The role of prostaglandins in the excitatory innervation of the rat urinary bladder

The possible role of PGs in hyoscine-resistant nerve mediated responses of the rat urinary bladder was investigated. Responses to electrical stimulation were inhibited by cinchocaine (30 μmol/l) but were only partially inhibited by a high concentration of hyoscine (25 μmol/l) or by the choline uptake inhibitors, hemicholinium-3 (500 μmol/l) and troxypyrrolidinium (500 μmol/l). Indomethacin (50 μmol/l) produced partial blockade (30%) of responses to electrical stimulation without markedly affecting responses to acetylcholine and the degree of blockade was of a similar order in the presence of hyoscine or troxypyrrolidinium. PGE₂ (0.028 – 2.8 μmol/l) or F_2α (0.029 – 2.9 μmol/l) produced a slowly developing increase in tone and spontaneous activity. Responses to electrical stimulation were at most only slightly increased in the presence of either PG. However, the PGs always increased the responses to electrical stimulation after indomethacin, indomethacin plus hyoscine or indomethacin plus troxypyrrolidinium. Responses to acetylcholine in the presence of indomethacin were not increased by PGE₂. It is concluded that PGE₂ and F_2α do not function as transmitters responsible for resistance to anti-muscarinic drugs in the bladder but may exert a modulating effect on nervous transmission.     

Electrophysiological investigation of central neurons of the electroreceptor system of the skate

Bioelectrical responses of acoustico-lateral neurons to electrical stimulation of the ampullae of Lorenzini were investigated in acute experiments on the anesthetized Black Sea skateTrigon pastinaca. Three types of responses were found: a primary composite response, prolonged activity, and single unit activity. Excitation of the neurons corresponded to a more marked negative phase, and inhibition to a more marked positive phase of the primary response. The thresholds of the unit responses to adequate electrical stimulation were 10^–9–10^–10 A/mm² and the minimal latent period 20 msec. The spontaneous activity of some neurons clearly depended on the animal's respiration. The character of the response depended on stimulus polarity, as reflected in the appearance of on- and off-responses. A tonic type of response with features of adaptation was predominant. The dependence of some response parameters (latent period of on- and off-responses, firing rate, duration of the contrast interval, response thresholds) on those of the stimulus is analyzed. The mechanisms of these bioelectrical responses are discussed.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol.6, No.1, pp.59–67, January–February, 1974.     

Electrophysiological investigation of medullary neurons connected with lateral line organs of the catfish (Ictalurus nebulosus)

Unit responses in the acoustic-lateral region of the medulla to electrical and mechanical stimulation of the lateral line organs were investigated in acute experiments on curarized catfish. Of the total number of neurons 70% possessed spontaneous activity. An electrical stimulus evoked a tonic response both in spontaneously active and in "silent" cells. Three main types of firing pattern of the neurons were distinguished: fast-adapting, slow-adapting, and grouped. As regards the relation of the neurons to polarity of the stimulus they were subdivided into two groups. The thresholds of unit responses to electrical stimulation varied considerably: from 2.5·10^–9 to 5·10^–12 A/mm². The effect of intensity of the electrical stimulation on unit responses in the medulla is analyzed. The precise dependence of on- and off-responses of each neuron on stimulus intensity of any polarity was determined. The neurons were shown to be sensitive to both electrical and mechanical stimuli. It is postulated that this phenomenon is due to convergence of impulses from electrical and mechanical receptors of the lateral line on the neurons. The properties of the central neurons are compared with those of the peripheral electroreceptor system in catfish.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 5, No. 2, pp. 156–163, March–April, 1973.     

