Preganglionic Nerve Stimulation Research Articles

Ketamine inhibits synaptic transmission and nicotinic acetylcholine receptor-mediated responses in rat intracardiac ganglia in situ

The intravenous anaesthetic ketamine, has been demonstrated to inhibit nicotinic acetylcholine receptor (nAChR)-mediated currents in dissociated rat intracardiac ganglion (ICG) neurons (Weber et al., 2005). This effect would be predicted to depress synaptic transmission in the ICG and would account for the inhibitory action of ketamine on vagal transmission to the heart (Inoue and König, 1988). This investigation was designed to examine the activity of ketamine on (i) postsynaptic responses to vagal nerve stimulation, (ii) the membrane potential, and (iii) membrane current responses evoked by exogenous application of ACh and nicotine in ICG neurons in situ. Intracellular recordings were made using sharp intracellular microelectrodes in a whole mount ICG preparation. Preganglionic nerve stimulation and recordings in current- and voltage-clamp modes were used to assess the action of ketamine on ganglionic transmission and nAChR-mediated responses. Ketamine attenuated the postsynaptic responses evoked by nerve stimulation. This reduction was significant at clinically relevant concentrations at high frequencies. The excitatory membrane potential and current responses to focal application of ACh and nicotine were inhibited in a concentration-dependent manner by ketamine. In contrast, ketamine had no effect on either the directly-evoked action potential or excitatory responses evoked by focal application of γ-aminobutyric acid (GABA). Taken together, ketamine inhibits synaptic transmission and nicotine- and ACh-evoked currents in adult rat ICG. Ketamine inhibition of synaptic transmission and nAChR-mediated responses in the ICG contributes significantly to its attenuation of the bradycardia observed in response to vagal stimulation in the mammalian heart.

Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses.

Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.

Effect of percutaneous pulsedmagnetic stimulation of the sacral nerve for the treatment of paraplegic patients with constipation

Objective To observe the effect of percutaneous pulsedmagnetic stimulation of the preganglionic parasympathetic nervous system of spinal at T 12-L1 vertebral level （2-4 sacral spinal cord）, in order to promote gastrointestinal peristalsis paraplegics and relieve symptoms of constipation .Methods Totals of 52 patients were divided into two groups by their admission date .The control group were applied the routine nursing care, including the psychology nursing care , drug intervention, diet, water balance, lower abdominal massage therapy, enema, pelvic floor muscle training and hyperbaric oxygen therapy .Based on the routine care, the intervention group was given the early percutaneous spinal cord pulsed magnetic stimulation of the preganglionic parasympathetic nerves of the spine at T 12 -L1 vertebral level （ 2 -4 sacral spinal cord ） . Results In the intervention group , 1 patient had cervical fracture and dislocation;2 patients had tumor invasion of the primary caudaequina of spinal cord.88.46%（23/26） patients had regular bowel movements.In the control group, only 61.54% （16/26） patients had regular bowel movements.The difference was statistically significant （χ2 =5.026,P〈0.05）.The effective rate of the intervention group was 76.9%（20/26）, which was significantly higher than 50.0% （13/26） in the control group （χ2 =4.046,P〈0.05）.Conclusions Percutaneous pulsed magnetic stimulation of the parasympathetic preganglionic nerve can improve the recovery of neurological function and provide a simple , noninvasive and painless method to reduce the constipation and improve patients ’ quality of life. Key words: Constipation; Paraplegia; Percutaneous pulsed magnetic stimulation

GABA inhibits excitatory neurotransmission in rat pelvic ganglia.

Intravenous GABA inhibited, in a bicuculline-sensitive manner, contractions of the urinary bladder induced by preganglionic nerve stimulation in urethane anaesthetized rats, while it had no significant effect on contractions produced by postganglionic nerve stimulation. In addition, intravenous GABA strongly inhibited DMPP-induced bladder contractions; this effect was also prevented by bicuculline. These experiments suggest that GABA inhibits excitatory neurotransmission in rat pelvic ganglia through a mechanism involving, at least in part, the activation of postsynaptic GABA A receptors.

The effect of acute adrenalectomy on the blood pressure responses to noradrenaline and to preganglionic nerve stimulation.

