Showing papers in "Naunyn-schmiedebergs Archives of Pharmacology in 1973"
TL;DR: Gammahydroxybutyric acid may act by directly or indirectly mimicking an inhibitory GABA mechanism on the dopamine cells in the substantia nigra, which induced increases in brain dopamine of rats.
Abstract: Injections of gammahydroxybutyric acid or gammaaminobutyric acid (GABA), but not betahydroxybutyric acid or carnitine, into the substantia nigra induced increases in brain dopamine of rats. No effect was found after injections into the neostriatum. The noradrenaline in the forebrain was unchanged after all the treatments. Gammahydroxybutyric acid may act by directly or indirectly mimicking an inhibitory GABA mechanism on the dopamine cells in the substantia nigra.
190 citations
TL;DR: A delayed rise and the secondary decline of cyclic AMP levels after hormonal stimulation can be accounted for by adenosine released from fat cells.
Abstract: The effect of lipolytic stimulants on cyclic AMP levels and glycerol production is strongly dependent on the concentration of fat cells in the incubation medium After addition of noradrenaline cyclic AMP levels in diluted fat cell suspensions (20 000 cells/ml) reached 10 fold higher levels and declined much more slowly than in concentrated cell suspensions (100 000 cells/ml) An inhibitory substance appeared in the incubation medium which, after addition to a suspension of fresh fat cells caused a dose-dependent inhibition of hormone effects The inhibitor was produced during preincubation periods of the fat cells and was removed by washing the cells with fresh medium
189 citations
TL;DR: The assay procedures are based both on the native fluorescence of 5-hydroxyindoles in strong acid and on the considerably higher fluorescence intensity of the fluorophores obtained by means of condensation with orthophthaldialdehyde.
Abstract: Procedures for the fluorimetric assay of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-hydroxyindole-3-acetic acid in tissues are described. The assay procedures are based both on the native fluorescence of 5-hydroxyindoles in strong acid and on the considerably higher fluorescence intensity of the fluorophores obtained by means of condensation with orthophthaldialdehyde. A tissue blank procedure, utilizing potassium ferricyanide and cysteine, common to both assays in the joint procedure, is incorporated. The assays have been adjusted to previously described chromatographic procedures, using a strongly acidic cation exchange column, in which these 5-hydroxyindoles and their precursor, tryptophan, and also other biogenic amines and related compounds, are isolated from a single Dowex 50 column. Data illustrating the reproducibility, sensitivity and increased specificity of the overall procedures compare favourably with previously published results. The possibility of the differential estimation of different 5-hydroxyindoles in a mixture, by means of simultaneous determinations of native and orthophthaldialdehyde-condensate fluorescence in the joint assays, is pointed out.
173 citations
TL;DR: The different time course for DA and NA suggests that part of the spinal DA serves an independent non-precursor role.
Abstract: For intervals up to 15 days after transection of the rat spinal cord the level of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were studied above and below the lesions. In the upper part NA, DA and 5-HT increased continuously, while 5-HIAA increased during the first 3 to 5 days and then returned to its original level. In the lower part NA had disappeared almost completely after 15 days, DA after 9 days, 5-HT and 5-HIAA after 5 days. During the first day after transection 5-HT showed an increase in the lower part as did DA for the first 3 days. The different time course for DA and NA suggests that part of the spinal DA serves an independent non-precursor role.
150 citations
TL;DR: It is concluded that the non-specific membrane affinity of the β-sympatholytics can be predicted by the determination of their octanol-buffer partition coefficients, or even by simple calculation of their respective Σπ-values.
Abstract: In order to characterize the non-specific membrane affinity of β-adrenergic blocking agents (phenylethanolamino- and phenoxypropanolaminoderivatives), hydrophobicity (i. e. partition coefficients) and surface activity were determined as physicochemical properties of the drugs. Local anaesthetic activity (isolated frog nerve) and effects on myocardial conduction velocity (frog heart) were used as pharmacological parameters. In addition, the hydrophobicity of the β-sympatholytics was calculated according to the method of Hansch and Fujita (1964).
141 citations
TL;DR: The increases in brain DA described may be due to an inhibition of the nerve impulse flow to the DA nerve terminals to prevent the increase in DA observed after hemisection or treatment with GHBA.