Pharmacological study of inhibited frog olfactory bulb glomerular input produced by a puff of air on the olfactory mucosa

The effects of applying 4-aminopyridine (10^–2 M), aminooxyacetic acid (AOAA — 10^–4–10^–3 M), -alanine (10^–3–10^–2 M), and bicuculline (10^–5, 10^–4 M) to the intact frog olfactory bulb were investigated. Having measured inhibition of orthodromic potential postsynaptic components produced either by a puff of air on the olfactory mucosa (OB input inhibition) or by single electrical stimulation of the olfactory nerve (postsynaptic inhibition) or by single electrical stimulation of the olfactory nerve (postsynaptic inhibition), it was found that 4-aminopyridine greatly intensified postsynaptic inhibition but strongly reduced that of OB input; inhibition of the latter was raised by AOAA or bicuculline and decreased by -alanine. These substances failed to exert any consistent, clear-cut effects on postsynaptic inhibition. Findings would support the hypothesis that OB input inhibition produced by a puff of air on the olfactory mucosa could occur as a result of GABA release from glial cells and subsequent binding of GABA to presynaptic GABA_B-receptors in glomeruli.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol. 19, No. 1, pp. 12–20, January–February, 1987.     

Effects of indomethacin and PGE1 on the vasoconstrictor responses of the rabbit ear artery to nerve stimulation

Actions of PGE₁ and indomethacin on electrically induced vasoconstriction in isolated ear arteries of rabbits were studied. PGE₁ (8.5 × 10⁻⁹ M) reduced the vasoconstriction; this inhibition was inversely related to the rate of stimulation. Indomethacin (1.5 × 10⁻⁶ M) potentiated the constrictor responses to nerve stimulation. The degree of this potentiation was also frequency-dependent being greater at low (1 – 2 Hz) than at high (8 – 16 Hz) rate of stimulation. These findings support the view that prostaglandins, in addition to their action on vascular smooth muscle cells, play a functional role in the regulation of tone of the rabbit ear artery by a negative feed-back control of adrenergic neurotransmission.     

Electrical activity of an intestinal epithelial cell line: Hyperpolarizing responses to intestinal secretagogues

Summary Cultured epithelial cells (Intestine 407) derived from fetal human small intestine exhibited spontaneous oscillations of membrane potential between the resting level of about –20 mV and the activated level of about –75mV. The cells were hyperpolarized to the latter level in response to mechanical or electrical stimuli. The hyperpolarizing responses were also elicited by the application of intestinal secretagogues: acetylcholine, histamine, serotonin and vasoactive intestinal polypeptide (VIP). The spontaneous oscillation of membrane potential became prominent and long-lasting in the presence of acetylcholine, histamine, serotonin or VIP. These secretagogue-induced responses were mediated by individual independent receptors on the cell membrane. Muscarinic receptors were responsible for the acetylcholine response, and H₁-receptors for the histamine response. The cells also responded with a slow hyperpolarization to calcium ionophore A23187, which is known to induce intestinal secretion. The spontaneously occurring hyperpolarizing responses and those induced by stimuli were both due to an increase in the K⁺ conductance of the cell membrane. Since acetylcholine, histamine, serotonin and A23187 are known to promote mobilization of cellular Ca²⁺ ions in intestinal secretory cells, it is hypothesized that these electrical activities of the cell are closely related to the receptor stimulation which leads to the Ca²⁺-mediated intestinal secretion.     

The effect of electrical currents and tobramycin onPseudomonas aeruginosa biofilms

The combined use of antibiotics with low levels of electrical current has been reported to be more effective in controlling biofilms (the bioelectric effect) than antibiotics alone. An electrical colonisation cell was designed to study the effect of antibiotics on biofilms formed on a dialysis membrane away from the electrode surface. To avoid the electrochemical generation of toxic products,Pseudomonas aeruginosa biofilms were formed in minimal salts medium that excluded chloride-containing compounds. Under these conditions, electrical currents of up to 20 mA cm^–2 did not prevent biofilm formation or have any detrimental effect on an established biofilm. Tobramycin alone at concentrations of 10 g ml^–1 did not affect the biofilm, but were significantly enhanced by 9 mA cm^–2. The effect of tobramycin concentrations of 25 g ml^–1 were enhanced by a 15 mA cm^–2 electrical current. In both cases higher levels of electrical current, up to 20 mA cm^–2, did not further enhance the effect of the antibiotic. The possible mechanisms of action of the bioelectric effect have been reported to involve electrophoresis, iontophoresis and electroporesis, thus overcoming the biofilm biomass and cell wall barriers. Our results suggest that other factors may also be important, such as the metabolic activity and growth rate of the bacteria. Such factors may be critical in maximising antibiotic efficacy.     

