Effects of amphetamine derivatives on brain dopamine and noradrenaline.
(33/50)
1. Intracisternally administered metaraminol, alpha-methyl-octopamine, alpha-methyl-m-tyramine, and alpha-methyl tyramine were found to lower brain noradrenaline without having an effect on brain dopamine.2. Amphetamine, mephentermine, and norephedrine had no effect on brain catecholamines after intracisternal injection.3. There was no reduction in brain dopamine content after intracisternal injection of alpha-methyl-m-tyramine, yet the resulting brain concentration of alpha-methyl-m-tyramine was several times higher than after intraperitoneal injection of alpha-methyl-m-tyrosine, which decreased brain dopamine.4. The decreased synthesis of labelled catecholamines from (14)C-tyrosine after alpha-methyl-m-tyrosine suggested that this compound inhibits tyrosine hydroxylase in addition to its action of displacing brain amines. (+info)
Effects of a combination of atropine, metaraminol and pyridine aldoxime methanesulfonate (AMP therapy) on normal human subjects.
(34/50)
Four hundred and seventeen medical students at the University of Toronto were used as both subjects and observers in a series of double-blind experiments to determine possible toxic effects following oral ingestion of various combinations of 2 mg. atropine, 10 mg. metaraminol and 1 g. pyridine aldoxime methanesulfonate (P(2)S). Heart rate, blood pressure, pupil diameter, and visual accommodation were measured before and at 20-minute intervals after drug administration for 100 minutes. A visual and memory perceptual test (Mackworth) was performed before and 100 minutes after drug ingestion.No toxic effects were observed following administration of the triple combination of atropine, metaraminol and P(2)S (AMP therapy). The AMP combination might be useful prophylactically for persons facing exposure to organophosphorus anticholinesterase compounds. It must not be considered an adequate substitute for treatment should poisoning occur. (+info)
The role of uptake2 in the extraneuronal metabolism of catecholamines in the isolated rat heart.
(35/50)
1. (+/-)-(3)H-NA and labelled metabolites of NA were estimated in rat hearts after perfusion with various concentrations of NA in the range 0.01-50.0 mug/ml. Labelled metabolites of NA accounted for only a small proportion of the total uptake of radioactivity at low perfusion concentrations, but accounted for 50% of the total uptake at 1 mug NA/ml., thereafter declining to progressively smaller proportions at higher perfusion concentrations.2. If the formation of labelled metabolites of (3)H-NA was blocked by a combination of monoamine oxidase and catechol-O-methyl transferase inhibitors, the accumulation of unchanged (3)H-NA was doubled when hearts were perfused with 1 mug NA/ml.3. In hearts perfused with 0.5 mug NA/ml., an accumulation of unchanged (3)H-NA was demonstrated in the presence of a combination of metabolic inhibitors and metaraminol. This appeared to be due to Uptake(2), since the accumulation of NA under these conditions could be prevented by a low concentration of normetanephrine.4. Phenoxybenzamine prevented extraneuronal uptake (Uptake(2)) and metabolism of (3)H-NA with an estimated ID50 of 2.5 muM. The inhibition of Uptake(2) by phenoxybenzamine (2.0 muM) was diminished at very high NA concentrations, suggesting that the drug may act competitively with NA.5. It was concluded that Uptake(2) operates at all catecholamine concentrations in the rat heart, but that in the lower range (less than 2.5 mug/ml. for NA and less than 0.75 mug/ml. for adrenaline) any catecholamine taken up by this process is rapidly metabolized. Thus the accumulation of unchanged amine is seen only at high perfusion concentrations.6. The relevance of these results to an understanding of the possible physiological and pharmacological importance of Uptake(2) is discussed. (+info)
An ultrastructural and histochemical study of the short-term effects of 6-hydroxydopamine on adrenergic nerves in the domestic fowl.
