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F F Foldes

Publications and source records attributed to F F Foldes.

At least 19 recordsLinked to original sources
PubMed1991

Presynaptic interaction between vagal and sympathetic innervation in the heart: modulation of acetylcholine and noradrenaline release.

It is generally accepted that there is a functional antagonism between the sympathetic and parasympathetic (vagal) effects on the heart. In this study guinea-pig right atria loaded either with [3H]noradrenaline or [3H]choline were used and the release of [3H]noradrenaline or [3H]acetylcholine in response to field stimulation was measured under conditions when the negative feedback modulation was excluded. Strong evidence was obtained for a one-sided interaction between the sympathetic and vagal nerves at the level of the prejunctional axon terminals that send the final chemical message to the heart muscle affecting heart rate and force. Acetylcholine released from the vagal nerve inhibited its own release and also decreased the release of noradrenaline from the sympathetic axon terminals through muscarinic receptor stimulation. But muscarinic receptors located on cholinergic axon terminals are different from those present on the noradrenergic axon terminals. There is a significant difference in the dissociation constants (Kd) of different antimuscarinic drugs: The Kd values of pancuronium on vagal and sympathetic axon terminals were 5.68 +/- 0.41 and 7.20 +/- 0.25, respectively. By contrast, noradrenaline released from the sympathetic nerves or exogenous noradrenaline were not able to modulate the release of acetylcholine from the cholinergic axon terminals even under condition when the negative feedback modulation of acetylcholine release was excluded. These findings indicate that vagal axon terminals are not equipped with alpha 2- or alpha 1-adrenoceptors. However, noradrenaline released from the sympathetic axon terminals was able to inhibit its own release via alpha 2-adrenoceptor stimulation.

Acetylcholine↗
PubMed1991

The neuromuscular effects of ORG9426 in patients receiving balanced anesthesia.

In searching for a nondepolarizing muscle relaxant with intermediate duration but more rapid onset of action than the presently available compounds, the neuromuscular and circulatory effects of ORG9426 were investigated in two studies in humans receiving fentanyl, droperidol, thiopental, and nitrous oxide-oxygen anesthesia. Eighty patients, randomly assigned to one of four groups of 20 each, received 0.12, 0.16, 0.20, or 0.24 mg/kg ORG9426. In the first study, the doses (in milligrams per kilogram) of ORG9426 that caused 50% (ED50), 90% (ED90), or 95% (ED95) neuromuscular block were determined by the individual dose-response method; they were 0.170, 0.268, and 0.305 mg/kg, respectively. In the second study, after induction of anesthesia, patients received 0.6 mg/kg (about 2 x ED95) of ORG9426, either in a single bolus (group 1) or in two unequal (0.1 and 0.5 mg/kg) increments 4 min apart (group 2). After the administration of 0.6 mg/kg ORG9426, maximal neuromuscular block developed in 1.5 +/- 0.12 min in group 1 and in 1.2 +/- 0.14 min in group 2. Patients tracheas were intubated after development of the maximal neuromuscular effect of the intubating dose and after the recording of heart rate and systolic and diastolic blood pressure. There was no difference in the clinical duration of the intubating doses, which were 40.0 +/- 3.2 (15-73) min in group 1 and 39.3 +/- 2.4 (19-57) min in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pain control with intrathecally and peridurally administered opioids and other drugs.

Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.

Analgesics, Opioid↗
PubMed1990

Neuromuscular and cardiovascular effects of pipecuronium.

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Heterogeneity of presynaptic muscarinic receptors involved in modulation of transmitter release.

In order to extend the characterization of muscarinic receptors at presynaptic sites their inhibitory effect on the stimulation-evoked release of [3H]noradrenaline and [3H]acetylcholine from different axon terminals was studied and the dissociation constants and potencies of different antagonists were estimated, in guinea-pig and rat. While oxotremorine reduced the release of [3H]acetylcholine and [3H]-noradrenaline in a concentration-dependent manner from different release sites (Auerbach plexus, noradrenergic neurons in the right atrium, cerebral cortex), McN-A 343, an M1 receptor agonist, enhanced their release evoked by field stimulation. When the inhibitory effect of oxotremorine on transmitter release was studied, pancuronium, pirenzepine and atropine were competitive antagonists of presynaptic muscarinic receptors located on the noradrenergic axon terminals of the atrium. While atropine and pirenzepine inhibited the muscarinic receptors of cholinergic axon terminals in the Auerbach plexus, pancuronium and gallamine had a very low affinity. Significant differences were found in the affinity constants of antagonists for muscarinic receptors located in the cholinergic axon terminals of Auerbach plexus and cerebral cortex, and noradrenergic axon terminals of the atrium. While atropine and pirenzepine exerted similar effects on these presynaptic sites, pancuronium, gallamine and (11-(2-[diethylamino)-methyl)-1-piperidinyl)acetyl)-5, 11-dihydro-6(1-pyrido(2,3-b)(1,4)-benzodiazepin-6-on) were much more effective on muscarinic receptors controlling acetylcholine release from the cerebral cortex and noradrenaline release from the heart. There was more than 100-fold (2.0 pA2 units) difference in affinities of these antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMed1989

The influence of temperature and calcium concentration on the myoneural effect of antibiotics.