Membrane structural and functional responses to vasopressin in toad bladder

Summary Freeze-fracture electronmicroscopy demonstrates that vasopressin stimulation of isolated toad bladder results in a striking morphologic alteration of epithelial membrane structure. This alteration is characterized by the aggregation of intramembranous particles in orderly linear arrays at multiple sites in the luminal membranes of granular cells specifically. The size of these aggregates varies considerably, in terms of area, over a range from 0.5 to 70×10^–3 m². The median aggregate size is about 10.5×10^–3 m². Since the extent of vasopressin-associated particle aggregation, in terms of frequency of sites per area of membrane or cumulative area of membrane occupied by them, closely correlates with induced changes in transport function, as measured by osmotic water flow, the aggregates themselves appear to be of physiologic significance in the mechanism of action of vasopressin. This hypothesis is supported by the observations that sites of aggregation occur (a) in response to serosal exposure to hormone specifically, (b) independently of an osmotic gradient, and (c) following stimulation with cyclic adenosine monophosphate.     

Investigation of neuronal connections in the dorsocaudal tegmentum of the cat by a microstimulation method

Unit responses in the caudal part of the tegmentum were investigated by a microstimulation method in the mesencephalic cat. The thresholds of appearance of direct and synaptic responses with latencies of 0.8–1.4 and 1.1–2.0 msec were found to depend on the distance from the electrode to the cell recorded. Responses with a low threshold (0.2–1.1 µV) were found much more often in neurons located 6.3–7.0 mm from the surface of the inferior colliculus than in more dorsal or more ventral zones. The relationship between the threshold I, in A, of the direct response of the low-threshold cells and their distance r, in , from the stimulating electrode is approximated satisfactorily by the equation I=3.3·10^–4r^1.8+0.2. The curve of I as a function of r for synaptic responses is usually more sloping and it has minima for responses recorded not near the cell. The index of synaptic response of some cells rose with an increase in the frequency of stimulation to 20–60/sec.Institute of Problems in Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 5, No. 6, pp. 593–601, November–December, 1973.     

An hypothesis for the interpretation of the contractile response of vascular smooth muscle at the cellular level

The long preservation and recovery of functional (contractile) properties in cultured aortic smooth muscle cells, even after replating or deep-frozen storage and the measurement of their responses are now technically settled issues. We could thus study extensively the responses of single cultured cells from rat thoracic aorta. Responses were elicited by the addition of KCl 40 mmol/L without or with a calcium blocker PN 200-100 (10^–6 mol/L); angiostein II (10^–11–10^–6 mol/L) without or with antagonist (losartan 10^–5 mol/L); or serotonin (10^–9–10^–4 mol/L) without or with antagonist (naftidrofuryl 10^–5 mol/L). Results thus obtained enabled us to propose a new hypothesis for the interpretation of the contractile responses of an elastic vascular smooth muscle. The different maximal effects of different agonists result mainly from the different proportions of cells they can mobilize; the agonist concentration-contraction relationship is mainly due to the increase of the proportion of cells involved up to a maximal value typical of the agonist used. An antagonist primarily reduce the proportion of cells an agonist can mobilize. Some of the consequences of this hypothesis are briefly outlined.     

Effects of Ca2+ and vitamin E on posttranslational regulation of acetylcholine receptor expression in the somata of identified molluscan neurons

The effects of Ca²⁺ and vitamin E (-tocopherol) on acetylcholine (Ach)-induced Cl^– currents in LP11 and RBc4 neurons of the snail Helix pomatia have been studied. Injection of Ca²⁺ into the cells and application of vitamin E (10^–5 mole/liter) induced the appearance of potentiation of Ach-induced currents in membrane parts more remote from the axon than the Ach-sensitive regions in the control. The Hill coefficient (n) for such Ach receptors was equal to 0.8, unlike 1.8 for Ach receptors active in the control. Arachidonic acid (10^–5 mole/liter) and phorbol ester TPA (10^–6 mole/liter) inhibited Ach responses, while oleoylacetyglycerol (10^–6 mole/liter) produced no effect. Calmidazolium (10^–6 mole/liter) decreased the effects of Ca²⁺ and vitamin E on Ach responses, while nordihydroquiaretic acid (5 · 10^–6 mole/liter) enhanced the modulating effect of vitamin E and weakened that of arachidonic acid. It is suggested that the expression of Ach receptors activated by Ca²⁺ and vitamin E is mediated through posttranslational mechanisms, since cycloheximide and actinomycin D, inhibitors of protein synthesis, did not influence the effects of C²⁺ and vitamin E. The mechanisms responsible for the stimulating effects of Ca²⁺ and vitamin E are discussed.Translated from Neirofiziologiya, Vol. 25, No. 1, pp. 31–39, January–February, 1993.     

