0.260). In contrast, renal perfusion did not change in areas supplied by arteries undergoing RDN in acute (day-1: 263.5 [245.9-273.6] vs. day + 1: 256.5 [242.9-273.5] ml/min/100 g, p = 0.953) and 3 M (245.4 [235.5-269.7] ml/min/100 g, p = 0.594). Accordingly, the acute change in renal perfusion between day-1 and day + 1 was significantly greater in parenchymal areas supplied by arteries without compared to areas with RDN (p = 0.014), but not after 3 M. Renal function assessed by eGFR did not change between day-1 and day + 1 (80.3 ± 20 versus 79.8 ± 20 ml/min/1.73m, p = 0.885) as well as after 3 M of RDN (80.8 ± 18 ml/min/1.73m, p = 0.889). Despite an average of 7.0 ± 1.5 antihypertensive drugs, baseline office BP was 157/85mmHg, and was reduced by -11/-7mmHg after 3 M of RDN. Our data indicate an acute increase of renal perfusion in renal parenchymal areas perfused by arteries with intact renal nerves, whereas no change occurred in parenchymal areas perfused by arteries after RDN.

Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.

Sympathetic efferent and peptidergic afferent renal nerves likely influence hypertensive and inflammatory kidney disease. Our recent investigation with confocal microscopy revealed that in the kidney sympathetic nerve endings are colocalized with afferent nerve fibers (Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Am J Physiol Renal Physiol 297: F1427–F1434, 2009; Veelken R, Vogel EM, Hilgers K, Amman K, Hartner A, Sass G, Neuhuber W, Tiegs G. J Am Soc Nephrol 19: 1371–1378, 2008). However, it is not known whether renal afferent nerves are influenced by sympathetic nerve activity. We tested the hypothesis that norepinephrine (NE) influences voltage-gated Ca2+ channel currents in cultured renal dorsal root ganglion (DRG) neurons, i.e., the first-order neuron of the renal afferent pathway. DRG neurons (T11–L2) retrogradely labeled from the kidney and subsequently cultured, were investigated by whole-cell patch clamp. Voltage-gated calcium channels (VGCC) were investigated by voltage ramps (−100 to +80 mV, 300 ms, every 20 s). NE and appropriate adrenergic receptor antagonists were administered by microperfusion. NE (20 μM) reduced VGCC-mediated currents by 10.4 ± 3.0% ( P < 0.01). This reduction was abolished by the α-adrenoreceptor inhibitor phentolamine and the α2-adrenoceptor antagonist yohimbine. The β-adrenoreceptor antagonist propranolol and the α1-adrenoceptor antagonist prazosin had no effect. The inhibitory effect of NE was abolished when N-type currents were blocked by ω-conotoxin GVIA, but was unaffected by other specific Ca2+ channel inhibitors (ω-agatoxin IVA; nimodipine). Confocal microscopy revealed sympathetic innervation of DRGs and confirmed colocalization of afferent and efferent fibers within in the kidney. Hence NE released from intrarenal sympathetic nerve endings, or sympathetic fibers within the DRGs, or even circulating catecholamines, may influence the activity of peptidergic afferent nerve fibers through N-type Ca2+ channels via an α2-adrenoceptor-dependent mechanism. However, the exact site and the functional role of this interaction remains to be elucidated.

Renal and preganglionic adrenal sympathetic nerve activities (RSNA, ASNA) are regulated differentially. Various cardiopulmonary receptor (CPR) stimulation procedures were performed to distinguish short-term and prolonged as well as mechanical and chemical stimulatory effects on RSNA and ASNA. In anesthetized male Sprague-Dawley rats blood pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), RSNA and ASNA were recorded. CPRs were stimulated as follows: Short-term mechanical: LVEDP changes (+/-4, +/-6, +/-8 mmHg) via aortic and caval vein occlusion; Short-term chemical: phenylbiguanide (PBG-bolus, 0.1, 1, 10 microg IV); Prolonged mechanical (15 min): volume expansion (0.9% NaCl, 5% body weight) and hemorrhage, to modulate LVEDP; Prolonged chemical: PBG infusion (32 microg/min IV, for 15 min); Stimulations were done with 1) all afferents intact, 2) bilateral cervical vagotomy (VX), 3) VX + SAD (sino-aortic denervation; short-term protocols and hemorrhage).1) Short-term mechanical stimuli decreased RSNA (-52 +/- 12%) and ASNA (-37 +/- 13%). 2) PBG-bolus decreased RSNA (-54 +/- 12%) but increased ASNA (+40 +/- 13%). 3) Volume expansion decreased RSNA (-55 +/- 7%), ASNA was unaffected. 4) PBG infusion persistently decreased RSNA (-60 +/- 6%) but just shortly increased ASNA (+120 +/- 15%); VX abolished all responses. 5) Hypotensive hemorrhage decreased RSNA (-39 +/- 9%) but increased ASNA (+42 +/- 9%). VX abolished RSNA response; ASNA response only disappeared with VX + SAD.Short-term mechanical CPR stimulation uniformly decreased sympathetic activities, whereas chemical stimulation had opposing effects on renal and adrenal sympathetic responses. All prolonged stimuli decreased RSNA, whereas ASNA was virtually unaffected: Sympathetic out.ow is differentially controlled not only with regard to target organs or afferent receptors but also stimulus time pattern.

