Doxepin and imipramine: Effect on catecholamine inhibition of ganglionic transmission

Doxepin (DOX) and imipramine (IM) administered by close intra-arterial injection (25, 40 and 60 μg/kg) potentiated the inhibitory effect of norepinephrine (NE) on electrically-evoked postganglionic potentials in the superior cervical ganglion of the cat. Dose-response relationships indicated no significant difference between DOX and IM with regard to their effect on NE activity. Potentiation of dopamine (DA)-induced suppression of ganglionic transmission by DOX and IM (25, 40 and 60 μg/kg) was not as pronounced as the potentiation of NE activity by these two antidepressants. Significant potentiation of DA was evident only at the 40 and 60 μg/kg dose levels of DOX and IM. Dose-response relationships indicated that potentiation of DA by DOX was significantly greater than that produced by IM.     

The effect of dibutyryl cyclic AMP,dopamine and aminophylline on ganglionic surface potential and transmission

A study has been made of the effect of dibutyryl cyclic AMP, dopamine and aminophylline on the surface potential and transmission in the superior cervical ganglion of the cat. Both dibutyryl cyclic AMP(3.5 mg and 7.0 mg i.a.) and dopamine (2 μg i.a.) induced ganglionic hyperpolarization associated with a partial inhibition of transmission. The ganglionic response to aminophylline (4 mg i.a.) was triphasic, comprising an initial depolarization succeeded by a hyperpolarization and late depolarization. After the administration of smaller doses of aminophylline (1 mg and 2 mg i.a.), in part of the experiments, only ganglionic depolarization was observed. These studies provide indirect evidence for the mediation of dopamine hyperpolarization by cyclic AMP in sympathetic ganglia. The ganglion-depolarizing effect of aminophylline is discussed.     

Steady state and regenerating levels of acetylcholinesterase in the superior cervical ganglion of the rat following selective inactivation of propionylcholinesterase

Abstract— The effects of selective inactivation of propionylcholinesterase (PrChE) by tetramonoisopropylpyrophosphortetramide (iso-OMPA) on the steady state and regenerating levels of acetylcholinesterase (AChE) were investigated on the superior cervical ganglion (SCG) of the rat. Over the dosage range of 1.5-40.0 μmol iso-OMPA/kg intraperitoneally, which produced nearly total inactivation of ganglionic PrChE and 0-35% inactivation of AChE, there was no subsequent increase in AChE activity above the control level. Single or repeated injections of iso-OMPA at total doses of 5.0-40.0 μmol/kg intraperitoneally caused no reduction in the rate of regeneration of ganglionic AChE during the 24 h following its inactivation by sarin, 2.0 μmol/kg intravenously. Both sets of findings differ from those obtained previously in a similar study of ganglionic AChE and butyrylcholinesterase (BuChE) in the cat. Possible reasons for this distinct species difference are discussed.     

An AF-DX 116 sensitive inhibitory mechanism modulates nicotinic and muscarinic transmission in cat superior cervical ganglion in the presence of anticholinesterase.

The effect of the muscarinic receptor antagonist AF-DX 116 on the inhibitory action of muscarinic agonists and on responses mediated by nicotinic or muscarinic ganglionic transmission was studied in the superior cervical ganglion of the anesthetized cat. The postganglionic compound action potential evoked by cervical sympathetic trunk stimulation was depressed by methacholine or acetylcholine (ACh) injected into the ganglionic arterial supply. The depression was blocked by AF-DX 116. The compound action potentials evoked by preganglionic stimulus trains were also depressed when the intratrain frequency was 2 Hz or greater. This intratrain depression was, however, insensitive to AF-DX 116. The anticholinesterase drug physostigmine markedly enhanced the intratrain depression of the compound action potential. This effect was reversed by AF-DX 116. During nicotinic receptor block with hexamethonium, preganglionic stimulus trains with intratrain frequencies of 5 Hz or greater produced nicitating membrane contractions that could be blocked by the M1 muscarinic receptor antagonist pirenzepine. The amplitude of the contractions increased with frequency and reached a maximum at 20-40 Hz. AF-DX 116 had no effect on these responses. After administration of physostigmine, the amplitude of the nictitating membrane responses decreased with increasing intratrain frequency. AF-DX 116 reversed this effect. The data suggest that, in the superior cervical ganglion, AF-DX 116 sensitive muscarinic receptors which depress synaptic transmission are activated by exogenous agonists but not by the ACh released by the preganglionic axon terminals unless cholinesterase activity is inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparative study of the acute effects of cetamolol (AI-27,303), atenolol, propranolol, and dexpropranolol on blood pressure, sympathetic nerve and ganglion activity of cats

