Mary Lou Torchiana

(S)-norepinephrine in the tissues of mice and rats given racemic erythro-3, 4-dihydroxyphenylserine (DOPS)☆

Abstract The administration of racemic erythro-3, 4-dihydroxyphenylserine (DOPS) to mice resulted in increased concentrations of chemically determined norepinephrine in the hearts and brains. However, radioactive norepinephrine in the brains, resulting from the administration of [2- 14 C]DOPA, was decreased after the administration of erythro-DOPS. The pressor response to tyramine was attenuated in rats which had received this amino acid. It is concluded that in vivo the βS:αS isomer of DOPS, present in the racemic-erythro mixture, yields unnatural (S)-norepinephrine which replaces part of the natural (R)-norepinephrine in central and peripheral adrenergic tissues.

Effects ofl-dopa alone and in combination with dopa decarboxylase inhibitors on the arterial pressure and heart rate of dogs

Nach Vorbehandlung mitl-HMD (peripherer Hemmer der Dopa-Dekarboxylase) wird mitl-Dopa (25 und 50 mg/kg i.v.) Blutdruck und Herzfrequenz herabgesetzt.

Some biochemical and pharmacological actions of α-methylphenylalanine

Abstract The catecholamine-depleting activity and certain pharmacological actions of l - α -methylphenylalanine, a tyrosine hydroxylase inhibitor, were compared in a number of species with those of the related α-methyl amino acids, l - α -methyl- p -tyrosine and dl - α -methyl- m -tyrosine. α-Methylphenylalanine was more active than α -methyl- p -tyrosine in depleting heart norepinephrine, but was less effective in reducing central amines; in addition, its duration of action in the heart was more prolonged. α -Methyl- m -tyrosine proved to be the most active compound on both brain and heart catecholamines. Metaraminol was found to be a metabolite of α-methylphenylalanine and was identified in the hearts, brains and adrenals of mice, rats and dogs. No overt signs of sedation were seen in dogs or squirrel monkeys given α-methylphenylalanine, although loss of avoidance responding could be demonstrated. This contrasted with results obtained with α -methyl- m -tyrosine, which produces stimulation and an increase in lever-pressing behavior. α-Methylphenylalanine, as found with α -methyl- p -tyrosine and α -methyl- m -tyrosine, reduced cardiac responses to the indirect sympathomimetic amines and to adrenergic nerve stimulation. It was concluded that the pattern of biochemical and pharmacologie events after α-methylphenylalanine falls between those because of α -methyl- p -tyrosine, a relatively pure tyrosine hydroxylase inhibitor, and α -methyl- m -tyrosine, whose effects are related predominantly to its rapid metabolism to metaraminol with a consequent release and depletion of catecholamines.

Displacement of norepinephrine from the rat heart by 14C-metaraminol

Abstract Rats were injected with submaximal quantities (0.24 mg/kg) of 14 C-metaraminol, i.e. enough to lower the concentration of norepinephrine in the heart by about 60 per cent, measured 18 hr after drug administration. In the ventricles at 18,42 and 66 hr after metaraminol injection and in the atria at the two latter times, radioactivity was present in amounts sufficient to account exactly for the norepinephrine missing, on a mole-for-mole displacement basis. Atrial radioactivity 18 hr after metaraminol administration was insufficient to account for the whole of the missing catecholamine. Possibly at 18 hr a steady state had not been reached in the atria, an interpretation which is strengthened by the fact that other catecholamines (epinephrine and dopamine) were present only in trace amounts. Chemically determined metaraminol was consistently less than indicated by radiocounting. Even though no evidence was gained for the presence of 14 C-α-methylnorepinephrine in the tissue, it is possible that metabolites of metaraminol account for part of the norepinephrine displacement observed. The administration of larger amounts of 14 C-metaraminol (3 mg/kg) resulted in catecholamine depletion greater than that accounted for by radio-activity in the tissue, and this was particularly striking in the atria. Thus, the relationship between tissue radio-activity and norepinephrine concentration depends upon several factors, and only under certain conditions, as described above, is a one-for-one displacement of the catecholamine clearly demonstrated.