Left ventricular (LV) end-diastolic pressure (LVEDP) increase due to volume expansion (VExp) enhances mechanosensitive vagal cardiac afferent C-fiber activity (CNFA), thus decreasing renal sympathetic nerve activity (RSNA). Hypotensive hemorrhage (hHem) attenuates RSNA despite decreased LVEDP. We hypothesized that CNFA increases with any change in LVEDP. Coronary perfusion pressure (CPP), supposedly affected in both conditions, might also be a stimulus of CNFA. VExp and hHem were performed in anesthetized male Sprague-Dawley rats while blood pressure, heart rate, and RSNA were measured. Cervical vagotomy abolished RSNA response in both reflex responses. Single-unit CNFA was recorded while LVEDP was changed. Rapid changes (± 4, ±6, ±8 mmHg) were obtained by graded occlusion of the caval vein and descending aorta. Prolonged changes were obtained by VExp and hHem. Furthermore, CNFA was recorded in a modified Langendorff heart while CPP was changed (70, 100, 40 mmHg). Rapid LVEDP changes increased CNFA [caval vein occlusion: +16 ± 3 Hz (approximately +602%); aortic occlusion: +15 ± 3 Hz (approximately +553%); 70 units; P < 0.05]. VExp and hHem ( n = 6) increased CNFA [VExp: +10 ± 4 Hz (approximately +1,033%); hHem: +10 ± 2 Hz (approximately +1,225%); P < 0.05]. An increase in CPP increased CNFA [+2 ± 1 Hz (approximately +225%); P < 0.05], whereas a decrease in CPP decreased CNFA [−0.8 ± 0.4 Hz (approximately −50%); P < 0.05]. All C fibers recorded originated from the LV. CNFA increased with any LVEDP change but changed equidirectionally with CPP. Thus neither LVEDP nor CPP fully accounts directly for afferent C-fiber and reflex sympathetic responses. The intrinsic afferent stimuli and receptive fields accounting for reflex sympathoinhibition still remain cryptic.

Recent studies suggest a role of ion channels of the DEG/ENaC family for mechanosensation in different species and in baroreceptor reflex control in rats. We tested the hypothesis that ENaC within the cardiac sensory network are mandatory for mechanosensation. Experiments were performed in male Sprague-Dawley rats, isolated nodose ganglion cells with cardiac afferents and isolated vagus nerves. Epicardial delivery of the amiloride analogue benzamil intended to specifically inhibit ENaC presumably located on cardiac sensory afferents indeed blunted the mechanosensitive (i. e., sympathoinhibition by intravenous volume loading [-32% and -42% in treated groups vs. -67% in controls; n = 7 each; p0.05]) as well as-though to a lesser extent-the 5-HT(3)-mediated chemosensitive cardiorenal reflex in vivo in a dose-dependent manner. Using patch clamp technique, however, it turned out that neither amiloride nor benzamil influenced mechanically induced currents in ganglion nodosum cells in vitro, stimulated by hypoosmotic stress. The unspecific stretch activated ion channel blocker gadolinium completely abolished mechanically induced currents, indicating respective cells were mechanosensitive. In isolated vagus nerves benzamil impaired action potentials obtained by electrical stimulation (C-spike amplitude [-33%]; latency [+12%]; n = 8; p0.05). Our findings at least cast doubt on ENaC exclusively playing a specific role as mechanotransducers within the cardiac sensory network. Other ion channels might be involved. Furthermore the observed findings in vivo could also be due to unspecific disturbance of afferent signal conduction.