Time course of vasopressin-induced formation of microvilli in granular cells of toad urinary bladder

Summary Vasopressin-induced transformation of ridges to microvilli on the surface of granular cells of toad urinary bladder occurs in conjunction with induced alterations in the water permeability of the luminal membrane. This study was designed to establish the relationship between the time course for induction of microvilli and the time course for induction of increased water permeability after vasopressin stimulation. Hemibladders were examined at 2.5, 5, 10, 20 and 30 min following exposure to 20 mU/ml of vasopressin and at 5, 10, 20, 30, 40, 50 and 60 min after washout of vasopressin. Within 2.5 min, vasopressin initiated complete transformation of ridges to microvilli on approximately 13% of the granular cells, while osmotic water flow (Jv) was 0.31±0.10 l·min^–1·cm^–2. Five minutes following vasopressin stimulation, microvilli were present on approximately 30% of granular cells andJv was 2.27±0.13 l·min^–1·cm^–2. At 10 minJv was maximum at 4.03±0.15 l·min^–1·cm^–2 and 50% of the granular cells were covered with microvilli. This percentage increased to 70% at 20 min and was maintained at 30 min, althoughJv decreased to 3.9±0.35 l·min^–1·cm^–2 at 30 min. Five minutes following vasopressin washout, ridges interspersed with microvilli reappeared asJv fell to 1.10±0.30 l·min^–1·cm^–2. At 10 min after vasopressin washout,Jv approached basal levels, but the reversal of microvilli to ridges remained incomplete. At 60 min after vasopressin washout, the granular cells had regained their original ridgelike surface structures. Thus, these studies establish a temporal relationship between the induction and reversibility of vasopressin-induced microvillous formation and alterations in the osmotic water permeability of the apical plasmalemma.     

Investigation of mechanisms of synaptic transmission in ampullae of Lorenzini in the skate

The effect of magnesium ions, L-glutamate (L-GLU), and the diethyl ester of glutamic acid (DEE-GLU) on temperature and electrical sensitivity of the ampullae of Lorenzini in skates was studied by the method of perfusion of the basal membrane of electroreceptor cells and recording spike activity from single nerve fibers. Addition of 10^–4–10^–5 M L-GLU to the solution was shown to cause an increase in the spontaneous discharge frequency of receptors with low initial level of activity (8–20 spikes/sec) and a decrease in receptors with spontaneous activity of 22–42 spikes/sec. In solution with an increased magnesium ion concentration (15–50 mM) both spontaneous and evoked receptor activity was blocked, Under these conditions the addition of L-GLU to the solution caused partial recovery of spontaneous receptor activity. Reversible blocking of spontaneous and evoked receptor activity was observed in a solution containing 10^–4–10^–3 M DEE-GLU. It is suggested that L-GLU is the synaptic transmitter in the ampullae of Lorenzini of the skate.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 13, No. 3, pp. 292–298, May–June, 1981.     

Kidney and bladder function in a uricotelic treefrog (Phyllomedusa sauvagei)

Summary Phyllomedusa sauvagei, a xeric adapted treefrog, excretes large amounts of nitrogen as urate when fed insects, even when deprived of additional water. Most terrestrial anurans produce urea which they do not excrete when they are deprived of water. We investigated the differences in renal function underlying the unusual excretory capacities ofP. sauvagei. Glomerular filtration rates (GFR) were measured inP. sauvagei in water and when deprived of water, except that in food, for up to 27 days. For comparison a toad (Bufo boreas) was studied in water and during water deprivation. In water both species produced 30–40 ml urine kg^–1 h^–1 and resorbed only ca. 50% of the filtrate. With water deprivation, GFR rapidly approached zero inB. boreas, but remained high (20–40 ml kg^–1 h^–1) inP. sauvagei despite reductions in urine production of up to 100-fold. During water deprivation inP. sauvagei, urate excretion was between 250–300 moles kg^–1 h^–1 and 90% of this reflects net tubular secretion. Urate clearances were similar to those of para-amino hippurate, indicating effective removal of urate from the peritubular circulation. Urea, sodium and chloride showed net fractional resorptions of 98–99%, and 85% of the potassium was resorbed. At low rates of urine production, urine to plasma (U/P) ratios for inulin in bladder urine were 20–100 whereas those for ureteral urine were ca. 10. The urinary bladder also functions as a water reserve during dehydration.     