The effects of cetamolol (AI-27,303, Betacor), atenolol, propranolol, and dexpropranolol were evaluated in 36 chloralose-urethane anesthetized cats. Blood pressure, sympathetic nerve discharge, and ganglionic activity (from the superior cervical ganglion) were recorded after the intravenous administration of 2.5, 5.0, and 10 mg/kg doses of the compounds. The results indicate that cetamolol and atenolol decreased blood pressure and discharge in the postganglionic sympathetic nerve and impaired transmission at the level of sympathetic ganglia. Propranolol and dexpropranolol given at the same doses produced a larger decrease in blood pressure, but increased the sympathetic discharge and had no effect on ganglionic spike amplitude.     

The effects of morphine on sympathetic transmission in the stellate ganglion of the cat

The aim of this study was to investigate which of the processes involved in synaptic transmission are affected by morphine in concentrations comparable to those used during surgical procedures. The effects of morphine sulfate on ganglionic transmission were studied in the stellate ganglion of the cat using intracellular and extracellular recordings in vitro. The neurons of the stellate ganglion were depolarized using preganglionic nerve stimulation, postganglionic nerve stimulation, and intracellular stimulation before and after introduction of morphine sulfate (up to 20 micrograms/mL). Tissue concentrations of morphine were estimated using radiolabeled morphine. Axonal transmission and the excitability of the postganglionic neurons to direct intracellular stimulation was not affected at the concentrations of morphine studied. In addition, morphine had a dose-dependent depolarizing effect on the resting membrane potential of most of the neurons in the stellate ganglion. Such neuronal depolarizations alone could initially produce excitation in some cell populations, followed by inhibition, secondary to the membrane depolarization, leading to depression of sympathetic nerve activity. The overall ganglionic transmission as recorded using an evoked potential was biphasic. At low doses morphine facilitated transmission, while at larger doses morphine attenuated evoked potentials. These effects do not appear to be mediated through classical opiate receptors since they are not blocked by naloxone.     

Effect of Precursors on the Synthesis of Catecholamines and on Neurotransmission in the Superior Cervical Ganglion of the Rat

Abstract: Male Sprague-Dawley rats (325–350 g) were anesthetized with urethane (1.5 g/kg i.p.) and treated with physiological saline, Aspartame (APM; 552 μmol/kg), or tyrosine (Tyr; 552 μmol/kg). Ganglionic transmission and the synthesis of dopamine (DA) and norepinephrine (NE) were measured in the superior cervical ganglion (SCG) following electrical stimulation of the cervical sympathetic trunk (CST). When the CST was stimulated with single pulses, neither APM nor Tyr affected the synthesis of NE or DA. However, in response to low- (5 Hz, 20 s) and high- (20 Hz, 20 s) frequency pulses, the metabolism of DA was increased (p > 0.05), but to the same extent after saline, APM, or Tyr. In rats stimulated with similar low- and high-frequency pulses, the synthesis of NE was increased significantly (p > 0.05) after Tyr, but not after APM or saline. In saline-treated controls, ganglionic transmission was not changed in response to single pulses, or low- or high-frequency stimulation. However, after treatment with APM, ganglionic transmission was depressed significantly (p > 0.01) in response to high-frequency stimulation (single: 0.46 ± 0.09 mV; low: 0.39 ± 0.07 mV; high: 0.27 ± 0.07 mV). After treatment with Tyr, ganglionic transmission was depressed significantly (p > 0.05) in response to both low- and high-frequency stimulation (single: 0.44 ± 0.04 mV; low: 0.22 ±0.12 mV; high: 0.26 ± 0.07 mV). In the nonstimulated SCG, l-3,4-dihydroxyphenylalanine (25 mg/kg) caused a rapid, significant (p > 0.01) increase in the synthesis and metabolism of DA, but not of NE. Treatment with nialamide (200 mg/kg i.p.) followed by electrical stimulation (15 Hz, 15 min) of the CST caused a significant (p > 0.05) increase of both NE and DA in the stimulated SCG. It is concluded that there are both similarities and differences in the regulation of the synthesis of NE and in the modulation of ganglionic transmission after the administration of the precursors APM and Tyr. The results indicate that caution is needed in comparing the neurochemical and neurophysiological effects of different catecholamine precursors.     