Abstract The quantitative contribution of the adrenal medulla to the pressor response resulting from stimulation of the entire preganglionic sympathetic spinal outflow of the rat, has been estimated. Adrenalectomy reduced the pressor responses not only to preganglionic nerve stimulation but also to injected noradrenaline. This reduction in cardiovascular sensitivity occurred within about 10 min of adrenalectomy and continued throughout the course of each experiment. Intramuscular injection of cortisone (20 mg/kg) restored cardiovascular sensitivity to injected noradrenaline thus allowing analysis of the adrenal medullary component of the overall response to spinal nerve stimulation.

Effect of a sea snake (Enhydrina schistosa) venom on the ganglionic nicotinic actions of acetylcholine.

Abstract The effects of venom from a common sea snake, Enhydrina schistosa, on the actions of acetylcholine in the superior cervical ganglion, the adrenal medulla and in the atropinized cat were investigated. The crude venom reduced nictitating membrane responses to preganglionic nerve stimulation and intra-arterial injection of acetylcholine, without lowering the responses to postganglionic nerve stimulation or intra-arterial adrenaline. In the eviscerated cat, the venom also antagonized rises in heart rate and blood pressure induced by in-injections into the coeliac artery of acetylcholine but not those of histamine. Pressor effects due to splanchnic nerve stimulation and carotid artery occlusion were blocked. In the atropinized cat, the venom depressed heart rate and pressor responses to intravenous acetylcholine, but not the responses to adrenaline. It was concluded that the venom antagonized the actions of acetylcholine at autonomic ganglia and the adrenal medulla.

Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes

Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission in ganglia of the autonomic nervous system. Here, we determined the subunit composition of hetero-pentameric nAChRs in the mouse superior cervical ganglion (SCG), the function of distinct receptors (obtained by deletions of nAChR subunit genes) and mechanisms at the level of nAChRs that might compensate for the loss of subunits. As shown by immunoprecipitation and Western blots, wild-type (WT) mice expressed: alpha 3 beta 4 (55%), alpha 3 beta 4 alpha 5 (24%) and alpha 3 beta 4 beta 2 (21%) nAChRs. nAChRs in beta 4 knockout (KO) mice were reduced to < 15% of controls and no longer contained the alpha 5 subunit. Compound action potentials, recorded from the postganglionic (internal carotid) nerve and induced by preganglionic nerve stimulation, did not differ between alpha 5 beta 4 KO and WT mice, suggesting that the reduced number of receptors in the KO mice did not impair transganglionic transmission. Deletions of alpha 5 or beta2 did not affect the overall number of receptors and we found no evidence that the two subunits substitute for each other. In addition, dual KOs allowed us to study the functional properties of distinct alpha 3 beta4 and alpha 3 beta 2 receptors that have previously only been investigated in heterologous expression systems. The two receptors strikingly differed in the decay of macroscopic currents, the efficacy of cytisine, and their responses to the alpha-conotoxins AuIB and MII. Our data, based on biochemical and functional experiments and several mouse KO models, clarify and significantly extend previous observations on the function of nAChRs in heterologous systems and the SCG.

Synaptic and membrane properties of parasympathetic ganglionic neurons innervating mouse trachea and bronchi

The pathophysiology of airway diseases, such as asthma, is increasingly studied using transgenic mice and other mouse models of airway inflammation where allergen-induced changes in airway smooth muscle tone and mucous secretion is due, in part, to activation of preganglionic airway parasympathetic nerves. Ganglionic parasympathetic neurons located in the airways in several species, including humans, have anatomical and electrophysiological properties that limit transmission of preganglionic synaptic input. In this study, intracellular recordings were made from neurons in parasympathetic ganglia located on the trachea and bronchi of adult mice to determine electrophysiological properties associated with regulation of transmission of preganglionic input. Ganglionic neurons were characterized as having either tonic or phasic action potential accommodation patterns. Tonic neurons responded with repetitive action potentials sustained throughout a depolarizing current step, whereas phasic neurons generated one or a burst of action potential(s) and accommodated. A small subset displayed both patterns. Phasic neurons could be further differentiated as usually having either short- or long-duration afterhyperpolarizing potential following single and multiple action potentials. In most cells, stimulation of preganglionic nerves elicited one population of nicotinic fast excitatory postsynaptic potentials that were graded in amplitude, usually suprathreshold for action potential generation, and did not decrease in amplitude during higher frequency stimulation. Dye injection into the neurons revealed that dendrites were either absent or very short. These results provide evidence that in contrast to the characteristics of airway parasympathetic neurons reported in other species, including human, the electrophysiological and synaptic properties, and anatomical characteristics of mouse lower airway ganglionic neurons, are less associated with integration of presynaptic input.

