Effects Of Autonomic Nerve Stimulation Research Articles

Detection of Norepinephrine in Whole Blood via Fast Scan Cyclic Voltammetry.

Bioelectronic Medicines is an emerging field that capitalizes on minimally-invasive technology to stimulate the autonomic nervous system in order to evoke therapeutic biomolecular changes at the end-organ. The goal of Bioelectronic Medicines is to realize both 'precision and personalized' medicine. 'Precise' stimulation of neural circuitry creates biomolecular changes targeted exactly where needed to maximize therapeutic effects while minimizing off-target changes associated with side-effects. The therapy is then 'personalized' by utilizing implanted sensors to measure the biomolecular concentrations at, or near, the end-organ of interest and continually adjusting therapy to account for patient-specific biological changes throughout the day. To realize the promise of Bioelectronic Medicines, there is a need for minimally invasive, real-time measurement of biomarkers associated with the effects of autonomic nerve stimulation to be used for continuous titration of therapy. In this study we examine the feasibility of using fast scan cyclic voltammetry (FSCV) to measure norepinephrine levels, a neurochemical relevant to end-organ function, directly from blood. FSCV is a well-understood method for measuring electroactive neurochemicals in the central nervous system with high temporal and high spatial resolution that has yet to be adapted to the study of the autonomic nervous system. The results demonstrate that while detecting the electroactive neurochemical norepinephrine in blood is more challenging than obtaining the same FSCV measurements in a buffer solution due to biofouling of the electrode, it is feasible to utilize a minimally invasive FSCV electrode to obtain neurochemical measurements in blood.

Effects of autonomic nerve stimulation on colorectal motility in rats

Several disease processes of the colon and rectum, including constipation and incontinence, have been associated with abnormalities of the autonomic nervous system. However, the autonomic innervation to the colon and rectum are not fully understood. The aims of this study were to investigate the effect of stimulation of vagus nerves, pelvic nerves (PN) and hypogastric nerves (HGN) on colorectal motility in rats. Four strain gauge transducers were implanted on the proximal colon, mid colon, distal colon and rectum to record circular muscle contractions in rats. Electrical stimulation was administered to the efferent distal ends of the cervical vagus nerve, PN and HGN. Motility index (MI) was evaluated before and during stimulation. Electrical stimulation (5-20 Hz) of the cervical vagus elicited significant contractions in the mid colon and distal colon, whereas less pronounced contractions were observed in the proximal colon. Pelvic nerves stimulation elicited significant contractions in the rectum as well as the mid colon and distal colon. Atropine treatment almost completely abolished the contractions induced by vagus nerve and PN stimulation. Hypogastric nerves stimulation caused relaxations in the rectum, mid colon and distal colon. The relaxations in response to HGN stimulation were abolished by propranolol. Vagal innervation extends to the distal colon, while the PN has projections in the distribution of the rectum through the mid colon. This suggests a pattern of dual parasympathetic innervation in the left colon. Parasympathetic fibers regulate colorectal contractions via muscarinic receptors. The HGN mainly regulates colorectal relaxations via beta-adrenoceptors.

Vagus nerve stimulation inhibits the increase in Ca2+ transient and left ventricular force caused by sympathetic nerve stimulation but has no direct effects alone - epicardial Ca2+ fluorescence studies using fura-2 AM in the isolated innervated beating ra

