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PubMed1985

Cardiovascular effects of two potential beta-hydroxylase inhibitors.

The purpose of this study was to evaluate the cardiovascular effects of two potential beta-hydroxylase inhibitors, a dithiocarbamate and a thiourea derivative of d-amphetamine, 1 and 2, respectively. These compounds when given intravenously elicited a significant dose-dependent depressor effect in normotensive rats and dogs anesthetized with chloralose-urethane. The hypotensive effect of these compounds appears to be the result of a combination of two action components: (a) the major component, which can be blocked by atropine, exerted through the parasympathetic division and (b) a decreased availability of sympathetic neurotransmitter at the synaptic cleft. A CNS-stimulant effect of these compounds is suggested by their ability to reduce hexobarbital sleeping time in mice and their analeptic effect in all anesthetized animals employed.

Adrenergic alpha-Antagonists↗
PubMed1989

Antagonism of ethanol effects by Ro 15-4513: an electrophysiological analysis.

Ethanol (ETH) and general anesthetics have been reported to facilitate the chloride channel opening, possibly, or at least partly, through an interaction with the GABA-benzodiazepine (BZ) receptor-gated chloride ionophore "supramolecular complex". Recently Ro 15-4513, a novel BZ ligand, has been indicated as a potent and selective antagonist of various ETH-induced behavioral and biochemical effects. However, since its precise characterization is still a matter of debate, we have tested and compared the effect of Ro 15-4513, as well as its antagonism against ETH, in two objective electrophysiological parameters, i.e., the electroencephalograph (EEG) pattern in freely moving rats and single unit activity of reticulata neurons. Ro 15-4513 produced an EEG state of alertness and antagonized the behavioral impairment and the EEG deterioration by ETH. However, while its protective action was consistent against moderate doses (2 g/kg) of ETH, it was much less evident versus higher doses (4 and 8 g/kg). On reticulata cells, Ro 15-4513 potently stimulated their spontaneous firing and reversed the depression by both ETH and Na-pentobarbital. Moreover, the beta-carboline DMCM also had similar effects. The "pure" BZ antagonist Ro 15-1788 was completely inefective against ETH, yet fully cancelled the reversing actions of Ro 15-4513 and DMCM upon ETH or Na-pentobarbital effects. It is concluded that Ro 15-4513 behaves as a BZ inverse agonist, so that its opposition to ETH and Na-pentobarbital is probably the result of its "negative" coupling with the BZ recognition site that triggers the closing of chloride channels. It suggests that BZ inverse agonists might constitute, in the near future, a new class of analeptic drugs.

Action Potentials↗
PubMed1993

Do benzodiazepine ligands contribute to hepatic encephalopathy?

1. Levels of BZ receptor ligands are elevated in the brain of animal models of FHF and humans with FHF. Some of these ligands have agonist properties and some are known 1, 4-BZs which bind to the DS receptor. Much of the BZ receptor ligand activity in HE is unidentified and it is possible that some may bind to receptor subtypes other than the DS receptor. 2. Average levels of BZ receptor ligands in the brain in HE do not appear to be sufficient to augment GABAergic tone to a degree that would result in severe encephalopathy (i.e. coma). However, these ligands have a heterogeneous distribution in the brain and their neuroinhibitory effects may be potentiated by increased availability of GABA at GABAA receptors. Furthermore, that these ligands may contribute to HE is suggested by anecdotal reports of ameliorations of HE being induced in a majority of patients by the BZ receptor antagonist flumazenil. 3. The response of HE to flumazenil in humans is usually incomplete and in animal models may be modest. Potential explanations for these findings include pharmacokinetics, BZ receptor subtype specificity and higher levels of BZ receptor ligands in the brain in humans with HE than in animal models. 4. Certain BZ receptor ligands e.g. Ro 15-3505 and Ro 15-4513, that are structurally related to flumazenil, are more efficacious at ameliorating HE than flumazenil in animal models. These findings may be more dependent on differences in BZ receptor subtype specificity than differences in intrinsic activity. The properties of an ideal BZ receptor ligand for administration to a patient with HE would appear to be: (i) antagonist action at BZ receptors, (ii) no intrinsic activity apparent after a conventional pharmacologic dose, (iii) high specificity and affinity for BZ receptors, (iv) slow metabolism, and (v) absence of toxic effects. Promising ligands, such as Ro 15-3505, with weak partial inverse agonist actions and hence analeptic potential, require careful evaluation of their therapeutic index before clinical application. 5. BZ receptor ligands may be useful in the management of HE. Specifically, they may be given IV: (i) to reverse effects of exogenous BZs; (ii) to aid in the differential diagnosis of encephalopathy; (iii) to provide prognostic information; and (iv) to optimize brain function. They may also be given orally with the objective of reducing dietary protein intolerance in patients with chronic liver disease.