To obtain information on the sites and mechanisms of the myoneural effect of aminoglycoside and polypeptide type antibiotics, the influence of neomycin, streptomycin, gentamicin and polymyxin B on the depression of the force of contraction (P) of the rat phrenic nerve-hemidiaphragm preparation was investigated at 37 degrees C, 27 degrees C or 17 degrees C and also at 37 degrees C in electrolyte solutions containing 2.5, 1.25 or 0.625 mM CaCl2. Decreasing the temperature or the CaCl2 concentration ((CaCl2)o) of the bath significantly (p less than 0.001) decreased P. The depressant effect of aminoglycosides on P (about 50% of control at 17 degrees C) was increased more with lower temperatures than that of polymyxin B (about 20%). The effect of lowering the (CaCl2)o on the depression of P (about 90% of control at the lowest (CaCl2)o) was about the same with the 4 antibiotics. The development of the maximal effect and the recovery of P after washout was slower with polymyxin B than with the 3 aminoglycosides. 4-Aminopyridine antagonized the depression of P caused by polymyxin B less than that caused by aminoglycosides. The findings suggest that aminoglycosides depress myoneural activity primarily by inhibiting stimulated release of ACh. Polymyxin B also inhibits ACh release, but inhibition of the contraction of myofibrils contributes more significantly to its myoneural effects than with aminoglycosides. It is conceivable that blocking of the ionophores of the postjunctional membrane also contributes to the myoneural effects of polymyxin B.

Acetylcholinesterase↗
PubMed1989

Inhibition of mobilization of acetylcholine: the weak link in neuromuscular transmission during partial neuromuscular block with d-tubocurarine.

The authors have demonstrated earlier, by direct measurement of acetylcholine (ACh), that d-tubocurarine (d-Tc) and other nondepolarizing muscle relaxants decrease the release of ACh from the indirectly stimulated mouse hemidiaphragm preparation. It was the purpose of the present study to determine whether the decrease of the stimulated release of ACh and the increase in the intensity of the partial neuromuscular block observed at higher stimulation rates is caused by the inhibition of mobilization of ACh from reserve depots to release sites or by inhibition of the release process itself. To attain our objective, the authors have investigated the influence of the progressive increase of the rate of stimulation from 0.1 to 1, 2, 3, and 5 Hz on the force of contraction on the in vitro phrenic nerve-hemidiaphragm and in vivo sciatic nerve-tibialis anterior preparation in the absence of drugs and after about 20% neuromuscular block produced by d-Tc or by Mg2+. The latter is known to inhibit the Ca2+ dependent release of ACh. In the absence of drugs increasing the stimulation rate increased the force of contraction, in vivo and in vitro, during both indirect and direct stimulation. In the phrenic nerve-hemidiaphragm preparation the increase was significant at 1, 2, 3, and 5 Hz (P less than 0.001) with both types of stimulation. In the sciatic nerve-tibialis anterior preparation the force of contraction was only higher at 3 and 5 Hz (P less than 0.01). The similar magnitude of the increase of the force of contraction during direct and indirect stimulation indicates that it is caused by facilitation of the contraction of the muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Species variation in the site and mechanism of the neuromuscular effects of diadonium in rodents.

The unusually wide, 80-fold species variation observed by others (1,2) in the neuromuscular (NM) potency of diadonium, a nondepolarizing muscle relaxant (MR), between cat and man suggested that the site and mechanism of its NM effect may vary in different species. To obtain information on this question, the NM potency of diadonium and the reversibility of its NM effect by neostigmine and/or 4-aminopyridine (4AP) was investigated on the in vitro phrenic nerve--hemidiaphragm preparations of rats, mice and guinea pigs. The concentration of diadonium that caused 90% NM block (IC90) was much greater in guinea pigs, 1.74 +/- 0.02 and 1.28 +/- 0.01 mu, when the preparations were stimulated with single stimuli at 0.1 Hz or with 0.1 s trains of 50 Hz tetani every 10 s, respectively, than in rats (IC90 = 62.4 +/- 0.89 and 52.1 +/- 1.00 microM) or mice (IC90 = 51.9 +/- 0.98 and 44.4 +/- 0.22 microM). In guinea pigs, the NM blocking effect of diadonium could be antagonized by neostigmine. This indicates that in this species the NM blocking effect of diadonium is primarily caused by inhibition of the interaction of acetylcholine (ACh), released by the nerve impulse, with the cholinergic receptors (cholinoceptors) of the postjunctional membrane (p.j.m.). By contrast, in rats and mice diadonium was not antagonized by neostigmine but was reversed by 4-aminopyridine. This suggests that in these species, in contrast to other nondepolarizing MR, diadonium does not inhibit NM transmission postsynaptically, but by inhibiting the positive nicotinic feedback mechanism of mobilization of ACh from reserve depots to release sites, causes a presynaptic NM block.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