Abstract: Both a unilateral, frontal section of the brain at the level of the caudal hypothalamus (hemisection) and systemic treatment with gammahydroxybutyric acid (GHBA, sodium form, 1.5 g/kg i.p.) increased the dopamine (DA) in the rat forebrain by about 70% in 1 h. Both procedures also markedly decelerated the α-methyltyrosine-induced DA disappearance. The brain noradrenaline was significantly lowered after the hemisection, but was not influenced by the treatment with GHBA given either alone or in combination with α-methyltyrosine.
123 citations
TL;DR: The findings indicate that the inhibitory phase of the sympathetic discharge pattern during central stimulation is due to the rise in blood pressure and the ensuing baroreceptor-reflex activation.
Abstract: Arterial blood pressure, heart rate and discharges in the preganglionic splanchnic and a postganglionic renal sympathetic nerve were recorded in cats anaesthetized with urethane. Electrical stimulation of the posterior hypothalamus or the fastigial nucleus of the cerebellum elicited an immediate increase in sympathetic nerve activity and a rise in blood pressure and heart rate. The stimulation-induced discharge pattern in the sympathetic nerves was characterized by a strong initial burst followed by a phase of inhibition and a final stabilization of the discharges at a level definitely lower than the initial burst. This pattern was reversibly converted into a constant high amplitude firing during a lowering of the blood pressure by bleeding the cats and irreversibly so after cutting the buffer nerves. These findings indicate that the inhibitory phase of the sympathetic discharge pattern during central stimulation is due to the rise in blood pressure and the ensuing baroreceptor-reflex activation.
118 citations
TL;DR: The results suggest that, in addition to noradrenaline, the integrity of central dopaminergic systems may be essential for the behavioral expression of certain motivational processes.
Abstract: Drugs preferentially influencing dopaminergic neurotransmission mechanisms were administered to rats which lever-pressed to receive electrical stimulation in either the lateral hypothalamus or periaqueductal mesencephalon The same drug effects were observed regardless of the site of electrical stimulation Blockade of dopamine receptors by 035 or 05 mg/kg pimozide reduced self-stimulation rates Increasing the reward value of the stimulation by doubling of self-stimulation current induced control rates of lever-pressing in animals given 035 mg/kg pimozide but not in those receiving 05 mg/kg At doses of 075 and 15 mg/kg, apomorphine, a putative dopamine receptor stimulator, reduced self-stimulation rates at normal current Doubling of the stimulation current produced greater than normal rates of lever-pressing at 075 mg/kg apomorphine, but at 15 mg/kg no such increase in rate was observed l-DOPA, 75 and 150 mg/kg, also reduced self-stimulation, but doubled current restored rates to control levels at both doses For comparison purposes, pharmacological effects on predominantly noradrenergic mechanisms were also studied Inhibition of dopamine-β-hydroxylase by 150 mg/kg disulfiram reduced self-stimulation under normal current, but rates were increased to above control levels with doubled current That self-stimulation behavior could be reinstated by doubling of current suggests that motor incapacity is not a sufficient explanation for most of the observed reductions in lever-pressing rate These results further suggest that, in addition to noradrenaline, the integrity of central dopaminergic systems may be essential for the behavioral expression of certain motivational processes
114 citations
TL;DR: The results indicate that an α-receptor-mediated feed-back control of noradrenaline release, previously demonstrated in postganglionic sympathetic nerves, also operates in central Noradrenergic neurones.
Abstract: Slices of rat cerebral cortex were preincubated with 10−7 M (-)-3H-noradrenaline, and the outflow of tritium was determined. Oxymetazoline, phentolamine and cocaine did not change the spontaneous efflux. The overflow of tritium evoked by electrical field stimulation was decreased by oxymetazoline, and enhanced by phentolamine, phenoxybenzamine, and cocaine. Oxymetazoline did not counteract the increase of the stimulation-induced overflow caused by cocaine, but strongly antagonized the increase caused by phentolamine and phenoxybenzamine. When the stimulation-induced overflow was large under control conditions (high frequency of stimulation, addition of cocaine), the inhibitory effect of oxymetazoline was diminished. The results indicate that an α-receptor-mediated feed-back control of noradrenaline release, previously demonstrated in postganglionic sympathetic nerves, also operates in central noradrenergic neurones.