Effects of Cd++ on short-circuit current across epithelial membranes

Summary Cadmium ion (Cd⁺⁺) significantly increased potential difference (PD) and short-circuit current (SCC) across isolated frog skin when added to the outside Ringer's solution at 10^–4, 10^–3 and 5×10^–3 m concentration. Resistance was reduced by 10^–4 m Cd⁺⁺ but not significantly changed by the higher concentrations. When SCC was first stimulated by vasopressin, 10^–4 and 10^–3 m Cd⁺⁺ produced additive stimulation which was reversible by washing with Cd⁺⁺-free Ringer's. If SCC was first stimulated by Cd⁺⁺, further stimulation by vasopressin was additive with 10^–4 m Cd⁺⁺ but completely inhibited by 10^–3 m Cd⁺⁺. Elevating the calcium ion (Ca⁺⁺) concentration of the outer Ringer's from 10^–3 m to 5×10^–3 m or 10^–2 m prior to Cd⁺⁺ treatment did not reduce the magnitude of SCC stimulation by Cd⁺⁺. Removal of Ca⁺⁺ from the outside Ringer's with 2×10^–3 m EDTA increased SCC as predicted. Subsequent addition of 5×10^–3 m Cd⁺⁺ drastically reduced SCC below control levels while equimolar concentrations of Cd⁺⁺ and EDTA reduced SCC only to control levels. These results suggest that Cd⁺⁺ interacts with the components of the apical plasma membranes of epithelial cells which are associated with the stimulation of SCC by vasopressin and Ca⁺⁺ removal and may be a useful probe for elucidating these components.     

Distinct Responses of Osphradial Neurons to Chemical Stimuli and Neurotransmitters in Lymnaea stagnalis L.

1. In Lymnaea stagnalis L. (Pulmonata, Basommatophora) the neurons in the osphradium were visualized by staining through the inner right parietal nerve by 5,6-carboxyfluorescein (5,6-CF). Three types of neurons were identified: three large ganglionic cells (GC1-3; 80–100 m), the small putative sensory neurons (SC; 20 m) and very small sensory cells (3–5 m).2. The ganglionic and putative sensory neurons were investigated by whole cell patch-clamp method in current-clamp condition. The three giant ganglionic neurons (GC1-3) located closely to the root of osphradial nerve, had a membrane potential (MP) between –30 and –70 mV and showed tonic or bursting activities. The small putative sensory cells (SCs) scattered throughout the osphradial ganglion, possessed a MP between –25 and –55 mV and showed an irregular firing pattern with membrane oscillations. At resting MP the GC1-3 cells were depolarized and increased the frequency of their firing, while the SCs were hyperpolarized and inhibited by NaCl (10^–2 M) and L-aspartate (10^–5 M) applied to the osphradium.3. 5-Hydroxytryptamine (5HT, 10^–6 M), -aminobutyric acid (GABA; 10^–6 M) and the GABA_B agonist baclofen (10^–6 M) depolarized the neurons GC1-3 and increased their firing frequency. In contrast, on the GC1-3 neurons, acetylcholine (Ach; 10^–6 M) and FMRFamide (10^–6 M) caused hyperpolarization and cessation of the firing activity. The 5HT effect was blocked by mianserin (10^–6 M) but picrotoxin (10^–5 M) failed to block the GABA-induced effect on the GC1-3 cells.4. The small putative sensory neurons (SCs) were excited by Ach (10^–6 M) and 5HT (10^–6 M) but were inhibited by GABA (10^–6 M). FMRFamide (10^–6 M) had a biphasic response. The Ach effect was blocked by hexamethonium (10^–6 M) and tetraethylammonium (10^–6 M), indicating the involvement of nicotinic cholinergic receptors.5. The distinct responses of the two populations of osphradial neurons to chemical stimuli and neurotransmitters suggest that they can differently perceive signals from environment and hemolymph.     