The influence of aminopyridines on Ca2+-dependent evoked release of acetylcholine from rat cortex slices.

The release of acetylcholine (ACh) elicited by electrical stimulation was investigated in rat brain cortical slices preloaded with 3H-choline. Decreasing the [Ca2+]o from 2.5 to 0.3 mM caused a progressive reduction of the evoked release of ACh. 4-Aminopyridine (4AP) or LF14 [(1,1-dimethyl-3-(4-amino-3-pyridyl)], 4 x 10(-5) M doubled the evoked release of ACh when the [Ca2+]o was 2.5 mM and quadrupled it when it was 0.3 mM, to levels higher than those obtained with 2.5 mM [Ca2+]o alone. This indicates that both 4AP and LF14 decrease the Ca2+ requirements for the evoked release of ACh. The findings of this study indicate that LF14 may be suitable for the symptomatic treatment of senile dementia of Alzheimer's type, presumably caused by dysfunction of cholinergic transmission in the brain.

4-Aminopyridine↗
PubMed1988

A simple method for monitoring muscular relaxation during continuous infusion of vecuronium.

There is considerable individual variation in the dose of vecuronium required for the maintenance of surgical relaxation. Therefore to provide uninterrupted relaxation without overdosage it is advisable to regulate the IV infusion of vecuronium on the basis of appropriate monitoring. Monitoring with mechanomyography (MMG) or electromyography requires costly equipment and is too complex for routine clinical use. Visual observation of the adductor pollicis muscle contracting against zero resistance is not suitable for the reliable assessment of the degree of neuromuscular (NM) block. For clinical purposes satisfactory monitoring can be achieved with the simple device (Myoscan) described. The reliability of the Myoscan was tested in 30 patients by simultaneous monitoring of the force of contraction of the adductor pollicis on one side with the Myoscan and on the contralateral side with the MMG. Retrospective analysis of the MMG indicated that the conduct of anaesthesia would have been virtually the same if it would have been based on MMG monitoring.

Adult↗
PubMed1988

Potentiation of neuromuscular blocking agents by calcium channel blockers in rats.

The effect of calcium channel blockers (Ca-antagonists) on the potency and reversibility of muscle relaxants (MR) was investigated in the in vitro phrenic nerve-hemidiaphragm and in vivo sciatic nerve-tibialis anterior preparation of rats. To increase the relevance of the experimental findings to the clinical situation, the [Ca++] and [Mg++] in vitro were the same as in the plasma of rats and humans and the stimulation parameters used in vitro and in vivo were similar to those that elicit voluntary movements of the muscles used. Both verapamil and nifedipine significantly decreased the I50 and I90 of d-tubocurarine (d-Tc), pancuronium, vecuronium, and atracurium in vitro and those of the first three MR in vivo (P less than 0.001). In vitro, the depression of the force of contraction of the diaphragm (P) caused by all the Ca-antagonist-MR combinations could be reversed only partially by washout, neostigmine, or 4-aminopyridine. In vivo, because of limitations imposed by their cardiovascular depressant effect, the muscles were exposed to lower concentrations of Ca-antagonists for shorter periods. Under these circumstances the decrease of P caused by all Ca-antagonist-MR combinations recovered spontaneously close to control levels. This study indicates that acute administration of verapamil during anesthesia may increase MR potency, but it is unlikely that spontaneous recovery or reversibility of the residual neuromuscular (NM) block at the end of anesthesia will be significantly affected. However, long-term administration of Ca-antagonists may make difficult the reversal of the residual NM block.

Anesthesia↗
PubMed1987

Modulation of stimulation-evoked release of newly formed acetylcholine from mouse hemidiaphragm preparation.