Effect of Ganglion Blockade on Cerebrospinal Fluid Norepinephrine

The source of norepinephrine (NE) in CSF has been unclear. It has been suggested that CSF NE indicates central neural noradrenergic tone and is determined differently from plasma NE. If CSF NE depended specifically on NE release in the CNS, then interference with ganglionic neurotransmission would be expected to decrease plasma NE but not CSF NE. Hypotension caused by ganglionic blockade might be expected to increase CSF NE reflexively. We infused the ganglion blocker, trimethaphan, intravenously into anesthetized dogs and measured the effects on mean arterial blood pressure (MAP) and on cisterna magna CSF levels of NE. The results were compared with those obtained on administration of saline, clonidine (2 micrograms/kg), yohimbine (0.25 mg/kg), or nitroprusside and with those obtained when hypotension during ganglion blockade was prevented by concurrent treatment with phenylephrine. Trimethaphan decreased MAP by 40%, arterial NE by 64%, and CSF NE by 61%. Nitroprusside administered intravenously to produce the same 40% depressor response increased arterial NE by 612% and CSF NE by 155%. Prevention of ganglion blockade-induced hypotension using phenylephrine did not prevent the decrease in CSF NE caused by trimethaphan, and when phenylephrine was discontinued, the resulting hypotension was not associated with increases in CSF NE. The similar decreases in plasma NE and CSF NE during ganglionic blockade, and the abolition of reflexive increases in CSF NE during hypotension in ganglion-blocked subjects, cast doubt on the hypothesis that CSF NE indicates central noradrenergic tone and are consistent instead with at least partial derivation of CSF NE from postganglionic sympathetic nerve endings.     

Effects of Selective Alkylphosphorylation of Propionylcholinesterase on the Regeneration of Acetylcholinesterase in the Aqueous Soluble Fraction of Superior Cervical Ganglia of the Rat Following Sarin

Abstract: The rates of regeneration of acetylcholinesterase (AChE) and propionylcholinesterase (PrChE) in the supernatants of aqueous homogenates of rat superior cervical ganglia, centrifuged at 100,000 g for 90 min, were determined at 1,3, 6, and 16 h following their inactivation (>90%) by administration of sarin, 2.0μmol/kg i.v. Values were compared with those in animals in which the PrChE was continually suppressed by the repeated, fractional administration of iso-OMPA, in a total dose of 10 or 20 μmol/kg i.p. These doses of iso-OMPA alone produced 96–99% inactivation of PrChE with no detectable effect on AChE. Significant suppression of AChE regeneration by iso-OMPA administration was noted only at 6 h; in contrast with earlier findings in the cat, administration of iso-OMPA alone caused no significant increase in ganglionic AChE activity.     

Ionic mechanisms involved in the release of 3H-norepinephrine from the cat superior cervical ganglion

It has previously been reported that in the isolated cat superior cervical ganglion (SCG) labeled with tritiated norepinephrine (3H-NE), the stimulation of the preganglionic trunk at 10 Hz as well as the exposure to 100 microM exogenous acetylcholine (ACh), produced a Ca++-dependent release of 3H-NE. The present results show that a Ca++-dependent release of 3H-NE was produced also by exposure to either 50 microM veratridine or 60 mM KCl. Tetrodotoxin (0.5 microM) abolished the release of 3H-NE induced by preganglionic stimulation, ACh and veratridine but did not modify the release evoked by KCl. The metabolic distribution of the radioactivity released by the different depolarizing stimuli showed that the 3H-NE was collected mainly unmetabolized. In the cat SCG neither the release of 3H-NE evoked by KCl nor the endogenous content of NE was modified by pretreatment with 6-OH-dopamine (6-OH-DA). On the other hand, this chemical sympathectomy depleted the endogenous content of NE in the cat nictitating membrane, whose nerve terminals arise from the SCG. The data presented suggest that the depolarization-coupled release of NE from the cat SCG involves structures that are different to nerve terminals and that contain Na+ channels as well as Ca++ channels.     

Effect of lithium chloride on the thyroid gland of white rats]

The morphological and functional changes in the thyroid tissue of white rats injected lithium chloride at doses 0.5 mekv/kg and 1.0 mekv/kg (groups 1 and 2, respectively) during three weeks were studied by the radiometric, histological and biochemical methods. The radiometric, histological and biochemical methods. The inhibitory action of lithium chloride on hormonogenesis in the thyroid gland and secretion of thyroid hormones into the blood was proved to be directly related to the lithium dose and concentration in the blood. The data of intravital radiometric and morphological analysis of the organs of the 1st group animals suggest some activization of the gland function, with the secretion of the hormones into the blood being suppressed. Increased concentration of the drug inhibits hormonogenesis and secretion of thyroid hormones into the blood.     