The effects of direct autonomic nerve stimulation on the heart may be quite different to those of perfusion with pharmacological neuromodulating agents. This study was designed to investigate the effect of autonomic nerve stimulation on intracellular calcium fluorescence using fura-2 AM in the isolated Langendorff-perfused rabbit heart preparation with intact dual autonomic innervation. The effects of autonomic nerve stimulation on cardiac force and calcium transients were more obvious during intrinsic sinus rhythm. High-frequency (15 Hz, n = 5) right vagus nerve stimulation (VS) decreased heart rate from 142.7 +/- 2.6 to 75.5 +/- 10.2 beats min(-1) and left ventricular pressure from 36.4 +/- 3.2 to 25.9 +/- 1.9 mmHg, whilst simultaneously decreasing the diastolic and systolic level of the calcium transient. Direct sympathetic nerve stimulation (7 Hz, n = 8) increased heart rate (from 144.7 +/- 10.5 to 213.2 +/- 4.9 beats min(-1)) and left ventricular pressure (from 37.5 +/- 3.6 to 43.7 +/- 2.8 mmHg), whilst simultaneously increasing the diastolic and systolic level of the calcium transient. During constant ventricular pacing, the high-frequency right vagus nerve stimulation did not have any direct effect on ventricular force or the calcium transient (n = 8), but was effective in reducing the effect of direct sympathetic nerve stimulation.

Autonomic Nerve Stimulation Reverses Ventricular Repolarization Sequence in Rabbit Hearts

Sympathetic activity and spatial dispersion of repolarization (DOR) have been implicated as mechanisms that promote arrhythmia vulnerability; yet there are no direct measurements of the effects of autonomic nerve stimulation on DOR. Rabbit hearts were perfused in a Langendorff apparatus with full sympathetic and parasympathetic innervation and were optically mapped to measure action potential durations and DOR (apex-base) over the left ventricles. DOR was measured under sinus rhythm, during bilateral sympathetic nerve stimulation (SNS) and right and/or left vagus nerve stimulation and was compared with DOR during isoproterenol (100 nmol/L) or acetylcholine (1 micromol/L) infusion. In sinus rhythm, repolarization started at the apex and systematically progressed toward the base. SNS (10 to 15 Hz) increased DOR by 29% (from Deltaaction potential duration=17+/-0.7 to -22+/-1.6 ms, n=6) and reversed DOR as the direction of repolarization from apex-->base in sinus rhythm shifted to base-->apex in 5 to 15 seconds after SNS. DOR flipped back to its sinus rhythm DOR pattern 115+/-15 seconds after the interruption of SNS. During right or left vagus nerve stimulation, there was no change in the direction of DOR, but bilateral vagus nerve stimulation increased and reversed DOR to base-->apex direction. Infusion of isoproterenol or acetylcholine increased DOR but did not alter the direction of repolarization sequences. These findings demonstrate that bilateral autonomic activity (SNS or vagus nerve stimulation) cause reversible shifts of apex-base DOR and that the spatial heterogeneities of autonomic effects on the ventricles are most likely attributable to a greater innervation at the base than the apex of the heart.

Magnetism and cardiac arrhythmias.

Low-level electromagnetic fields (EMFs) have been used to treat various neurologic disorders. In the present study, we applied micro Gauss (microG) levels of EMFs either to the vagosympathetic nerve trunks, dissected in the neck, or across the chest in anesthetized dogs. Based on theoretical and empiric grounds, we compared EMFs (2.87 microG at 0.043 Hz) delivered to the vagosympathetic trunks in an experimental set (n = 5) with a sham control group (n = 6). Over a period of 2 to 3 hours, heart rate decreased after an initial 5-minute EMF exposure. The maximal heart rate changes in the experimental versus control groups was 29% versus 12% (P = 0.03). The voltage applied to the autonomic nerves required to induce atrioventricular (AV) conduction block decreased by 60% in the experimental group versus a 5% increase in the control group (P = 0.005). This effect also lasted 2 to 3 hours. Another EMF setting (amplitude 0.34 microG, frequency 2 kHz) applied for 5 minutes to the vagosympathetic trunks was associated with a significant increase in the occurrence of atrial premature depolarizations (APDs), atrial tachycardia (AT), and atrial fibrillation (AF) in response to autonomic nerve stimulation compared with control states before EMF exposure. No atrial arrhythmias could be induced after propranolol and atropine, even at the highest voltage used to stimulate the autonomic nervous input to the heart (n = 11). Only 2 dogs showed no response to this EMF application. In 3 dogs in whom atrial pacing (cycle length = 250 ms) and autonomic nerve stimulation induced AF, an EMF (2.87 microG at 0.043 Hz) delivered for 35 minutes across the chest suppressed AF for up to 3 to 4 hours, after which the same protocol again induced AF. We conclude that in these preliminary experiments, specific low-level EMFs alter heart rate, AV conduction, and heart rhythm. These effects were mediated through the autonomic nervous system inputs to the heart based on adjunctive effect of autonomic nerve stimulation and the inhibitory action of autonomic blockers.

Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart--a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation.

A novel isolated Langendorff perfused rabbit heart preparation with intact dual autonomic innervation is described. This preparation allows the study of the effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart. These hearts (n = 10) had baseline heart rates of 146 +/- 2 beats x min(-1) which could be increased to 240 +/- 11 beats x min(-1) by sympathetic stimulation (15 Hz) and decreased to 74 +/- 11 beats x min(-1) by stimulation of the vagus nerve (right vagus, 7 Hz). This model has the advantage of isolated preparations, with the absence of influence from circulating hormones and haemodynamic reflexes, and also that of in vivo preparations where direct nerve stimulation is possible without the need to use pharmacological agents. Data are presented characterising the preparation with respect to the effects of autonomic nerve stimulation on intrinsic heart rate and atrioventricular conduction at different stimulation frequencies. We show that stimulation of the right and left vagus nerve have differential effects on heart rate and atrioventricular conduction.

O-155 - Effects of autonomic nerve stimulation on the sites of earliest activation and rate of the sinoatrial pacemaker complex of the dog heart

O-155 - Effects of autonomic nerve stimulation on the sites of earliest activation and rate of the sinoatrial pacemaker complex of the dog heart

Synergistic nonuniform shortening of atrial refractory period induced by autonomic stimulation

We investigated the nonuniform effects of autonomic nerve stimulation of the effective refractory period (ERP) of the right atrium in the anesthetized dog. Stimulation of the discrete intracardiac sympathetic nerves to the sinoatrial (SA) nodal region uniformly shortened ERPs at three sites in the right atrium after administration of atropine. Right ansa subclavia (RS) stimulation similarly shortened ERPs in the absence of atropine. Stimulation of the discrete intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) shortened ERPs of the right atrium in a nonuniform manner. Simultaneous RS and SAP stimulation additively shortened ERPs at each site and decreased sinus rate much more than SAP stimulation alone. Shortening of ERP induced by SAP stimulation was greater than that induced by RS stimulation at similar absolute changes in heart rate. These results suggest that simultaneous activation of sympathetic and parasympathetic nerves nonuniformly shortens the ERP in the right atrium as the algebraic sum of the individual responses to each stimulation. However, parasympathetics exert the principal neural control over atrial ERP.

Effects of autonomic nerve stimulation, asynchrony, and load on dP/dtmax and on dP/dtmin

We studied asynchronous depolarization effects on mechanical responses to autonomic nerve stimulation (ANS) in 21 dogs with AV nodal block. In 11 of these dogs, we kept mean aortic pressure (AoP) at 85 mmHg and paced the hearts at 120 beats/min. We paced, in random order, either the LV apex or the RV anterior or lateral wall to increase the asynchrony of ventricular contraction and relaxation. During pacing at each site, we determined maximum rate of LVP rise (dP/dtmax) and fall (dP/dtmin) before and during stimulation of cardiac sympathetic and vagal nerves and during combined nerve stimulation. Changing the pacing site from LV to RV decreased dP/dtmax and also dP/dtmin (P less than 0.001); the decrease was most pronounced when we shifted pacing from LV apex to RV anterior wall. Sympathetic stimulation increased (P less than 0.0001) and vagal stimulation decreased (P less than 0.001) dP/dtmax and dP/dtmin during pacing at each site. Effect of vagal stimulation was substantially enhanced during concomitant sympathetic stimulation. However, the magnitude of changes in dP/dtmax and also in dP/dtmin due to nerve stimulations during pacing at each ventricular site was similar. In 10 additional dog experiments, we also varied AoP from a mean value of 74 to 113 mmHg during pacing at each site. An increase in AoP augmented dP/dtmax by a mean value of 582 mmHg/s and increased dP/dtmin by a mean value of 617 mmHg/s (both P less than 0.0001). Sympathetic stimulation increased, whereas vagal stimulation decreased, dP/dtmax and dP/dtmin at each afterload (P less than 0.001).

