Demonstration and distribution of phenylethanolamine in brain and other tissues.
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A specific and sensitive assay for phenylethanolamine in tissues is described. By this assay, phenylethanolamine was detected in many peripheral tissues and brains of rats. It is unequally distributed in rat brain, with the highest concentration present in hypothalamus and midbrain. Concentrations of brain phenylethanolamine were elevated after administration of phenylethylamine, phenylalanine, p-chlorophenylalanine, and monoamine oxidase inhibitors and decreased after administration of dopamine-beta-hydroxylase inhibitors. Denervation of sympathetic nerves caused a moderate fall in phenylethanolamine concentrations. These results indicate that phenylethanolamine is synthesized intraneuronally from phenylalanine and phenylethylamine, but that only part of the phenylethanolamine is stored in sympathetic nerves. (+info)
Interaction of cannabis and general anaesthetic agents in mice.
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1 A cannabis extract (I) (in a concentration equivalent to 10 mg Delta(9)-tetrahydro-cannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.2 The cannabis extract (I) (equivalent to 10 mg Delta(9)-THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.3 A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Delta(9)-THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.4 Delta(8)-THC, Delta(9)-THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Delta(9)-THC. Cannabinol (10 mg/kg) was inactive.5 The effects of cannabidiol and Delta(9)-THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Delta(9)-THC and cannabidiol when given in combination.6 Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, alpha-methyl tyrosine or parachlorophenylalanine did not affect the extract I-induced prolongation of pentobarbitone anaesthesia.7 It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis-induced prolongation of anaesthesia is probably unrelated to any effect on central 5-hydroxytryptamine or catecholamine neurones. (+info)
The responses of thalamic neurons to iontophoretically applied monoamines.
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1. The effects of noradrenaline (NA), adrenaline, dopamine (DA) 5-hydroxytryptamine (5-HT) and a number of related drugs were tested on the extracellularly recorded responses of neurones in the feline thalamus. Substances were applied iontophoretically and tested on synaptically, antidromically and chemically evoked neuronal activity.2. NA, adrenaline, isoprenaline and 5-HT had a variety of effects, depressing some cells, exciting others and not affecting the responses of a third group. DA depressed most of the cells tested; excitation was not observed with this compound.3. The magnitude of depressant actions and their duration varied considerably. The more sensitive cells responded to extremely small amounts of catecholamine or 5-HT and recovery often took several minutes. Recovery after DA was always rapid. Neurones in the dorsal thalamus were generally more susceptible to depression than those in the ventro-basal complex.4. Excitatory responses were most marked in the ventro-basal complex of the thalamus. Desensitization occurred if NA or adrenaline was applied repeatedly and this tachyphylaxis lasted for several minutes. After desensitization to the excitatory effects, some of these cells were depressed by catecholamines. These findings suggest the presence of at least two types of membrane receptor.5. beta-adrenergic antagonists (alderlin, D-INPEA and MJ 1999) and alpha-antagonists (phentolamine, dibenzyline and chlorpromazine) had pronounced depressant actions on some thalamic neurones. With the exceptions of D-INPEA and MJ 1999 they also excited cells that were excited by the catecholamines. Alderlin and phentolamine had both excitatory and inhibitory effects on some cells.6. The monoamine oxidase inhibitor, iproniazid, depressed neurones which were sensitive to NA depression. It did not appear to potentiate the effects of NA on most of the cells tested.7. Reticular formation stimulation depressed some neurones in the thalamus and excited others. The depressant effects of NA and reticular formation stimulation were reduced or abolished by an intravenous injection of picrotoxin (1 mg/kg).8. It is suggested that NA and 5-HT may be inhibitory transmitters in the thalamus, released at the terminals of ascending pathways from the brain stem that have been defined by fluorescence microscopy. The excitatory actions of these compounds may also be related to a synaptic role. (+info)
Release of endogenous noradrenaline from an isolated muscular artery. Release of endogenous noradrenaline from an isolated muscular artery.