(36/50)
1. The effects of 6-hydroxydopamine (6-OHDA) on adrenergic nerves in the domestic fowl have been investigated with ultrastructural and fluorescence histochemical methods.2. 6-OHDA depletes the nerves of catecholamine, initially by displacing it from the storage vesicles. 6-OHDA enters large as well as small vesicles, indicating that large granular vesicles in adrenergic nerves are sites of amine storage.3. Doses of 6-OHDA, insufficient to cause degeneration, still cause loading of the vesicles.4. The effects of various drugs on the action of 6-OHDA indicate that this drug must be taken up by the nerves and reach a critical extragranular axoplasmic concentration before degeneration will occur; 6-OHDA bound in the vesicles plays no part in the degenerative process. (+info)
An investigation of alpha-methyl amino-acids and their derivatives on isolated tissue preparations.
(37/50)
1. The ability of alpha-methyl amino-acids and their corresponding amines to restore the sympathomimetic actions of tyramine, and the uptake of the amino-acids and the amines, were studied in isolated tissue preparations obtained from reserpine pretreated animals.2. Tyramine relaxed isolated rat ileum preparations from non-reserpinized rats but not from reserpine treated animals. alpha-Methyldopa, alpha-methylnoradrenaline and lower concentrations of metaraminol restored the responses of reserpinized preparations. alpha-Methyldopamine, alpha-methyl-m-tyrosine, alpha-methyl-p-tyrosine and higher concentrations of metaraminol did not do so. The restoring effect of alpha-methyldopa was blocked by disulphiram. alpha-Methyl-p-tyrosine or alpha-methyl-m-tyrosine blocked the restoring action of alpha-methyldopa but not of alpha-methylnoradrenaline. Cocaine blocked the restoration of responses to tyramine by alpha-methylnoradrenaline but not by alpha-methyldopa. alpha-Methyldopa and alpha-methylnoradrenaline failed to restore responses to tyramine in the presence of sodium-free Tyrode solution.3. Tyramine increased the perfusion pressure in isolated rabbit ear preparations obtained from non-reserpinized animals but was very much less active in preparations obtained from reserpine treated animals. alpha-Methyldopa, alpha-methyl-m-tyrosine, alpha-methylnoradrenaline, alpha-methyl-p-tyrosine and metaraminol restored the effects of tyramine. alpha-Methyldopamine did not do so. The restoring effect of alpha-methyldopa and alpha-methyl-m-tyrosine was blocked by disulfiram. alpha-Methyl-p-tyrosine blocked the restoring effect of alpha-methyl-m-tyrosine.4. Tyramine produced positive inotropic effects in isolated rabbit heart preparations. This was either reduced or absent in preparations obtained from reserpine pretreated animals. alpha-Methyldopa, alpha-methylnoradrenaline, alpha-methyl-m-tyrosine and metaraminol restored the responses to tyramine. alpha-Methyldopamine and alpha-methyl-p-tyrosine did not do so. (+info)
Actions of noradrenaline, other sympathomimetic amines and antagonists on neurones in the brain stem of the cat.
(38/50)
1. The effects of (-)-noradrenaline ((-)-NA) and related compounds on brain stem neurones in decerebrate unanaesthetized cats have been investigated using the technique of iontophoretic application from micropipettes.2. Four types of response to (-)-NA have been described. These were short lasting inhibition, long lasting inhibition, excitation, and a biphasic response consisting of short lasting inhibition followed by excitation. A variable amount of desensitization of the excitatory response, but not of inhibitory responses, was observed.3. Experiments in which small currents were used to pass (-)-NA from pipettes with smaller tips did not lead to any appreciable change in the proportions of neurones excited or inhibited.4. A variety of sympathomimetic agonists was tested. Short lasting inhibition was less sensitive than excitation to changes in molecular structure. Long lasting inhibition was more sensitive to molecular change and was not mimicked by some of the agonists which mimicked short lasting inhibition.5. Although agonists without one ring hydroxyl had weaker effects than those with both, compounds in which both ring hydroxyl groups were absent (beta-hydroxyphenylethylamine, ephedrine and amphetamine) mimicked excitation strongly. It is possible that the compounds without both ring hydroxyl groups had some effect other than simple agonistic activity.6. A dissociation was observed between responses to dopamine and (-)-NA. p-Tyramine mimicked dopamine, rather than (-)-NA.7. Neither the alpha-agonist, phenylephrine nor the beta-agonist, isoprenaline mimicked neuronal responses to (-)-NA. The alpha-antagonists phentolamine and phenoxybenzamine and the beta-antagonists dichloroisoprenaline, propranolol and D(-)-INPEA and combinations of propranolol with phentolamine or phenoxybenzamine were ineffective in blocking either excitation or inhibition. Thus, the central receptors appear to be different from peripheral alpha- and beta-receptors.8. The most effective antagonist of excitation was (-)-alpha-methylnoradrenaline. Metaraminol and dihydroergotamine also had some antagonistic activity. None of the compounds tested blocked inhibition. The effects of (-)-alpha-methylnoradrenaline have been discussed in relation to the hypotensive action of alpha-methyldopa. (+info)
Importance of noradrenaline found in a functional pool in maintaining spontaneous locomotor activity in rats.