Effect of autonomic nerve stimulation on bleb formation in striated duct cells of the rat submandibular gland.

Several previous investigations have shown that blebs form on the apical surface of the striated duct cells of the rat submandibular gland on feeding after starvation. In the present report the influence of autonomic nerve stimulation on bleb formation was studied by electron microscopy. Both parasympathetic and sympathetic stimulation were performed, using electric nerve stimulation. In addition, sympathetic nerve stimulation in combination with alpha- or beta-adrenergic blockers was used. Massive bleb formation took place in response to sympathetic nerve stimulation. This response was almost completely abolished by the administration of alpha- but not by beta-adrenergic blocker. Bleb formation was not seen after parasympathetic nerve stimulation.

Gastric blood flow responses to autonomic nerve stimulation and related pharmacological studies in rats.

The effects of autonomic nerve stimulation on rat gastric blood flow (GBF) were studied using a cross thermocouple method. Stimulation of the periarterial nerve bundles along the left gastric artery produced a decrease in GBF which was antagonized by phenoxybenzamine (0.05 mg kg-1 i.v.), but not by propranolol (1 mg kg-1 i.v.). Stimulation of the vagus nerves elicited an increase in GBF, within a latency of 20 s, which was not apparently affected by atropine (0.15 and 1.5 mg kg-1 i.v.) but was completely blocked by hexamethonium (10 mg kg-1 i.v.). The GBF increase due to acetylcholine (0.25 micrograms rat-1 i.a.), was markedly blocked by atropine (0.15 mg kg-1 i.v.). Vagal stimulation also produced both the cholinergic excitation and non-cholinergic inhibition of gastric motility. The vagally induced GBF increase was little affected by any pretreatment with phentolamine, propranolol, indomethacin or aprotinin. These results suggest that sympathetic nerve stimulation creases GBF through alpha-adrenoceptors and parasympathetic nerve stimulation increases GBF through a non-cholinergic mechanism in rats and that the GBF increase may result from a primary dilator effect of vagal stimulation on the blood vessels because of the immediate initiation of the response.

Regulation of glucogen metabolism in liver by the autonomic nervous system VI. Possible mechanism of phosphorylase activation by the splanchnic nerve

The effects of autonomic-nerve stimulation on the activities of phosphorylase (EC 2.4.1.1), dephospho-phosphorylase kinase (EC 2.7.1.38) and phosphorylase phosphatase (EC 3.1.3.17), and on the concentration of adenosine 3′,5′-monophosphate in rabbit liver were investigated. Results were compared with the effects of epinephrine and glucagon on these enzymes. 1. 1. The activity of liver phosphorylase increased rapidly and markedly on electrical stimulation of the splanchnic nerve, or after intraportal administration of epinephrine or glucagon. the activity was not affected by vagal stimulation. 2. 2. The activity of dephospho-phosphorylase kinase increased about 2–3-fold 1 min after injections of epinephrine and glucagon, glucagon causing more activation than epinephrine. The enzyme activity was not altered by splanchnic-nerve, or vagal stimulation. 3. 3. Injections of epinephrine and glucagon caused marked elevation of liver adenosine 3′,5′-monophosphate within a few minutes. With epinephrine, the nucleotide concentration rose to a maximum after 1 min and amounted to about 3-fold increase, while with glucagon the maximum increase of approximately 8-fold increase was observed after 2 min. Stimulation of the splanchnic nerve for 10 min did not affect the adenosine 3′,5′-monophosphate level in the liver. Vagal stimulation also had no effect on the level. 4. 4. The activity of phosphorylase phosphatase decreased promptly (within 30 s) and markedly on splanchnic-nerve stimulation, but did not change significantly on administration of epinephrine or glucagon. A small but insignificant increase in phosphatase activity was observed upon vagal stimulation. 5. 5. The effect of Ca 2+ on purified dephospho-phosphorylase kinase was studied. The activity was found to depend partially on free Ca 2+ at low Ca 2+ concentrations (1 · 10 −7−1 · 10 −5 M). 6. 6. These results suggest that the rise in hepatic phosphorylase content upon splanchnic-nerve stimulation, unlike that induced by epinephrine and glucagon, is not mediated by adenosine 3′,5′-monophosphate and subsequent activation of dephospho-phosphorylase kinase, but rather by inactivation of phosphorylase phosphatase. The possible existence of a new factor in this mechanism is discussed.