102 citations
TL;DR: During anaerobic incubation with NADPH-reduced liver microsomes from phenobarbital pretreated rabbits, 14C-labelled halothane (1 mM) was covalently bound to microsomal proteins at a rate of 2 nmol/mg protein in 30 min (CCl4: 11 nmol/.
Abstract: 1.
In suspensions of rabbit liver microsomes reduced by dithionite or NADPH, halothane produces a difference absorption spectrum with a maximum at 473 nm and a minimum at 408 nm. The “optical affinity” (Ks) was in the region of 3–6×10−6 M for dithionite reduced microsomes. The maximal absorption with dithionite reduced microsomes for halothane (473–550 nm) was 0.017–0.019 and for CCl4 (454–500 nm) 0.04–0.05 per nmol of cytochrome P-450. The appearance of the difference absorption with halothane is faster than that with CCl4.
2.
During anaerobic incubation with NADPH-reduced liver microsomes from phenobarbital pretreated rabbits, 14C-labelled halothane (1 mM) was covalently bound to microsomal proteins at a rate of 2 nmol/mg protein in 30 min (CCl4: 11 nmol/mg protein in 30 min). Reduction by dithionite was ineffective. The binding of halothane was 60% inhibited in a gas phase of air, 75% by CO, 55% in the presence of 1 mM metyrapone, 50% by CCl4, but only 20% by red. glutathione. The binding of the radioactivity from labelled halothane and CCl4 to proteins of isolated rabbit lung and kidney microsomes was approximately proportional to the concentrations of cytochrome P-450 in the organ fractions.
3.
Like CCl4, halothane (1 mM) inhibited several microsomal drug oxidation reactions.
4.
Irreversible binding of halothane or its metabolite(s) to endoplasmic proteins might be connected with halothane liver damage.
96 citations
TL;DR: This preparation provides a possibility for studying the transmitter release in a preparation in which any interaction with prostaglandins was in all likelihood excluded, and direct evidence for the presynaptic inhibitory effect of α-adrenoceptor stimulation on transmitter release is provided by measuring the release of 3H-noradrenaline.
Abstract: It had been shown previously that in rat vas deferens prostaglandins fail to influence neurochemical transmission. Therefore, this preparation provides a possibility for studying the transmitter release in a preparation in which any interaction with prostaglandins was in all likelihood excluded.
TL;DR: Under the conditions chosen in these experiments there seems to exist only one binding site of the same type for all investigated benzodiazepines at the HSA molecule.
Abstract: The binding of eleven benzodiazepine derivatives to human serum albumin (HSA) was determined by means of sephadex gel filtration. The albumin binding of the substances was characterized by the percentage of bound drug, the binding constants k
+, K
1 and m, the number of binding sites per albumin molecule, and the free binding energy. Under the conditions chosen in these experiments there seems to exist only one binding site of the same type for all investigated benzodiazepines at the HSA molecule. The affinities of the benzodiazepines to this binding site are very different. It is discussed which part of the benzodiazepine molecule represents the main binding group.
TL;DR: It is concluded that superfusion with high concentrations of GABA enhances the pressor response by increasing the release of catecholamines, while the effect of low GABA concentrations is due to facilitation of release ofcatecholamine from the adrenergic nerve endings during electrical stimulation.
Abstract: The third ventricle and the aqueduct of anaesthetized cats were cannulated and the posterior area of the hypothalamus was stimulated with a monopolar electrode. Electrical stimulation of the posterior area evoked a rise of the arterial blood pressure which was inhibited by the injection of 0.2 ml of gammaaminobutyric acid (GABA, 2M) into the third ventricle. The impairment of the pressor response to electrical stimulation was accompanied by a fall of the “resting” blood pressure and depression of the respiration, presumably by action of GABA on brain areas in the vicinity of the fourth ventricle. In another series of experiments the posterior area was labelled with (±)-3H-noradrenaline and 2 h later superfused with a push-pull cannula and stimulated with the tip of the cannula. Superfusion with GABA (0.1 or 1 M) evoked a dose-dependent increase of release of catecholamines and enhanced the pressor response to electrical stimulation. 1×10−3 M of GABA enhanced the pressor response without increasing the spontaneous release of catecholamines but potentiated the output of radioactivity during electrical stimulation. Superfusion with sucrose (1 M) did not influence either pressor response or release of radioactive compounds. Superfusion with GABA increased slightly but significantly the relative concentration of catechols in the effluents and reduced that of normetanephrine. Pretreatment of animals with pargyline and tropolone evoked a pronounced increase of the relative concentrations of catechols in the effluent, while those of 3-methoxy-4-hydroxyphenylglycol and 3-methoxy-4-hydroxymandelic acid were strongly reduced. It is concluded that superfusion with high concentrations of GABA enhances the pressor response by increasing the release of catecholamines, while the effect of low GABA concentrations is due to facilitation of release of catecholamines from the adrenergic nerve endings during electrical stimulation.