Enhanced contractility of vascular smooth muscle after brief exposure to arsenate

Epidemiological studies indicate that arsenic exposure induces hypertension. We hypothesized that arsenate exposure modulates the contractility of vascular smooth muscle through the stress response. Intraperitoneal injection of sodium arsenate (15 mg/kg) 16 h before increased not only the blood pressure of rats but also the pressor response to preganglionic nerve stimulation (2 and 16 Hz) or to bolus injection of vasopressin or phenylephrine in pithed rats as compared with the control rats. Exposure of rat aortic rings to 4 mM sodium arsenate for 60 min enhanced the contractile responses to KCl or phenylephrine as well as the HSP 70 expression 8 h later, but did not affect the relaxation responses to acetylcholine, histamine, or sodium nitroprusside. These results suggest that brief exposure to arsenate is associated with enhanced contractility of vascular smooth muscle through the stress response.

횐쥐 대동맥의 수축반응과 열충격단백질에 대한 비소의 영향

In order to examine if arsenic, one of environmental stresses, contributes to hypertension as one of cardiovas cular pathological factors, this study was perfarmed in vivo and in vitro, using intacted or pithed rats and aorta ring preparation, respectively. And also the relationship between expression of heat shock protein (HSP) 90 and vasoactives-induced contractile response was elucidated. To measure blood pressure, the carotid arterial pressure was recorded on physiograph(Grass Co. 79E) connected to strain gauge. On the other hand, contractile response of vascular ring preparation isolated from rat was determined in organ bath and was recorded on physiograph connected to isometric transducer. And HSP was detacted by Western blotting whole cell Iysis. Preganglionic nerve stimulation was increased by 26.0% in arterial pressure of rat treated with arsenic. Vascular contractile response was monitored and HSP were measured by Western blotting of whole Iysis prepared from samples exposed with 0, 0.5, 1, 2 and 4 mM of arsenic for 8 hours. The dose-vascular responses of potassium chloride were augmented by increasing dose of arsenic in the strips exposed to arsenic for 8 hours, and were not augmented for 1, 3, 5 hours. And the response of relaxation of rat aorta induced by histamine was not influenced by arsenic stress. The increase of HSP 90 expression in rat aorta was pronounced at 8 hours after 4 mM of arsenic treatment, but HSP 60 expression was not. Arsenic stress not only increased the expression of HSP 90 in the rat aorta, but also augmented contractions to potassium chloride. These results indicated that arsenic stress was sufficient to induce heat shock protein 90, resulting in increased vascular contractility in rat aorta.

2,2′‐Nitrophenylisatogen potentiates P2X1 receptor mediated vascular contraction and blood pressure elevation

AbstractThe objective of this research was to examine the effects of chemical compounds with possible P2 receptor modulating effects and to characterize the potentiating effects of 2,2′‐nitrophenylisatogen (NPI) on P2X1 receptors in vitro and in vivo. Chemical compounds were tested in an in vitro pharmacological assay using vascular segments from the rat mesenteric artery stimulated by P2 receptor‐specific agonists. Contractions were expressed as a percentage of 60 mM K+‐induced contractions. Blood pressure was evaluated in pithed rats. NPI (30 μM) added 15 min before addition of the P2X1 receptor‐specific agonist αβ‐MeATP increased the maximum vasoconstriction from 23% to 49% (an increase of 113%). Furthermore, NPI prevented the desensitization of repeated αβ‐MeATP contractions. Related compounds were examined, and 2‐(3‐methoxy‐phenyl)‐1‐oxy‐indol‐3‐one (MPI) had similar effects as NPI, but several others lacked effect. NPI had no effect on ADPβS (P2Y1) or acetylcholine‐mediated vasodilatation, nor on UTP (P2Y2/4), UDP (P2Y6), or noradrenaline‐mediated contractions. In pithed rats, the blood pressure response to 50 nmol/kg‐infusion of αβ‐MeATP was increased from 50±6 to 63±5 mmHg (P&lt;0.05), but had no effect on basal blood pressure or on the cardiovascular response to preganglionic nerve stimulation. In conclusion, NPI and MPI potentiates P2X1 receptor vascular contractions in vitro and (NPI) blood pressure effects in vivo. It is possible that the effect is mediated by an inhibition of P2X1 receptor desensitization. Drug Dev. Res. 59:82–87, 2003. © 2003 Wiley‐Liss, Inc.

The integrative membrane properties of human bronchial parasympathetic Ganglia neurons.