Animals↗
PubMed1981

Unusual 'spike-wave stupor' in a patient with manic-depressive psychosis treated with amitriptyline.

'Spike-wave stupor' was observed in a 58-year-old male patient with manic-depressive psychosis. Almost continuous atypical spike-wave activity was seen in conjunction with a stuporous episode with stereotyped automatism. Intravenous diazepam ended both the electroencephalographic epileptiform discharges and the clinical stupor. Before and during this episode the patient was treated with an average-dose amitriptyline monotherapy. There was no family history of epileptic seizures. The patient had had electroconvulsive therapy. The history suggests that the analeptic property of amitriptyline induced the 'spike-wave stupor' in this patient.

Action Potentials↗
PubMed1981

Failure of muscarinic blockade to antagonize analepsis induced by thyrotropin-releasing hormone and MK-771 in the rat.

In the rat, the antimuscarinics atropine and scopolamine failed to block the reduction in pentobarbital-induced sleep time produced by either thyrotropin-releasing hormone (TRH) or MK-771 (a TRH analog). Previous reports have indicated that the marked analeptic effect produced by TRH is antagonized by such agents. It is not clear at this time whether the difference between our findings and these previous studies indicates a reduced sensitivity of cholinergic receptors in the rat to muscarinic blockade, a different neurochemical mechanism of action of TRH in the rat, or other unknown factors.

Animals↗
PubMed1978

Benzodiazepine receptor binding: the interactions of some non-benzodiazepine drugs with specific [3H] diazepam binding to rat brain synaptosomal membranes.

The interaction of several non-benzodiazepine drugs with [3H] diazepam binding to benzodiazepine receptors in rat brain synaptosomal membranes was investigated. Baclofen, benzoctamine, hydroxyzine, chlorpromazine, haloperidol, imipramine, and amitriptyline displace specific [3H] diazepam binding, but the concentrations needed are too high to explain pharmacological effects of these drugs by an interaction with benzodiazepine receptors. The most potent non-benzodiazepine drug for inhibiting specific [3H] diazepam binding was methaqualone (IC50 value of 150 micrometer). It is suggested that interactions with benzodiazepine receptors may account for the anxiolytic and anticonvulsive side effects of this drug. The analeptic drug pentylenetetrazole interacts with benzodiazepine receptor binding with an IC50 value of about 1 mM, which is possibly too high to explain its convulsive properties by an antagonism at the benzodiazepine receptor.

Animals↗
PubMed1988

First-derivative spectrophotometric and gas-liquid chromatographic determination of caffeine in foods and pharmaceuticals. I. Rapid determination of caffeine in coffee, tea and soft drinks.

A simple and rapid spectrophotometric method is described for the determination of caffeine in coffee, tea and soft drinks. To exclude the irrelevant absorptions, due to the presence of some accompanying naturally occurring ingredients in the analysed multicomponent drinks, the derivative method is found to be superior. Another gas-liquid chromatographic (GLC) procedure for the quantitation of the analeptic agent, in bulk form and in the same drinks, is also investigated. The recovery testing of the proposed methods gives good percentage mean recoveries with relatively low deviations. The results of the methods described are compared with those obtained by direct UV-spectrophotometry as well as by applying an official pharmacopoeial procedure for caffeine.

Beverages↗
PubMed1976

The in vivo effects of 2.45 GHz microwave radiation of rabbit serum components and sleeping times.