Membrane potential and input resistance in acinar cells from cat and rabbit submaxillary glands in vivo: effects of autonomic nerve stimulation

1. Membrane potential and input resistance measurements were made from acinar cells of cat and rabbit submaxillary glands in vivo, using intracellular glass micro-electrodes.2. The mean resting cell membrane potential was higher than previously reported, but ranged widely from -15 to -80 mV.3. Single shock electrical stimulation of the parasympathetic nerve fibres evoked characteristic potential changes. In some cases monophasic hyperpolarizations, in others biphasic responses (depolarization - hyperpolarization) were observed.4. The latency of the hyperpolarizing response was considerably longer (300-550 msec) than the latency of the biphasic response (about 150 msec).5. Hyperpolarizing and biphasic responses could be observed in the same cell at different levels of membrane potential. The initial depolarization of the biphasic response was dependent on the magnitude of the resting potential in such a manner that it was very small or absent at the lowest potentials and increased gradually with increasing level of the resting potential.6. Single-shock stimulation of the sympathetic nerve fibres to the gland did not evoke any response. In the cat, repetitive stimulation evoked hyperpolarizing or biphasic responses similar to those seen after repetitive stimulation of the parasympathetic nerve fibres. In the rabbit small hyperpolarizations were seen in a few cells only; mostly there was no response. Repetitive stimulation of the parasympathetic nerve fibres to the rabbit submaxillary gland evoked complex potential changes mostly of the depolarization-hyperpolarization type.7. Both single shock and repetitive stimulation of the parasympathetic nerve fibres evoked marked reductions in cell input resistance. In the hyperpolarizing cell type the conductance change sometimes preceded the potential change whereas they always occurred simultaneously in the biphasic cell type.8. It is concluded that both the hyperpolarizing and the biphasic secretory potentials are derived from the same type of acinar cells. The neurotransmitter released by the parasympathetic nerve endings (ACh) acts on the acinar cell membrane by increasing the ion permeability.

Influence of brief vagal and stellate nerve stimulation on pacemaker activity and conduction within the atrioventricular conduction system of the dog.

Experiments were performed on open-chest anesthetized dogs to determine the quantitative effects of autonomic nerve stimulation on pacemaker activity and conduction. The lead II electrocardiogram together with bipolar electrograms were recorded from the atria, the His bundles, and the ventricles. The vagi or the stellate ganglia were stimulated in dogs which exhibited either sinus rhythm, ectopic atrial rhythm, junctional rhythm, or ectopic ventricular rhythm. The time courses of the change in heart rate in response to vagal or stellate stimulation were characteristic for each type of rhythm. The characteristic responses of different cardiac pacemaker sites to autonomic influence were demonstrated to be important factors in the production of wandering pacemakers and in the emergence of ectopic beats. Sinus pacemaker activity was more sensitive to modification by autonomic stimulation than was atrioventricular (AV) conduction. However, subliminal autonomic effects on AV transmission were brought out during conduction of premature atrial beats, thereby demonstrating a coupling interval dependency of autonomic influences on AV conduction. The present experiments also showed how fluctuations in autonomic activity could result in Mobitz type II second-degree heart block, pseudosupernormal conduction, and the concertina effect observed in the preexcitation syndrome.