Parasympathetic ganglia neurons in the lower airway of laboratory animals have membrane properties associated with integration of signals from the central nervous system. In this study, intracellular recordings were made from parasympathetic ganglia located on bronchi from human lungs in order to determine the level of integration provided by human neurons. Ganglion neurons were characterized as either tonic or phasic: tonic neurons responded with repetitive action potentials sustained throughout a depolarizing current step whereas phasic neurons generated one action potential and accommodated. Phasic neurons could be further differentiated as having either short or long duration after hyperpolarizing potentials following single action potentials. In phasic neurons, stimulation of preganglionic nerves elicited one or two populations of nicotinic fast excitatory postsynaptic potentials (fEPSPs) that were graded in amplitude, subthreshold for action potential generation, and decreased in amplitude during higher frequency stimulation. In tonic neurons, single preganglionic stimuli evoked two to five populations of fEPSPs, one to three of which were at threshold for action potential generation. Dye injection into the neurons revealed multiple, branching dendrites. These results provide evidence that human bronchial ganglion neurons have unique membrane properties and anatomical characteristics associated with integrating presynaptic stimuli. Changes in these properties may thus affect output from these ganglia and, consequently, autonomic tone in the lower airways.

Fos expression in rat celiac ganglion: an index of the activation of postganglionic sympathetic nerves.

To develop an index of the activation of abdominal sympathetic nerves, we used Fos immunostaining of the celiac ganglion (CG) taken from rats receiving nicotine, preganglionic nerve stimulation, or glucopenic agents. Subcutaneous nicotine injection moderately increased Fos expression in the principal ganglionic cells of the CG (17 +/- 4 Fos+ per mm(2), approximately 12% of all principal CG cells), whereas subcutaneous saline had no effect (0 +/- 0 Fos+ per mm(2); n = 7; P < 0.01). Greater Fos expression was obtained by applying nicotine topically to the CG (71 +/- 8 Fos+ per mm(2); 52% of all principal CG cells, n = 5; P < 0.01 vs. topical saline, n = 4) and by preganglionic nerve stimulation (126 +/- 9 Fos+ per mm(2); 94% of all principal CG cells, n = 11; P < 0.01 vs. nerve isolation, n = 7). Moderate Fos expression was also observed in the CG after intraperitoneal 2-deoxy-D-glucose (2DG) injection (21 +/- 2 Fos+ per mm(2); 16% of all principal CG cells, n = 5; P < 0.01 vs. saline ip) or insulin injection (16 +/- 2 Fos+ per mm(2); 12% of all principal CG cells, n = 6; P < 0.01 vs. saline ip). Furthermore, Fos expression induced by 2DG was dose and time dependent. These data demonstrate significant Fos expression in the CG in response to chemical, electrical, and reflexive stimulation. Thus Fos expression in the CG may be a useful index to describe various levels of activation of its postganglionic sympathetic neurons.

Amplitude modulation of pulsatile insulin secretion by intrapancreatic ganglion neurons.

Neuron activity and insulin release were measured simultaneously from 33 preparations of intrapancreatic canine ganglia and pancreatic parenchyma adjacent to the ganglia. The electrical activity of single neurons of the ganglia was recorded with intracellular microelectrodes, and insulin release from the attached islets was determined with an enzyme-linked immunosorbent assay. Insulin release was 62 +/- 18 fmol preparation/min in the presence of 10 mmol/l glucose and pulsatile (3.7 +/- 0.4 min/pulse). Corresponding measurements of neuronal electrical activity showed a stable membrane potential of -53.5 +/- 0.6 mV. Short, high-frequency (20 Hz) preganglionic nerve stimulation evoked action potentials and, in 46% of the preparations, a threefold rise in the insulin secretory rate associated with increased amplitude of the insulin pulses. The effects were blocked by 10 micromol/l tetrodotoxin (TTX). In other preparations, continuous low-frequency (0.05-0.5 Hz) preganglionic nerve stimulation evoked action potentials and, in 50% of the preparations, a gradual increase of insulin release associated with augmentation of insulin pulse amplitude without alteration of the duration. The effects were blocked by 50 micromol/l hexamethonium (HEX). In the remaining preparations, no change in insulin release was observed during nerve stimulation. In the absence of stimulation, neither TTX nor HEX affected the membrane potential or insulin secretion. These first simultaneous measurements of intrapancreatic ganglion activity and insulin secretion are consistent with amplitude modulation of pulsatile insulin secretion induced by changes in electrical activity in a population of intrapancreatic ganglion neurons.