An investigation was conducted to determine the effects of relatively low power density microwave exposures on various serum components of the Dutch rabbit. Both continous wave and pulsed mode exposures at 2.45 GHzwere used at power densities of 25,10 and 5 mW/cm2. Studies of 10 serum components were performed. Additional studies were conducted on changes in sleeping times of pentobarbital-sedated rabbits at various power densities. Gross and histopathological examinations were performed on representative samples of animals. Changes in the blood chemistry of irradiated animals were consistent with a dose-dependent response to a non-specific thermal stress at all power densities used. Observed physiological response, as well as rectal temperature measurements, indicated that the thermoregulatory capability of the rabbits was sufficient to compensate for the thermal burden at 5 and 10 mW/cm2, but could be overridden by a 2 h exposure at 25 mW/cm2. Pathology findings included a mild, repairable nephrosis in animals exposed at a power density of 25 mW/cm2. A further investigation of analeptic effects at power densities varying from 5 mW/cm2 to 50 mW/cm2 resulted in a statistically significant decrease in sleeping times, apparently proportional to power density below 15 mW/cm2.

Anesthesia, Intravenous↗
PubMed1991

Postoperative opisthotonus and torticollis after fentanyl, enflurane, and nitrous oxide.

Most drug-induced extrapyramidal symptoms are due to blockade of dopaminergic receptors and are treated with anticholinergic drugs. We report a patient with severe postoperative extrapyramidal symptoms which responded to physostigmine and indicated a different aetiology. A young, healthy female outpatient developed severe extrapyramidal symptoms after an uneventful 50 min anaesthetic with thiopentone, fentanyl (100 micrograms), enflurane, and nitrous oxide. Although the trachea was not extubated until she obeyed commands, the patient developed opisthotonus, which resolved initially after treatment with thiopentone (40 mg), diazepam (5 mg), and diphenhydramine (50 mg). The opisthotonus recurred approximately 25 min later, in association with torticollis, obtundation, and periodic apnoea. A tentative diagnosis of central anticholinergic syndrome was proposed, and fentanyl was considered to have been responsible. Naloxone (0.4 mg) induced no improvement, but physostigmine (2 mg) reversed the dystonic symptoms and periodic apnoea and improved her mental status. The response to physostigmine may have been due specifically to increased levels of acetylcholine at the cholinergic receptors, or to a nonspecific analeptic effect.

Adult↗
PubMed1997

Differential effects of ventilatory stimulation by sex hormones and almitrine on hypoxic erythrocytosis.

In the absence of pulmonary disease, hypoventilation is considered to be the primary cause of Chronic Mountain Sickness, and there is some reason to believe that chronic administration of respiratory analeptics could be useful for treatment of this disease. The present study was intended to define comparatively the influence of two potent ventilatory stimulants, namely a combination of progesterone and estrogen and the pharmacological agent almitrine, on catecholaminergic structures implicated in the chemoreflex pathway and on hypoxia-induced polycythemia. Three groups of young male rats born and living at high altitude (3 600 m) were examined: untreated animals (n = 25), rats given ovarian steroids (progesterone plus 17beta-estradiol, n = 25) or almitrine (n = 25) for 6 weeks until sacrifice. Ovarian steroids or almitrine had pronounced neurochemical effects on the afferent chemoreflex circuitry. Both treatments inhibited norepinephrine (NE) and dopamine (DA) turnover in the carotid body, but central processing of chemosensory inputs differed between the two respiratory drugs. Ovarian steroids inhibited noradrenergic activity in the projection area of the chemosensory nerve fibers within the caudal portion (A2C) of the nucleus tractus solitarius (NTS). In contrast, almitrine stimulated neurochemical activity of other brainstem noradrenergic cell groups involved in cardiorespiratory control, i.e. , the rostral portion (A2R) of the NTS, the nucleus reticularis lateralis (A1), the nucleus olivaris superior (A5) and the locus ceruleus (A6). Although both treatments increased chemoreflex drive and ventilation, only sex hormones decreased erythropoietin (EPO) levels and the degree of polycythemia. These results suggest that stimulation of ventilation through activation of peripheral arterial chemoreceptors activation alone is not sufficient for reducing EPO levels and polycythemia. The better efficiency of female sex hormone treatment as compared to almitrine could be related either to the central effects of progesterone and estrogen and/or to the impact of these hormones on erythropoiesis at the kidney/bone marrow level.

Almitrine↗
PubMed1984

The effect of solvent polarity upon rotational barriers in nikethamide.