TL;DR: Cat papillary muscles were depolarized by raising the external K concentration so that resting potential went from about −80 mV to −50 mV, which caused inactivation of the transmembrane Na system, and the remaining Ca-mediated action potentials showed greater overshoot, reduced upstroke velocity and action potential duration, and higher threshold of excitation.
Abstract: Cat papillary muscles were depolarized by raising the external K concentration so that resting potential went from about −80 mV to −50 mV. This caused inactivation of the transmembrane Na system. The remaining Ca-mediated action potentials showed greater overshoot, reduced upstroke velocity and action potential duration, and higher threshold of excitation. A graded electrical response to stimulous strength was also present. These action potentials depended mainly on the extracellular Ca concentration [16]. Further, the specific Ca-antagonistic compounds verapamil and D 600 [10] or Ca-with-drawal completely abolished the ability of the K-depolarized fibres to respond to stimulation with propagated electrical activity. Conversely, extra Ca, epinephrine or isoproterenol overcame this inhibitory effect by increasing the Ca transmembrane influx. Also, within 1 min after returning treated muscles to normal K
0 Tyrode solution, the Na system was reactivated and apparently normal electrical activity possible. In this case, Ca-withdrawal and the Ca-antagonists lose their electrical inhibitory influence, while excitation-contraction uncoupling still persist.
TL;DR: It is tentatively suggested that adenosine may be involved in the physiological control of lipolysis and that this nucleoside has its site of action on the cell membrane.
Abstract: Basal lipolysis in isolated fat cells of rats was increased by adenosine in a dose-dependent manner. Low concentrations of this nucleoside (1–10 μM) inhibited noradrenaline-induced glycerol production by about 50% and completely blocked the effect of theophylline on fat cells. Glycerol release, induced by dibutyryl cyclic AMP, was increased by 5 μM adenosine. Inosine, hypoxanthine, and xanthine had weaker antilipolytic properties, whereas adenine was virtually without effect.
TL;DR: It was concluded that theTime course of the inotropic response to ouabain parallels the time course of (Na++K+)-activated ATPase inhibition, and that the dissociation of ouABain from the enzyme may terminate the inotrop response.
Abstract: The time course of the inotropic response to ouabain in Langendorff preparations was compared with that of the in vitro ATP-dependent (3H)-ouabain binding to cardiac (Na++K+)-activated ATPase preparations, and subsequent dissociation, to determine the temporal relationship between the inotropic response and (Na++K+)-activated ATPase inhibition. Species differences were minimal either in the onset of inotropic response or the (3H)-ouabain binding. The rates of both loss of the inotropic response to ouabain during washout and the dissociation of the ouabain-enzyme complex, however, were rapid in guinea pig and rabbit (relatively ouabain-insensitive species) and slow in cat and dog (ouabain-sensitive species). The half-time of the loss of the inotropic response was similar to the half-time of the dissociation of the ouabain-enzyme complex in each species. Since ATP-dependent binding of cardiac glycosides has been related to enzyme inhibition, it was concluded that the time course of the inotropic response to ouabain parallels the time course of (Na++K+)-activated ATPase inhibition, and that the dissociation of ouabain from the enzyme may terminate the inotropic response.
TL;DR: It was shown that the toxin, by acting on the presynaptic apparatus, disturbs the neuromuscular transmission in tetanus intoxication andFragments of antitoxin [F(ab′)2 and Fab′] are more effective for complete neutralization of toxin bound on protagon than the initial JgG-antitoxin.