The effects of lithium on high energy phosphate and glucose levels in the rat superior cervical ganglion

Abstract— The effects of acute treatment with lithium ion (25 mm ) on the levels of ATP, phosphocreatine and glucose were measured in an in vitro preparation of rat superior cervical ganglion. Similar analyses were performed on ganglia from rats fed a chronic lithium diet (0.5 mm ). Ganglia were excised and de-sheathed, then stimulated (5 Hz) or rested for 20, 40 or 80 min in normal or lithium-containing Krebs-Ringer bathing solutions. Following freeze drying, enzymatic pyridine nucleotide methods were used to measure fluorometrically ATP, phosphocreatine and glucose on portions of a ganglionic perchloric acid extract. After 20 min of incubation, normal ganglionic contents of ATP and phosphocreatine were higher than the initial zero time levels. Incubation for periods longer than 20 min resulted in ATP and phosphocreatine levels which were lower than those at zero time. Stimulation of normal ganglia caused a decrease in the contents of high-energy phosphates relative to those in the resting state. Except for the 20 min time period the ATP levels were lower than normal in ganglia from rats chronically fed lithium. Levels of ATP and phosphocreatine in ganglia acutely exposed to lithium were significantly lower than in both normal ganglia and ganglia from chronically-treated rats. In comparison to normal ganglia, significantly lower levels of glucose were found only for stimulated ganglia acutely exposed to lithium.     

Differential Uptake of Lithium Isotopes by Rat Cerebral Cortex and Its Effect on Inositol Phosphate Metabolism

Twenty hours following the subcutaneous administration of 5 mEq/kg doses of 6LiCl and 7LiCl to two groups of rats, the cerebral cortex molar ratio of 6Li+/7Li+ is 1.5. The effects of the lithium isotopes on cortex myo-inositol and myo-inositol-l-phosphate levels are the same as we have reported earlier: a Li+ concentration-dependent lowering of myo-inositol and increase in myo-inositol-1-phosphate. Thus 6LiCl, when administered at the same dose as 7LiCl, produces the larger effect on inositol metabolism. When the 6LiCl and 7LiCl doses were adjusted to 5 mEq/kg and 7 mEq/kg, respectively, the cortical lithium myo-inositol and myo-inositol-1-phosphate levels of each group of animals became approximately equal, suggesting that the isotope effect occurs at the level of tissue uptake, but not on inositol phosphate metabolism. The inhibition of myo-inositol-1-phosphatase by the two lithium isotopes in vitro showed no differential effect. The isotope effect on cerebral cortex uptake of lithium is in the same direction as that reported by others for erythrocytes and for the CSF/plasma ratio, but of larger magnitude.     

A comparative and quantitative study of small intensely fluorescent (SIF) cells in the sympathetic ganglia of some small mammals

This comparative study of the number of SIF cells in the ganglions of the rat, cat, rabbit, mouse and hamster has confirmed that the mean number of SIF cells in the same ganglion of different species varies greatly, for instance in the superior cervical ganglion (SCG) of the rat and the cat, in the stellate ganglion of the cat and the mouse, or in the inferior mesenteric ganglion of the hamster and the other species. There is also considerable variability among individuals of the same animal species. In the SCG, the only ganglion for which there are data on the number of neurons, the ratio of SIF cells to neurons is around 1% in the rat, 0.2% in the rabbit, 0.3% in the mouse and 0.05% in the cat, i.e. a twenty-fold difference between the cat and the rat. Williams et al. (1975) distinguished type 1 SIF cells, corresponding to interneurons, from type 2, which are purely endocrine cells. Type 2 appears to be predominant in all ganglia, except the rabbit SCG where type 1 is highly predominant, and in all species, except the rat, in which this distinction is not applicable. The possible implications of these data on ganglionic functioning are discussed.     

Changes in the afferent activity of the vagus nerve and the rectal temperature in rats following Escherichia coli endotoxin administration]

In anaesthetised rats, i.p. administration of the Echerichia coli lipopolysaccharide in doses 5 mcg/kg (LPS) increased afferent activity of the cervical vagus, whereas 100 and 1000 mcg/kg doses inhibited the afferent discharges. Pyrogen-free saline (PFS) did not alter the activity. Rectal temperature (RT) was decreased by the PFS and by large doses of the LPS. Sodium salicylate administration prevented the effects.     