Pharmacological antagonism of the toxic manifestations of amitriptyline and protriptyline in dogs

Abstract In unanesthetized dogs intoxication with amitriptyline produced tachycardia and neurologic changes characterized chiefly by agitation and restlessness. The chronotropic actions of such intoxication were reduced by inhibitors of cholinesterase (physostigmine, pyridostigmine), by mecamylamine, a ganglionic blocking agent, and by propranolol, a β-receptor blocking agent. Neurologic patterns were favorably influenced only by physostigmine. Protriptyline, given in toxic doses, produced a lesser degree of tachycardia, did not cause neurologic disturbances and was less susceptible to physostigmine reduction of heart rate changes than amitriptyline. The data suggest that the weak anticholinergic activities of amitriptyline and protriptyline may be responsible for some of the toxic manifestations. Activation of the sympathetic nervous systems may participate to some extent in the tachycardia.

Post Seizure Mortality Following Electroshock Convulsions in Certain Strains of Mice

Summary An acute lethal effect from electroshock convulsions has been demonstrated to occur among mice of the DBA, CFW and C57 strains, and to a lesser extent the ICR strains. CF#1 mice were rarely susceptible. Death was ascribed to failure to resume breathing and appeared to be dependent upon occurrence of maximal seizure and independent of intensity of current employed to elicit the seizure. The mechanisms involved were not revealed, but attention was directed to the finding that strains susceptible to post-seizure electroshock death are identical to those which are susceptible to audiogenic seizures.

4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, an effective inhibitor of dopamine-β-hydroxylation in vivo

Abstract 4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, although considerably less potent (1/500) than disulfiram as an inhibitor of dopamine-β-hydroxylation in vitro , is 10–20 times as potent as disulfiram, both administered intraperitoneally, in vivo . The pyrimidinethiol decreases the concentration of norepinephrine in the brain (mice and rats) but does not decrease the concentration of dopamine in that organ; it inhibits the depleting action of methyldopa and α- methyl -m- tyrosine on brain and heart norepinephrine, and of α- methyl -m- tyramine and α-methyl-dopamine on heart norepinephrine, and its effects upon tissue catecholamines are additive to those of DOPA and of a monoamine oxidase inhibitor; it inhibits restoration of the tyramine-pressor response in reserpine-treated rats by α-methyldopamine. The pyrimidinethiol is perhaps twice as potent as disulfiram as an inhibitor of alcohol metabolism in the rat, and in this function it, like disulfiram, acts at the aldehyde dehydrogenase step of oxidation. The pyrimidinethiol, like other thiourea derivatives, blocks the uptake of iodine by the rat thyroid gland in vivo . In this function it is about 1/150 as potent as propylthiouracil and six times as potent as disulfiram. The pyrimidinethiol is well absorbed after oral administration; for this reason, and because of its potency advantage over disulfiram, the compound should be superior to dilsulfiram in a number of situations.

Some biochemical and pharmacological actions of (—) erythro-meta-(meta-chlorobenzyloxy) -2-(1-aminoethyl)-benzyl alcohol: A derivative of metaraminol☆

Abstract (—)Erythro-meta-(meta-chlorobenzyloxy)-2-(1-arninoethyl)-benzyl alcohol, a meta-chlorobenzyl ether of metaraminol, administered to mice, rats and dogs, causes depletion of peripheral stores of norepinephrine and their partial replacement with metaraminol. Consequently, the ether depresses adrenergic nerve transmission in dogs and lowers blood pressure in renal hypertensive rats. However, acute presser responses are either minimal (rats) or absent (dogs) following administration of the ether, due to the slow formation of metaraminol. Unlike α -methyl- m -tyrosine, the chlorobenzyl ether of metaraminol does not produce central nervous system effects. In the brain the amino acid is converted to metaraminol, while metaraminol as derived from the ether is absent or appears only in low concentration.

Effect of antispasmodic and ganglionic blocking agents on mortality following electroshock convulsions in mice.

Summary Ability of several antispasmodic and ganglionic blocking substances to produce immediate death following maximal electro-shock convulsions in mice has been demonstrated. With most agents studied (atropine, atropine methyl nitrate, benactyzine, mepiperphenidol, methantheline, propantheline, scopolamine, scopolamine methiodide, mecamylamine, chlorisondamine, pentolinium and hexamethonium), the post seizure lethal effect was produced in doses approximating that required to produce a peripheral anticholinergic effect in the same species (pupil dilatation). Neither atropine nor mecamylamine altered the electroconvulsive threshold. Respiratory failure appeared to be the cause of drug-induced post seizure deaths, but the mechanism of action was not revealed.