Abstract: 1.
In experiments involving injection of tetanus toxin into the rat diaphragm it was shown that the toxin, by acting on the presynaptic apparatus, disturbs the neuromuscular transmission.
2.
Electron microscopic investigation does not reveal any visible ultrastructural changes in neuromuscular and axosomatic synapses of spinal motoneurons in tetanus intoxication. However, synaptic vesicles accumulate in the axon terminals.
3.
Neuraminidase splits off the sialic acid and liberates the toxin from the protagon-tetanus toxin complex.
4.
Toxin neutralized by antitoxin is still able to react with protagon.
5.
Toxin bound to protagon can be neutralized by antitoxin; when neutralized, the toxin is retained in complex with protagon. Partial neutralization of the toxicity of the protagon-toxin complex is effected by small amounts of antitoxin; complete neutralization of residual toxicity requires comparatively greater amounts of antitoxin.
6.
Fragments of antitoxin [F(ab′)2 and Fab′] are more effective for complete neutralization of toxin bound on protagon than the initial JgG-antitoxin.
7.
Injections of antitoxin into the cisterna magna during the incubation period and at earlier stages of experimental tetanus ascendens and descendens are more effective than intramuscular, intravenous or intracarotid injections. At later stages of intoxication all ways of antitoxin injection used are ineffective.
8.
The tetanus toxin molecule has at least three groupings; one of them is responsible for the binding on its receptor in brain substance, the other for the interaction with antitoxin and the third for tis specific toxic effect.
TL;DR: The antihypertensive drug clonidine increased the secretion of gastric acid in apparently the same way as histamine did, i.e. by stimulation of H2-receptors and subsequent increase in the formation of cAMP.
Abstract: In the presence of theophylline (10−3 M), histamine stimulated the production of cAMP by minced gastric tissue of guinea pigs in a dose-dependent manner. This stimulation was competitively inhibited by the histamine2-receptor blocking agent burimamide but not by the histamine1-receptor blocking agent diphenhydramine. Since the histamine-stimulated secretion of acid by the stomach is also inhibited by blockade of H2-receptors but not by blockade of H1-receptors, our findings support the role of cAMP as the mediator in the action of histamine on the secretion of gastric acid.-The antihypertensive drug clonidine increased the secretion of gastric acid in apparently the same way as histamine did, i.e. by stimulation of H2-receptors and subsequent increase in the formation of cAMP.
TL;DR: The results of these investigations are in favour of the hypothesis that in the brain stem an α-receptor mechanism exists, which is able to mediate a blood pressure decreasing effect of centrally applied catecholamines.
Abstract: Experiments in cats with perfusion of the fourth and parts of the third cerebral ventricle gave the following results:
1.
Perfusions with α-methyldopa, α-methyldopamine, α-methylnoradrenaline, noradrenaline, or tyramine produced a significant decrease of the systemic arterial blood pressure. A dose-response relationship of this effect was demonstrated with noradrenaline and α-methylnoradrenaline.
2.
The blood pressure lowering effect of the amines was inhibited or abolished by perfusion with phentolamine or yohimbine.
3.
The depressor effect of perfusions with tyramine was inhibited after addition of 2μg/ml cocaine to the perfusion fluid. Cocaine perfusion enhanced the depressor effect of α-methylnoradrenaline.
4.
In the reserpine-pretreated cat the effect of tyramine was strongly inhibited. α-Methylnoradrenaline had no effect under these conditions.
5.
Perfusions with angiotensin produced an increase of the peripheral blood pressure, while isoprenaline and propranolol showed no significant activity.
6.
In the intact anaesthetized, as well as in the spinal, cat the intravenous pressor activities of noradrenaline and α-methylnoradrenaline were nearly identical. The response of the isolated aortic strip of the rat was somewhat more pronounced to α-methylnoradrenaline than to noradrenaline.
7.
The results of these investigations are in favour of the hypothesis that in the brain stem an α-receptor mechanism exists, which is able to mediate a blood pressure decreasing effect of centrally applied catecholamines. The central hypotensive action of α-methyldopa may be explained by this mechanism.
TL;DR: The authors showed that α-methylnoradrenaline had only a weak depressant action, and that the depressions do not represent a non-specific depression by noradrenergic of the neuronal membrane.