A radioisotope method has been developed for measuring the stimulation-evoked release of acetylcholine without the use of cholinesterase inhibitors from the mouse hemidiaphragm preparation which had been loaded with 3H-choline. Evidence has been obtained that 3H-choline was taken up by and released from both innervated and non-innervated mouse hemidiaphragm preparations. However, it was released in the form of 3H-acetylcholine in response to electrical field stimulation only from the innervated preparations. Long lasting (51 min) S1 stimulation of the preparations exhausted the radioactive acetylcholine stores to the extent that S2 did not evoke any release of 3H. These data suggest that when the labelled acetylcholine stores become exhausted, the labelled choline, still present in the tissue, cannot be released by electrical stimulation. Tetrodotoxin (1 mumol/l) administration and Ca withdrawal inhibited, 20-100 mumol/l 4-aminopyridine enhanced the release of 3H-acetylcholine in response to electrical stimulation. Activation of the presynaptic muscarinic receptors by the agonist oxotremorine (50 mumol/l) decreased the liberation of 3H-acetylcholine. The muscarinic antagonist atropine (1 mumol/l) abolished the inhibitory effect of oxotremorine and by itself increased the evoked release of the newly formed 3H-acetylcholine. Adenosine (50 mumol/l) reduced the evoked release of radioactivity. Theophylline (30 mumol/l) prevented the inhibitory effect of adenosine and itself enhanced the release. Xylazine (1 mumol/l), an alpha 2-adrenoceptor agonist did not affect the release. It is concluded that the stimulation-evoked release of 3H-acetylcholine from the mouse phrenic nerve hemidiaphragm preparation preloaded with 3H-choline is derived from the motor nerves. The release of acetylcholine is modulated by activation of presynaptic muscarinic and adenosine receptors.

4-Aminopyridine↗
PubMed1987

Effect of mono- and diaminopyridines on release of [3H]norepinephrine from isolated guinea-pig atrium.

Neurochemical evidence has been obtained that 4-aminopyridine, 3,4-diaminopyridine and 3,3-dimethyl-1-(4-amino-3-pyridyl)urea HBr (LF-14), concentration-dependently enhanced the stimulation-evoked release of [3H]norepinephrine ([3H]NE) from isolated guinea-pig atrium. The effects of aminopyridines, compounds known to inhibit potassium channels, were Ca0-dependent. High pressure liquid chromatography, combined with radiochemical detection, indicated that the increased stimulated release of radioactivity was due to [3H]NE. Since the aminopyridines studied also enhanced the release of [3H]NE from atrium treated with cocaine, a blocker of uptake1, it seems likely that the increased release of NE caused by the aminopyridines is due to the enhanced release of NE from sympathetic axon terminals and not to the inhibition of reuptake. It is probable that the sympathomimetic cardiac effects (positive inotropic and chronotropic effect) of aminopyridines observed in animal experiments is due to the increased release of NE, caused by these compounds.

4-Aminopyridine↗
PubMed1987

Direct evidence that pancuronium and gallamine enhance the release of norepinephrine from the atrial sympathetic nerve by inhibiting prejunctional muscarinic receptors.

The effect of different non-depolarizing muscle relaxants (gallamine, pancuronium, vecuronium, D-tubocurarine) on [3H]norepinephrine release in response to electrical stimulation was studied in isolated guinea-pig atrium. High pressure liquid chromatography combined with electrochemical and radiochemical detection revealed that the released radioactivity was mainly in the form of [3H]norepinephrine release. Oxotremorine, a pure muscarinic agonist, reduced the release of tritium. Gallamine and pancuronium, like atropine, prevented the inhibitory effect of oxotremorine. D-Tubocurarine and vecuronium had no such effect. These findings indicate that gallamine and pancuronium exert a presynaptic antimuscarinic, atropine-like effect, by inhibiting muscarinic receptors located on the axon terminals of sympathetic neurons thereby enhancing norepinephrine release. It is suggested that this phenomenon might play some role in tachycardia observed during surgical anaesthesia when gallamine or pancuronium have been administered.

Adrenergic Fibers↗
PubMed1985

A simple and sensitive method of acetylcholine identification and assay. Bioassay combined with minicolumn gel filtration or high-performance liquid chromatography.

A modified technique of acetylcholine assay on the guinea pig ileum has been combined with either minivolume gel filtration or high-performance liquid chromatography separation of the samples. In addition, labeled acetylcholine (14C-ACh) was eluted with unlabeled acetylcholine or with the samples expected to contain acetylcholine, and their elution profiles were compared by bioassay plus radioassay of eluate fractions. When the elution of both biological activity and label occurred in the same eluates, it was concluded that the substance assayed on guinea pig ileum was acetylcholine. The method was sensitive to 0.5 ng (1.8 pmol) of acetylcholine and its reproducibility was within 5%. It thus represents a substantial improvement in chemical specificity over the previous bioassay method described by Paton and Vizi (1969).

Acetylcholine↗