On the Nature of the Three-Phase Response of Scenedesmus quadricauda Populations to the Action of Imazalil Sulfate

Three-phase dose responses of biological systems of different levels of organization are often called paradoxical because the biological effects are clearly manifested under low- and high-intensity treatments, but are absent during moderate-strength treatments. In this work, we found anomalous changes in the cell number of a green alga Scenedesmus quadricauda (Turp.) Breb. grown in the presence of the fungicide imazalil sulfate. At low imazalil concentrations (2.5 × 10^–9–2.5 × 10^–6 M), the slow increase in the cell number as compared to an untreated culture was not related to cell death. As seen by the dynamics of the population structure and cell functional characteristics (photosynthesis, thermal stability of photosynthetic membranes, etc.), the decrease in the growth rate at low concentrations of imazalil (2–10 × 10^–9 M) was due to a long-term arrest of cell division in a fraction of the cell population rather than to a decrease in the rate of division. The absence of a toxic effect or even a slight stimulation of culture growth at moderate concentrations (0.05–1.25 × 10^–6 M) was due to the resumption of cell division after a temporal cessation. At these concentrations, imazalil induced cell stress and adaptive elevation of cell tolerance to the fungicide (acclimation). Cell death was observed only at a high fungicide content in the medium (6.25 × 10^–6 and higher). Thus, the three-phase (bimodal) dose response corresponds to two regimes (steady-states) of cell functioning which differ in cell sensitivity to external stimuli. The low-sensitivity state, which is characteristic of cells that have experienced stress, is likely to be the state known as hormesis.     

Frequency characteristics of skate electroreceptive central neurons responding to electrical and magnetic stimulation

Responses of single neurons in the lateral lobes of the medulla to stimulation of the electroreceptive system by homogeneous sinusoidal electrical and magnetic fields were investigated in acute experiments on the skateRaja radiata. Thresholds of neuronal responses to electrical stimulation varied from 0.03 to 10 µV/cm. The optimal frequency ranges for electrical and magnetic reception were in the regions of 0.05–5 and 2–3 Hz respectively. The possible mechanisms and functional significance of frequency characteristics of central neurons are discussed.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 16, No. 4, pp. 464–470, July–August, 1984.     

Reception of millimeter-band electromagnetic radiation by the ampullae of Lorenzini of skates

During recording of impulse activity from single nerve fibers of electroreceptors of the ampullae of Lorenzini of skates, we studied the responses to electromagnetic radiation (EMR) at a frequency of 37–55 GHz and an intensity of 1–100 mW/cm².Exposure of the ampullar canal pore to EMR at an intensity of 1–5 mW/cm² and a distance of 1–10 mm evoked a transient increase in the frequency of low-threshold receptor activity (current threshold was 0.04–0.2 µA). An increase in EMR intensity by more than 8–10 mW/cm² produced, together with elevation of receptor activity, an inhibition due to a rise in temperature of 1–3°C in the region exposed. The phase of increase in frequency of activity was absent in high current-threshold receptors (0.3–2.0 µA) when exposed to EMR. The receptors responded to irradiation of the ampullar canal pore at a distance of 15–20 mm by an increase in discharge frequency for 20 min. Direct irradiation of the ampullae of Lorenzini induced only inhibitory responses in receptor cells regardless of their excitability.The results obtained indicate that the sensory receptors of vertebrates are sensitive to EMR. It is concluded that the excitatory effects are due to direct reception of EMR by electroreceptors, and the inhibitory effects are related to local heating of the Lorenzini ampullar pore.Neirofiziologiya/Neurophysiology, Vol. 25, No. 5, pp. 325–329, September–October, 1993.     

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study

IntroductionVagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.MethodsWe performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5–C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0–10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg⁻¹Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation.ResultsNo serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS.ConclusionstVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01944228","term_id":"NCT01944228"}}NCT01944228. Registered 12 September 2013.