Abstract: Noradrenaline and pharmacologically related substances have been applied to identified pyramidal tract cells in the cerebral cortex of rats anaesthetised usually with urethane. 64% of these cells were depressed by noradrenaline, and this response could be potentiated by iproniazed. It could also be blocked occasionally by phentolamine, and more frequently by propranolol, and was mimicked closely by isoprenaline. α-methylnoradrenaline had only a weak depressant action. This specific blockade of noradrenaline depressions, suggests that noradrenaline may be acting on receptors resembling β-receptors in the periphery, and that the depressions do not represent a non-specific depression by noradrenaline of the neuronal membrane. There was no correlation between cells responding to noradrenaline and cells responding to thalamic, transcallosal or epicortical stimulation. Noradrenaline is therefore concluded not to be a transmitter in pathways from these sites.
TL;DR: Experiments on the canine SA node preparation cross-circulated with the arterial blood from the donor dog through the cannulated sinus node artery indicate that the deceleration response induced by subthreshold electrical stimulation is due to excitation of preganglionic fibres of the parasympathetic nerve, contradict previous observations in excised atria perfused with physiological salt solution.
Abstract: Experiments were conducted on the canine SA node preparation cross-circulated with the arterial blood from the donor dog through the cannulated sinus node artery The sinus rate of 98±4 beats/min persisted with a regular rhythm over 10 h Subthreshold electrical stimulation to the myocardium was applied to various portions of the right atrium Stimulation of the caval margin caused a simple deceleration of the sinus rate, and a portion slightly anterior to the mid-point between the two caval ostia was most sensitive Stimulation at the portion where the sinoatrial node was supposed to be caused far less deceleration, while that at the atrial free wall failed to affect sinus rhythm The negative chronotropic response to subthreshold electrical stimulation was abolished either by injection of hexamethonium or pempidine, or by that of tetrodotoxin or atropine into the sinus node artery, while physostigmine enhanced it These results indicate that the deceleration response induced by subthreshold electrical stimulation is due to excitation of preganglionic fibres of the parasympathetic nerve On the other hand, the propranolol-sensitive acceleration did not occur until myocardial excitation was induced by a stronger intensity of stimulation This suggests that the sympathetic postganglionic fibres have a higher electrical threshold than the parasympathetic preganglionic fibres These results contradict previous observations in excised atria perfused with physiological salt solution in which hypoxia of the peripheral neurone cannot be avoided
TL;DR: It is suggested that adrenergic neurones ascending from the locus coeruleus to the posterior hypothalamus may be involved in the hypothalamic regulation of the arterial blood pressure.
Abstract: Electrical stimulation of the locus coeruleus or of the hypothalamic posterior area of cats under pentobarbitone anaesthesia elicited a rise of the arterial blood pressure. Electrocoagulation of the hypothalamic posterior area or its lesion by the injection of ethanol significantly diminished the pressor response to electrical stimulation of the locus coeruleus. The pressor response to electrical stimulation of the area posterior was almost completely abolished after electro-coagulation and strongly inhibited after injection of ethanol. It is suggested that adrenergic neurones ascending from the locus coeruleus to the posterior hypothalamus may be involved in the hypothalamic regulation of the arterial blood pressure.
TL;DR: The increase in brain DA usually observed after axotomy was not found when the rats were also treated with reserpine and nialamide, indicating that the negative feed-back of cytoplasmic DA on the DA synthesis operates also in the absence of nerve impulses.
Abstract: The influence of blockade or stimulation of dopamine (DA) receptors on the selective increase in brain DA seen after axotomy or injection of gammahydroxybutyric acid (sodium form, 1.5 g/kg i.p.) was studied in rats. The increases were not changed after blockade of the DA receptors by haloperidol but were slightly reduced after stimulation of these receptors by apomorphine. Since pretreatment with haloperidol counteracted this effect of apomorphine, a diminished stimulation of DA receptors may partially be responsible for the increase in brain DA seen when the nerve impulse flow has been blocked in the DA neurones by axotomy or treatment with gammahydroxybutyric acid. The NA content was usually somewhat lowered on the lesioned side and this reduction was not changed after treatment with haloperidol, apomorphine or amphetamine. The increase in brain DA usually observed after axotomy was not found when the rats were also treated with reserpine and nialamide. This effect indicates that the negative feed-back of cytoplasmic DA on the DA synthesis operates also in the absence of nerve impulses. Injection of amphetamine before or after axotomy or treatment with gammahydroxybytyric acid markedly inhibited the increase in brain DA, probably due to release of newly synthesized DA.