Characterization of non‐adrenergic, non‐cholinergic inhibitory responses of the isolated guinea‐pig trachea: differences between pre‐ and post‐ganglionic nerve stimulation

1 Differences in the mechanism of non-adrenergic, non-cholinergic (NANC) inhibitory responses to preganglionic- and post-ganglionic nerve stimulation were investigated in the guinea-pig isolated trachea. 2 Stimulation of the vagus nerve at frequencies above 4 Hz elicited NANC relaxation of the trachealis muscle. Responses to low frequencies of stimulation (4-8 Hz) were abolished by the nitric oxide (NO) synthase inhibitor L-NOARG (10 microM), while a L-NOARG resistant component was observed at higher stimulus frequencies. The L-NOARG-resistant component of NANC inhibitory responses to higher frequencies of vagus nerve stimulation were significantly attenuated by the proteinase alpha-chymotrypsin (2 U/ml), suggesting that a neuropeptide such as VIP may contribute to NANC responses. 3 When postganglionic nerves were stimulated by electrical field stimulation (EFS), responses were readily elicited at frequencies below 4 Hz. Like responses to vagus nerve stimulation, responses to low frequency (<4 Hz) EFS were abolished by L-NOARG while a L-NOARG-resistant component was apparent at higher stimulus frequencies. 4 The L-NOARG-resistant component of NANC inhibitory responses to EFS was sensitive to alpha-chymotrypsin only if stimuli were delivered in either long trains at a low frequency (4 Hz for 10-30 s) or short trains of high frequency (16 Hz for 2.5-7.5 s). 5 Responses to preganglionic nerve stimulation were approximately 35% of the amplitude of responses to EFS in the same preparations. 6 In conclusion, responses to preganglionic and postganglionic NANC inhibitory nerve stimulation in the guinea-pig trachea differ in maximum amplitude, frequency-response characteristics and the contributions of cotransmitters. We suggest that these differences may be explained by filtering of preganglionic input to postganglionic NANC neurons. These results have implications in all studies where EFS is considered to be representative of physiological stimulation of post-ganglionic nerve stimulation.

Release-depletion and receptor-mediated neuronal internalization of endogenous neurotensin in the stellate ganglion of the cat

The release and depletion of neurotensin in sympathetic preganglionic axon terminals and internalization in principal ganglion cells were investigated in the cat stellate ganglion by means of combined immunohistochemical staining, image analysis and confocal microscopy. Neurotensin stored in preganglionic boutons was released by 40 or 5 Hz electrical stimulation of preganglionic nerves, being depleted to 7.4 and 19.2% of control levels by continuous stimulation lasting 20 or 160 min (both stimuli delivered 48,000 pulses). Once released, neurotensin was internalized by the principal ganglion cells as evidenced by a ring of bright spot-like granules in the perinuclear region indicating the sites of intracellular neurotensin accumulation. Neurotensin internalization was time-dependent, thus, different content was found when the time between the end of stimulation and start of perfusion was varied. The onset of neurotensin internalization appeared in the first minutes, intracellular accumulation was evident at 20 min, maximal internalization occurred at 120 min and, 24 h later internalized neurotensin content had faded. Internalization was partially blocked by the nonpeptide neurotensin antagonist SR48692. These data provide evidence of presynaptic neurotensin release and depletion by electrical stimulation with varied frequencies. They also provide evidence for in situ receptor-mediated internalization of endogenously released neurotensin, raising the possibility that internalization may represent, in addition to some kind of turnover dynamics, an important part of the mechanisms of neuropeptide signaling.

Optical imaging of the spatiotemporal patterning of neural responses in the embryonic chick superior cervical ganglion