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1. The release of noradrenaline by field stimulation of vasoconstrictor nerves has been studied in isolated preparations of the main uterine artery of the guinea-pig.2. In preparations from virgin animals stimulation with trains of 3000 square pulses at 5 and 25 pulses/sec resulted in mean overflows of 0.56 ng/g.pulse and 1.53 ng/g.pulse respectively.3. Inhibition of monoamine oxidase and catechol-O-methyltransferase had no consistent effect on overflow at either stimulation frequency.4. Desmethylimipramine (10(-5)M) caused, on the average, a 2.4-fold increase in overflow following stimulation at 5 pulses/sec while phenoxybenzamine (10(-5)M) caused a 3.8-fold increase. Neither of these drugs caused a significant alteration of the overflow during stimulation at 25 pulses/sec.5. Treatment of the tissues with desmethylimipramine plus normetanephrine (4.5 x 10(-4)M) caused no more increase in overflow than treatment with desmethylimipramine alone.6. It is concluded that enzymatic metabolism of noradrenaline at the synapse is of little functional importance in this tissue, and that the most important mechanism of transmitter inactivation is by nervous re-uptake. Although phenoxybenzamine was more effective than desmethylimipramine in increasing transmitter overflow, no evidence was obtained to support the view that this effectiveness was due partly to blockade of ;Uptake 2'.7. There was sometimes very low overflow of noradrenaline from arteries taken from animals in the last week of pregnancy. In these instances overflow following stimulation at 5 pulses/sec was not increased by phenoxybenzamine treatment of the tissue.8. Methylene blue and fluorescence microscopic techniques indicated that the terminal adrenergic axons in each artery possess approximately 8.74 x 10(5) varicosities. The mean tissue content of noradrenaline was found to be 9.6 mug/g or 29 ng/artery. These results have been correlated with known morphological and electrophysiological data to derive a peak post-junctional concentration of noradrenaline during transmission of about 4 x 10(-4)M.9. The fraction of total noradrenaline content of the artery released per pulse (under the influence of phenoxybenzamine) had a mean value of 2.2 x 10(-4). (+info)
Analysis of the inhibition of pethidine N-demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man.
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1. N-Demethylation of pethidine was studied in microsomal suspensions from unstarved male rat liver and the N-demethylase identified as belonging to the class of hepatic microsomal mixed function oxidases.2. A study of the structure/action relationships of compounds inhibiting pethidine N-demethylase revealed that hydrazine derivatives including phenylhydrazine, methylphenylhydrazine and mebanazine were all potent competitive inhibitors.3. Pethidine N-demethylase was only slightly inhibited by histamine and amphetamine but not by adrenaline and ephedrine nor by several miscellaneous compounds including piperidine, N-ethylpiperidine, N-methylpiperidine, N-methylammonium, hydrallazine or pethidinic acid.4. Several psychotropic drugs were all found to be potent competitive inhibitors of pethidine N-demethylase. These included monoaminoxidase inhibitors (the most active being nialamide and phenoxypropazine [K(i)=0.01 mM]; the least active iproniazid [K(i)=1.05 mM]); the tranquillizers promazine, propiomazine and chlorpromazine and tricyclic antidepressants (opipramol [K(i)=0.01 mM], imipramine [K(i)=0.03 mM], desipramine [K(i)=0.03 mM] and amitryptyline [K(i)=0.03 mM]). Hydrocortisone [K(i)=0.3 mM], prednisolone [2.8 mM] and nalorphine [0.07 mM] were also inhibitors, whilst SKF 525A was the most active of all [K(i)=0.002 mM].5. These results are discussed in relation to the clinically observed drug interactions which may occur between monoamineoxidase inhibitors and pethidine. It is concluded that since many different groups of drugs, including monoamineoxidase inhibitors, tranquillizers, tricyclic antidepressants, steroids, nalorphine, SKF 525A and barbiturates compete for cytochrome P(450) reductase, it is possible that this mechanism may account, at least in part, for the observed interactions of these various drugs in man. (+info)
Peripheral cardiovascular effects, in the pithed rat, of compounds used in the treatment of hypertension.
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A method for stimulating discrete segments of the spinal autonomic outflow in the pithed rat was found suitable for differentiating between the group of centrally acting antihypertensive agents alpha-methyldopa, clonidine and iproniazid and other antihypertensive compounds which additionally have peripheral vascular effects mediated via the peripheral sympathetic nerves. (+info)
Effect of sympathomimetic drugs in eliciting hypertensive responses to reserpine in the rat, after pretreatment with monoamineoxidase inhibitors.
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1. The effects of some rapidly metabolized sympathomimetic amines, such as beta-phenylethylamine and p-tyramine, in eliciting hypertensive responses to reserpine in the anaesthetized rat, have been studied.2. Retardation of metabolism, by pretreatment with the monoamineoxidase inhibitors iproniazid or phenelzine, causes beta-phenylethylamine (which in untreated rats has no effect) to induce hypertensive responses to reserpine. Tyramine and other hydroxy substituted phenylethylamines are much less active in this respect, probably because of relatively poor lipid solubility.3. Hypertensive responses to reserpine are due to catecholamine release, which is believed to be from stores made accessible to indirectly acting sympathomimetic amines with high lipid solubility by an action of reserpine on cell membranes. (+info)
Actions of levodopa on the blood pressure of conscious rabbits.
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1. In conscious rabbits, the rapid intravenous injection of levodopa alone does not have any significant effects on the blood pressure in doses up to 10 mg/kg.2. After inhibition of monoamine oxidase, levodopa induces a sustained pressor response.3. This response can be blocked by inhibition of extracerebral decarboxylase.4. Possible mechanisms for these interactions are discussed, together with their therapeutic implications in Parkinsonism. (+info)