TL;DR: In this article, no significant interaction was observed for phentermine in NMR-binding studies with phosphatidylcholine, which is known to interfere with lipid metabolism in vivo.
Abstract: Chlorphentermine which is known to interfere with lipid metabolism in vivo shows strong interaction with phosphatidylcholine in NMR-binding studies. This complexation is supposed to alter the phospholipid metabolism thus giving rise to intracellular accumulation of lipids. No significant interaction was observed for phentermine.
TL;DR: Changes in cAMP precede the increase in isotonic contractions brought about by isoprenaline, histamine or oxyfedrine in maximum effective doses, and also clearly precedes the decrease in the inotropic effect of isop Renaline or histamine.
Abstract: Experiments in isolated, perfused guinea-pig hearts (Langendorff) have shown that
1.
Inotropic effects of catecholamines and histamine are potentiated by the PDE-inhibitor theophylline, but antagonized by the PDE-activators imidazole or N-methyl-imidazole.
2.
Maximum effective doses of isoprenaline (0.5 μg) or histamine (10 μg) increase cardiac cAMP 4–5-fold at 15 sec after injection whereas maximum effective doses of oxyfedrine (10 μg) produce a 2-fold increase in cAMP at 15 sec, along with a considerably weaker inotropic response than isoprenaline or histamine.
3.
Changes in cAMP precede the increase in isotonic contractions brought about by isoprenaline, histamine or oxyfedrine in maximum effective doses, and also clearly precede the decrease in the inotropic effect of isoprenaline or histamine.
4.
No dissociation between the increase in cAMP and the positive inotropic effect was observed after very small doses of isoprenaline or histamine which only increased the amplitude of contraction by about 12–14%. A significant correlation (r=0.94, p<0.01) between increases in isotonic contractions and increases in cAMP was found over the whole tested dose range of both compounds.
5.
Increases in cAMP as well as in contractions induced by 2 μg of histamine—in contrast to an equieffective dose of 0.1 μg of isoprenaline—were not blocked by the β-blocking compound Ko 592 (50 μg), demonstrating again a close relationship between cAMP and inotropic effect of histamine or isoprenaline.
6.
The data support the mediator role of cAMP for the inotropic effect of substances which activate the adenyl cyclase system in the heart.
TL;DR: Incubation with 14C-dopamine or 14C(±)-noradrenaline revealed that the vesicles were able to take up catecholamines by two different transport mechanisms; one was dependent on ATP, magnesium and temperature, the other one was independent of ATP and magnesium, and partially dependent on temperature.
Abstract: Dopamine storing vesicles were isolated from the caudate nucleus of the pig by differential centrifugation and incubated at various temperatures. The spontaneous release of endogenous dopamine was temperature-dependent. Incubation with 14C-dopamine or 14C(±)-noradrenaline revealed that the vesicles were able to take up catecholamines by two different transport mechanisms; one was dependent on ATP, magnesium and temperature, the other one was independent of ATP and magnesium, and partially dependent on temperature. The Km of the ATP-magnesium-dependent uptake was 1.52×10−6 M for dopamine and 3.45×10−6 M for noradrenaline. Incubation with dopamine increased the dopamine content of the vesicles and diminished the endogenous dopamine by approximately 90%. Addition of ATP and magnesium further increased the dopamine content without influencing the per cent exchange between endogenous and exogenous dopamine. The dopamine uptake at 37°C in the presence of ATP and magnesium was of short duration because of the thermo-lability of the vesicles. (+)-amphetamine competitively inhibited the ATP-magnesium-dependent uptake of dopamine and noradrenaline. Amantadine and desipramine influenced neither the ATP-magnesium-dependent nor the ATP-magnesium-independent uptake of the catecholamines.
TL;DR: Alpha-adrenoreceptors are present in the posterior hypothalamus and are involved in the blood pressure rise elicited by its electrical stimulation, and two adrenergic systems localized in different areas of the central nervous system oppose each other in their regulatory effects on arterial blood pressure.