Multiple-site optical recording of transmembrane potential changes with a voltage-sensitive dye was used to reveal the functional expression and developmental changes of the postsynaptic potentials in the early embryonic chick superior cervical ganglion. The ganglia were isolated from five- to 12-day-old chick embryos with preganglionic nerve fibres (vertebral and/or cervical carotic nerves) attached. The preparations were stained with a voltage-sensitive merocyanine-rhodanine dye (NK2761). Voltage-related optical (absorbance) changes were recorded simultaneously from 127 contiguous loci in the preparation, using a 12×12-element photodiode array. Optical changes having two components were evoked by preganglionic nerve stimulation. One component was the fast spike-like signal and another the delayed slow signal. The amplitude of the slow signal was decreased by repetitive stimulation, reduced by low external calcium ion concentrations and eliminated in the presence of manganese or cadmium ions. The slow signals were also eliminated in the presence of d-tubocurarine. Accordingly, we concluded that the slow signal corresponds to cholinergic excitatory postsynaptic potentials. In the five- and six-day-old superior cervical ganglia, only the fast optical signals (referred to as the action potentials) were recorded. Slow optical signals (referred to as the excitatory postsynaptic potentials) were detected from preparations older than seven days. The amplitude of the slow optical signal gradually increased, together with an expansion of the response area, as the developmental stage proceeded from seven to 10 days. To compare the distribution patterns of the neural responses evoked by stimuli applied to the cervical carotic and vertebral nerves, we have mapped and imaged the spatial patterning of the synaptic responses. In the maps, the positions of the peak size regions of the slow signals were assessed, and we found that there were differences in the location of these areas for the cervical carotic vs vertebral nerves. From these experimental results, we conclude that synaptic function within the chick superior cervical ganglion is initiated at the seven-day-old embryonic stage, and reaches a maximum level at 10 days. Synaptic transmission at these stages is mediated solely by nicotinic acetylcholine receptors. The spatial mapping of the synaptic responses reveals that the neural populations related synaptically to the cervical carotic and vertebral nerves are located separately within the ganglion, even at an early developmental stage.

Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor.

Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of dopamine beta-hydroxylase, which modulates catecholamine levels (reduces norepinephrine and elevates dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of nepicastat. Acute oral administration of nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In inactin-anesthetized SHRs, the antihypertensive effects of nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs, nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex tachycardia. Long-term, concurrent administration of nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of enalapril (1 mg/kg/day, p.o.) produced greater antihypertensive effects than those produced by nepicastat alone. In normal dogs, nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to tyramine. These findings suggest that nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as hypertension and congestive heart failure.

Inhibitory effects of arachidonic acid on nicotinic transmission in bullfrog sympathetic neurons.

Inhibitory effects of arachidonic acid on nicotinic transmission in bullfrog sympathetic neurons. J. Neurophysiol. 78: 2396-2401, 1997. Arachidonic acid (AA, 0.2-40 mu M) reversibly reduced the amplitude of the fast excitatory postsynaptic potentials and the underlying currents (fast EPSCs) of bullfrog sympathetic neurons evoked by preganglionic nerve stimulation in a Ca2+-deficient solution. AA reduced the acetylcholine (ACh)-induced nicotinic currents (nIACh) evoked by brief applications of ACh to the ganglion cells in a dose-related manner. AA reduced the maximum amplitude of nIACh estimated from the dose-response relationship without causing an appreciable change in the apparent dissociation constant. Indomethacin (2 mu M) and nordihydroguaiaretic acid (20 mu M), blockers of cyclooxygenase and lipoxygenase pathways, respectively, had no effect on the inhibition of fast EPSC by AA. AA did not obviously affect the preganglionic nerve terminal spike configuration, synaptic delay, facilitation, quantal content of transmitter release, or the presynaptic long-term potentiation elicited by the repetitive stimulation applied to the preganglionic nerve fibers. These results suggest that AA acts on an allosteric site of the nicotinic receptor-channel complex either directly or indirectly and in turn inhibits ion permeation through these channels without affecting the release of ACh from preganglionic nerve terminals.

Picrotoxin-sensitive receptors mediate γ-aminobutyric acid-induced modulation of synaptic plasticity in rat superior cervical ganglion

Activity-dependent changes of synaptic efficacy in the superior cervical ganglion (SCG) can be prevented by γ-aminobutyric acid (GABA). We have studied the effects of picrotoxin (PTX) on GABA-mediated inhibition of long-term potentiation (LTP) of synaptic transmission in the rat SCG. Compound action potentials were recorded extracellularly in the postganglionic internal carotid nerve in response to preganglionic nerve stimulation. PTX (100 μM) antagonized the inhibition by exogenous GABA (250 μM) of LTP induced by strong tetanic stimulation (20 Hz, 20 s, supramaximal stimulation, partial blockade of transmission by hexamethonium). Additionally, PTX alone (50 μM) facilitated the induction of LTP by a weak tetanus (20 Hz, 5 s, submaximal stimulation). These results further support previous data indicating that activation of GABA A-like receptors can prevent the occurrence of synaptic plasticity at this peripheral synapse. © 1997 Elsevier Science B.V. All rights reserved.