(39/50)
1. Spontaneous locomotor activity (activity) in male Wistar rats was compared with the concentrations of brain noradrenaline (NA), dopamine (DA) and metaraminol.2. alpha-Methyl-m-tyrosine (alphaMMT) (400 mg/kg) reduced the concentrations of DA as well as NA but activity remained high in the presence of metaraminol formed from the alphaMMT. When tetrabenazine (TBZ) was given after alphaMMT pretreatment there was a fall in the levels of activity and in the concentrations of NA, DA and metaraminol.3. alpha-Methyl-p-tyrosine (alphaMT) produced a fall in activity which was correlated with falls in the concentrations of NA and DA. 5-Hydroxytryptamine (5-HT) did not appear to be affected.4. After depletion of NA and DA by alphaMT and TBZ, administration of L-dopa produced a return in activity which was significantly correlated with the concentration of NA but not DA. When alphaMMT was given to a similar group of pretreated animals there was no recovery of activity despite high concentrations of DA and metaraminol.5. The dopamine beta hydroxylase inhibitor, diethyldithiocarbamate (DDC), suppressed activity as well as the concentrations of NA and DA at high doses (750 mg/kg) but smaller doses (400 mg/kg) plus L-dopa gave high DA concentrations without activity.6. It is concluded that NA and not DA is associated with activity but that it is only part of the total NA which is in the biosynthetic storage granule affected by drugs like alphaMT and TBZ, which controls activity. Drugs that do not affect this pool may lower NA concentrations but not reduce activity.7. The replacement of NA by metaraminol in this functional pool does not restore activity. (+info)
Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine.
(40/50)
1. After intracisternal administration, 6-hydroxydopamine had a greater effect on brain noradrenaline than on dopamine.2. Administration of two doses of 6-hydroxydopamine increased the depletion of noradrenaline but not of dopamine.3. Small doses of 6-hydroxydopamine decreased the concentration of noradrenaline with little or no effect on dopamine. Tyrosine hydroxylase activity was not reduced with these treatments.4. While pargyline pretreatment offered no advantage in the depletion of brain noradrenaline after 6-hydroxydopamine, depletion of brain dopamine was greatly potentiated by this treatment. The reduction of striatal tyrosine hydroxylase activity observed after 6-hydroxydopamine was also potentiated by pargyline pretreatment.5. The amounts of labelled noradrenaline and dopamine formed from (3)H-tyrosine were greatly reduced by 6-hydroxydopamine treatment. After (3)H-DOPA, formation of noradrenaline was greatly reduced while formation of labelled dopamine was only moderately reduced suggesting that decarboxylation of DOPA can occur in other than catecholamine containing neurones.6. Desmethylimipramine and imipramine inhibited depletion of noradrenaline produced by 6-hydroxydopamine but did not alter depletion of dopamine. Reserpine did not inhibit depletion of catecholamines produced by 6-hydroxydopamine.7. Administration of 6-hydroxydopamine to developing rats lowered both noradrenaline and dopamine concentrations as well as the tyrosine hydroxylase activity in the brains of these animals. (+info)