Abstract: The posterior area of the hypothalamus of anaesthetized cats was superfused with artificial cerebrospinal fluid through a push-pull cannula. Electrical stimulation with the non-insulated tip of the cannula elicited a rise of the mean arterial blood pressure. Superfusion of the hypothalamic posterior area with tolazoline or piperoxan caused a dose-dependent inhibition of the pressor responses to electrical stimulation. Labelling of the posterior area with 3H-noradrenaline 2 h before the beginning of the superfusion showed that the inhibitory effect of tolazoline on the pressor responses was accompanied by an increased release of total radioactivity and an enhanced per cent release of 3H-noradrenaline, while that of its metabolites was reduced. Superfusion of the nucleus of the solitary tract with clonidine evoked a dose-dependent inhibition of the pressor responses to electrical stimulation of the ipsilateral hypothalamic posterior area. It is concluded that 1. Alpha-adrenoreceptors are present in the posterior hypothalamus and are involved in the blood pressure rise elicited by its electrical stimulation. 2. A feedback mechanism is present in the hypothalamus which regulates the release of noradrenaline and which is mediated by alpha-adrenoreceptors; inhibition of the regulation of the release of noradrenaline by alpha-adrenoreceptors blocking agents leads to an enhanced release of the neuro-transmitter. 3. Activation of the inhibitory pathways of the nucleus of the solitary tract by clonidine diminishes the pressor response to electrical stimulation of the hypothalamic posterior area. 4. Two adrenergic systems localized in different areas of the central nervous system oppose each other in their regulatory effects on arterial blood pressure.
TL;DR: The lesion studies give some support to the suggestion made on the basis of initial drug interaction studies that the stereotypic effects of ET495 may be induced via an effect upon presynaptic catecholaminergic events.
Abstract: The role of catecholaminergic systems in the mediation of ET495 stereotyped behaviour was investigated using agents known to modify presynaptic events. Pretreatment with the benzoquinolizine derivatives tetrabenazine and Ro 04-1284 and the indole derivatives oxypertine and solypertine, agents considered to exert their effects via depletion of catecholamines from the terminal storage granules, was found to reduce or abolish the stereotypic effects of ET495. Similarly, inhibition of the synthesis of catecholamines at the tyrosine hydroxylation stage using α-methyl-para-tyrosine was also found to reduce or abolish the effect of ET495. These observations suggest that presynaptic events are important for the mediation of the stereotypic effect of ET495.
TL;DR: The results support the hypothesis of prostaglandins as modulators of hormone effects and vascular responses to both angiotensin and vasopressin and capsular responses to angiotENSin are augmented.
Abstract: Isolated perfused cat spleens release prostaglandins E and F in response to the injection of angiotensin, an agent which produces contraction of vascular and capsular smooth muscle. The injection of vasopressin, which acts exclusively on the vasculature, releases only prostaglandin E. The release of all prostaglandins is abolished by perfusion of the spleen with 2 μg/ml indomethacin. After inhibition of synthesis and, consequently, of release of prostaglandins vascular responses to both angiotensin and vasopressin and capsular responses to angiotensin are augmented. The results support the hypothesis of prostaglandins as modulators of hormone effects.
TL;DR: Synthesis and release of 3H-DA were examined during the continuous superfusion of a limited area of the ventricular surface of the cat caudate nucleus with l-3,5-3H-tyrosine, using a cup technique and Alpha-methyl-paratyrosine inhibited rapidly and simultaneously both 3H−H2O formation and 3h-DA release.
Abstract: Synthesis and release of 3H-DA were examined during the continuous superfusion of a limited area of the ventricular surface of the cat caudate nucleus with l-3,5-3H-tyrosine, using a cup technique. 3H−H2O, an index of the conversion of l-3,5-3H-tyrosine into 3H-Dopa, and 2H-DA were estimated in serial superfusate fractions. Alpha-methyl-paratyrosine (α-MpT) (10−4 M) inhibited rapidly and simultaneously both 3H−H2O formation and 3H-DA release. Transection of the nigro-striatal dopaminergic pathway immediately blocked 3H-DA release but 3H−H2O levels were reduced by 30% one hour later.