In summary, dynamic nuclear magnetic resonance techniques were used to study the hindered internal rotation of the amide bond of the analeptic nikethamide. The rotatory motion of this bond was studied in a series of solvents of increasing polarity: CDCl3, CH3(CH2)3OD, CH3CH2OD, CH3OD and D2O. Motion about the amide bond was increasingly hindered in direct proportion to solvent polarity, correlating with enhanced hydrogen bond formation between nikethamide and the more polar solvent molecules. Diethylamide group motion would be expected to affect binding of the carbonyl oxygen to cholinergic receptor sites. The degree to which association to a receptor site can be affected by this rotatory motion may vary from 0 to 4 kcal/mole, the variability being entirely dependent upon the polarity of the binding site. An increase in rotamer lifetime, corresponding to a more polar environment, would be expected to enhance the kinetics of nikethamide association to the receptor site.

Animals↗
PubMed1986

Solvent interactions with N, N-dialkylnicotinamides and their effects on rotational barriers.

Carbon-13 nuclear magnetic resonance techniques were employed to examine the effects of solvent environment on rotational barriers in a series of molecules structurally-related to the analeptic, nikethamide: N,N-dimethylnicotinamide, N,N-di-n-propylnicotinamide, and 1-nicotinoyl piperidine. Total bandshape analysis was performed for the exchanging alkyl carbon resonances of these compounds as a function of temperature in four solvent systems: D2O, CH3OD, CH3CH2OD and CDCl3. The rate constants for rotation about the amide bond obtained in this way were used to calculate free energy (delta G), enthalpy (delta H) and entropy (delta S) of activation parameters for this process. Our results indicate that rotational barriers are less affected by the nature of the alkyl chain attached to the amide nitrogen than by the size and polarity of the solvent molecules. Interpretation of the thermodynamic parameters in light of both nikethamide analogue structure and solvent type has further clarified the manner in which hydrogen bonding interactions between solvent molecules and the carbonyl oxygen of these analogues stabilize transition state conformers.

Hydrogen Bonding↗
PubMed1981

Effect of septohippocampal lesions on thyrotropin-releasing hormone antagonism of pentobarbital narcosis.

Thyrotropin-releasing hormone (TRH) has been shown to antagonize pentobarbital narcosis in a variety of mammalian phylogeny, and many lines of evidence indicate that TRH action in the septum to modulate the septohippocampal system may be the neuroanatomical substrate mediating this effect. To further examine this hypothesis, the analeptic response following injection of TRH into the lateral ventricles or ventromedial septum was measured after lesions of the septum, fimbria or hippocampus. Lesions were induced using either radiofrequency current, aspiration or microinjection of kainic acid. Bilateral electrolytic lesions of the fimbria were found to block the antagonism of pentobarbital narcosis by intraseptal injection of 500 ng TRH, indicating that intraseptal TRH is acting via the septohippocampal system. In contrast, complete aspiration of the dorsal hippocampi did not attenuate intracerebroventricular (i.c.v.) administration of TRH. However, large electrolytic septal lesions effectively blocked i.c.v. TRH. These findings indicate first that i.c.v. TRH can cause arousal from pentobarbital narcosis via interaction with alternative neuroanatomical substrates from the septohippocampal system, and secondly, that these alternative substrates have axons which either synapse in or pass through the septum. The fact that injection of kainic acid into the ventromedial septum did not antagonize i.c.v. TRH supports the likelihood that the effectiveness of electrolytic septal lesions results from disruption of fibers in passage and not destruction of neuron perikarya in the septum.

Anesthesia, General↗
PubMed1978

Studies on the neuropharmacology of thyrotropin releasing hormone (TRH) and a new TRH analog.

TRH and a new TRH analog (all L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide, MK-771) have been compared with several other peptides for their "analeptic" activity and their ability to enhance the excitatory actions of microiontophoretically applied acetylcholine (ACh) on cerebral cortical neurons of rats. TRH and MK-771 offset the narcosis induced by pentobarbital in mice, whereas the C-terminal free acid derived from TRH, melanostatin, somatostatin and pyroglutamyl-histidineamide have been found inactive. Similarly, of these peptides only TRH and MK-771 induced a tremor of the forepaws in pentobarbital-anesthetized mice. Employing comparable ejection currents and durations, only TRH and MK-771, applied by microiontophoresis, enhanced the excitatory actions of ACh on spontaneously active cortical neurons in anesthetized rats. Based on these findings and other recent data, it is suggested that the interactions of TRH and MK-771 with cholinergic mechanisms may underlie some of the actions, including their anti-anesthetic effects, of these peptides.