Inhibitory effect on gastric motility of chloroquine and mepacrine.

Measured on isolated rat-stomach fundus strips, the isolated cervical sympathetic trunk, and on the superior cervical ganglion, chloroquine and mepacrine have parasympatholytic, spasmolytic, ganglionic blocking and local anaesthetic effects. On rising the doses these manifest themselves in a given sequence. On the basis of this fact it is concluded that the inhibition of gastric motility by chloroquine and mepacrine in the rat, is based on the parasympatholytic property of the drugs in question.     

Effects of Systemically Administered Lithium on Phosphoinositide Metabolism in Rat Brain, Kidney, and Testis

A single subcutaneous dose of 10 mEq/kg LiCl gives rise to an increase in the cerebral cortex level of myo-inositol-1-P (I1P) that closely follows cortical lithium levels and, at maximum, is 40-fold above the control value. Kidney and testis show smaller increases in I1P level following LiCl administration. The I1P level is still sixfold greater than that of untreated rat cortex 72 h later. In cortex, parallel increases also occur in myo-inositol-4-P (I4P) and myo-inositol 1,2-cyclic-P (cI1,2P), whereas myo-inositol-5-P (I5P) remains unchanged. The cortical increases in I1P and I4P levels are partially reversed by administering 150 mg/kg of atropine 22 h after the LiCl, treatment that does not affect cI1,2P. When doses of LiCl from 2 to 17 mEq/kg are given, the cerebral cortex levels of I1P and myo-inositol, measured 24 h later, are found to reach a plateau at about 9 mEq/kg of LiCl, whereas cortical lithium levels continued to increase with greater LiCl doses. Levels of all three of the brain phosphoinositides are unchanged by the 10 mEq/kg LiCl dose, as is the uptake of 32Pi into these lipids. Chronic dietary administration of LiCl for 22 days showed that the effects of lithium on I1P and myo-inositol levels persist for that period. Over the course of the chronic administration of the lithium, levels of I1P, myo-inositol, and of lithium in cortex remained significantly correlated. We believe that these increases in inositol phosphates result from endogenous phosphoinositide metabolism in cerebral cortex and that lithium is capable of modulating that metabolism by reducing cellular myo-inositol levels. The size of the effect is a function of both lithium dose and the degree of stimulation of receptor-linked phosphoinositide metabolism. This property of lithium may explain part of its ability to moderate the symptoms of mania. Our chronic study suggests that prolonged administration of LiCl does not result in compensatory changes in myo-inositol-1-P synthase or myo-inositol-1-phosphatase.     

Effect of lithium on norepinephrine metabolic pathways

We investigated lithium-induced changes in norepinephrine (NE) catabolism. NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenyl glycol (DHPG), ions such as lithium (Li(+)), magnesium (Mg(2+)), and potassium (K(+)) were measured in rat plasma and cerebral cortex using an HPLC method with electrochemical detection for amines. The results obtained with a group of rats treated by lithium chloride (2 mmol/kg/IP) were compared with a control group receiving sodium chloride (2 mmol/kg/IP). Animals were killed at different times over a period of six hours in the morning following salt administration to minimize possible chronobiological effects. There are two pathways leading to MHPG formation: way A, without DHPG, and way B, with DHPG. In plasma and cerebral cortex of lithium treated rats, way A catabolism seems to be preferential. Lithium increases Mg(2+) and K(+) plasma levels. These results suggest that lithium may increase inactivation of NE and decrease NE available for adrenergic receptors.     

Acetylcholine release during burst-patterned stimulation of a sympathetic ganglion: its relation to transmission efficiency

The time-course of increase in acetylcholine (ACh) output during burst-patterned preganglionic stimulation of the cat superior cervical ganglion has been determined. The increase in output corresponded closely with the increase in transmission efficiency found earlier in the stellate ganglion subjected to similar preganglionic stimulation. ACh output however continued to increase following the time of attainment of full neuronal recruitment. The results indicate that the increase in ACh output may largely account for the increase in transmission; but they leave unexplained the synaptic function of the continuing increase in transmitter release.     

Ganglionic blocking effect of some antibiotics on isolated rat sympathetic ganglion.

It was shown on the isolated superior cervical ganglion of the rat that some antiobiotics exerted a blocking effect nearly as potent as that exhibited by hexamethonium or d-turbocurarine. The ganglionic blockade thus induced proved to be non-specific and due to the local anaesthetic effect of the tested drugs.