Animals↗
PubMed1979

A study of the changes in motor behaviour caused by TRH on intracerebral injection.

20 microgram TRH injected bilaterally into the caudate-putamen, tuberculum olfactorium, nucleus accumbens, amygdala, lateral ventricles, midbrain or cerebral cortex failed to induce any increase in locomotor activity (measured using photocells), although other behavioural changes were observed after each injection, and included body shakes, limb tremor, repetitive head and limb movements, biting, scratching and an alert appearance. These behavioural changes could result in positive readings from equipment used to measure locomotor activity, but careful investigations focussing on the nucleus accumbens used photocell boxes, activity wheels and Animex recorders to emphasise the inability of intracerebral TRH (10--40 microgram) to enhance locomotor activity. Intraaccumbens TRH also failed to enhance amphetamine hyperactivity or reduce the motor depression caused by haloperidol and analeptic drugs. The data do not support a central locomotor stimulant action of TRH.

Animals↗
PubMed1991

Stimulant effect of the beta-carboline FG 7142 in the open-field test.

The anxiogenic activity of N-methyl-beta-carboline-3-carboxamide (FG 7142) is sometimes difficult to observe in rats. As the open field has recently been applied successfully to test the anxiogenic potential of n-butyl-beta-carboline-3-carboxylate (beta-CCB) in mice, a comparable experiment was performed with FG 7142 (1, 5, 10, 30 mg/kg i.p.) in rats. In contrast to the inhibitory effects measured with beta-CCB, FG 7142 significantly increased the ambulation and rearing scores and induced aggressivity in some animals. A differential sensitivity of mice and rats to beta-carbolines, predominant analeptic properties of FG 7142, and differences in the types of anxiety induced are proposed to account for this discrepancy.

Animals↗
PubMed1987

Differential effects of caffeine, picrotoxin, and pentylenetetrazol on hippocampal afterdischarge activity and wet dog shakes.

We identified changes in hippocampal afterdischarge activity that follow administration of subcon vulsant doses (one-half the convulsant dose) of analeptic agents with known pharmacological action. Long-Evans rats (N = 104) with chronic bipolar electrodes implanted in the dorsal hippocampus, were injected i.p. with saline, caffeine (75 mg/kg), picrotoxin (2 mg/kg), or pentylenetatrazol (20 mg/kg) in 1 ml/kg volume 15 min before testing. Body temperature was measured at the beginning of the session to determine if significant change was associated with any of the treatments. Beginning at 10 microA, current (2-s train of 50-Hz biphasic pulses) was applied to hippocampal electrodes and intensity was increased in 10-microA steps until the afterdischarge sequence was elicited. Afterdischarge threshold, wet dog shake frequency, and the duration of the primary afterdischarge, the postprimary depression, and the rebound afterdischarge were measured. Caffeine administration produced a dramatic prolongation of the rebound afterdischarge, without affecting the duration of the primary afterdischarge. All other afterdischarge variables were unchanged by the caffeine treatment. Because caffeine blocks adenosine receptors at physiologic concentrations, adenosine action is implicated in the termination of the second, but not the first, spike train. Picrotoxin and pentylenetetrazol had no influence on the EEG, despite evidence of slight (1 degrees C) hypothermia. A decrease in wet dog shake frequency, however, was associated with picrotoxin administration. As picrotoxin and pentylenetetrazol are known gamma-aminobutyric acid (GABA) antagonists, the results suggest that GABA is involved minimally, if at all, in the hippocampal afterdischarge sequence.

Animals↗
PubMed1987

Nitrous oxide-induced hypothermia in the rat.

Exposure of rats to high levels of nitrous oxide (N2O) in oxygen (O2) reduced body temperature in a concentration-related manner. The hypothermia was partly reversed by pretreatment with naloxone but not naltrexone. But in rats rendered tolerant to morphine by pellet implantation, exposure to 75% N2O/25% O2 evoked a marked hypothermia similar to that observed in morphine-naive animals. In another experiment, the hypothermic effect of chloral hydrate was also sensitive to antagonism by pretreatment with naloxone but not naltrexone. These observations lead us to suspect that N2O-induced hypothermia in rats is possibly not mediated by opiate receptors. The thermotropic activity of N2O may result from some non-opioid action of N2O. Its selective antagonism by naloxone (but not naltrexone) may be due to a unique non-opioid analeptic action of naloxone.

Animals↗