Clement A. Stone

(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.

Action of angiotensin on isolated guinea pig ileum.

Conclusions 1. Atropine and morphine effectively block angiotensin and nicotine-induced spasm on the isolated guinea pig ileum. 2. Mecamylamine, pempidine, pentolinium and hexamethonium blocked nicotine-induced spasms; however, only mecamylamine and pempidine blocked angiotensin spasms, but very high concentrations were required. 3. It is proposed that angiotensin acts on the post-ganglionic cholinergic mechanism of the ileum and that its site of action is probably peripheral to the ganglion.

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.

Effect of New Synthetic Analogs of Somatostatin on Gastric Secretion in the Chronic Fistula Dog

Summary Somatostatin is a potent inhibitor of pentagastrin-evoked gastric secretion in the dog. Exploration of some of the structural requirements for antisecretory activity in this species has revealed that potency in reducing T.A.O. has been retained in compounds wherein alanine (Ala 1 ) and glycine (Gly 2 ) and the amino and carboxyl groups of terminal cysteine314, have been omitted. Locking the ring structure by replacing the sulfur with carbon retained activity. Compared to somatostatin, the active analogs (des-(Ala 1 , Gly 2 )-desamino-Cys 3 -somatos-tatin, des-(Ala 1 , Gly 2 )-desamino-Cys 3 -dicar-basomatostatin, and des-(Ala 1 , Gly 2 )-desa-mino-Cys 3 -decarboxy-dicarbasomatostatin) were slightly less effective in reducing the concentration of acid secreted. We thank Dr. N. R. Bohidar for statistical analysis. The somatostatin derivatives were prepared under the direction of Dr. R. F. Hirschmann by Drs. F. W. Holly and D. F. Veber and Messrs. M. J. Paleveda and R. G. Strachan. Insulin (RIA) determinations were made by Dr. R. Saperstein, Merck Institute, Rahway, N. J.

Preclinical toxicological studies of carbidopa and combinations of carbidopa and levodopa

Abstract Carbidopa was administered po at 25, 45 and 135 mg/kg/day to monkeys for up to 1 year and to rats for up to 96 weeks. No physical signs were produced in monkeys although rats exhibited flaccidity at all dosage levels. No deaths, weight changes, or changes in the results of ophthalmologic, hematologic, or pathologic examinations were produced in either species. Carbidopa given to dogs resulted in pyridoxine deficiency, which was prevented by coadministration of pyridoxine. Rats and monkeys were given combinations of carbidopa and levodopa ( 10 20 , 10 50 , and 10 100 mg/kg/day ). Rats given the highest dosage level daily for 2 years exhibited decreased activity, ptyalism, and retardation of weight gain. Some evidence of temporary salivary gland acinar hypertrophy was also noted. Increased activity at the middle and high dosage levels was noted in monkeys given the combined drugs for one year. No other physical signs or ophthalmologic, hematologic, or pathologic changes were noted. Carbidopa inhibits extracerebral decarboxylase activity so that lower doses of levodopa can be used in treatment of Parkinsonism with a reduction in side effects.

Some cardiovascular effects of germine-3-monoacetate

Abstract In anesthetized dogs germine-3-monoacetate (GMA), 40 to 640 μg/kg i.v., increased mean arterial pressure, right ventricular contractile force, left ventricular pressure and left ventricular dp/dt max. At 160 μg/kg i.v., GMA slightly increased the heart rate. The positive inotropic effect of GMA was not prevented by denervation of the carotid sinuses, pithing of the spinal cord, or adrenalectomy; it was blocked or greatly reduced by propranolol, sotalol, reserpine, mecamylamine or tetrodotoxin. When administered to the superior cervical ganglion of cats GMA enhanced contractions of nictitating membrane caused by electrical stimulation of preganglionic fibers with single electrical stimuli. At 6 to 100 μg/ml GMA had dose dependent positive inotropic and chronotropic effects on the isolated guinea pig atria. The in vivo effects of GMA were apparently mediated by the sympathetic nervous system; in addition, at high concentrations, GMA had a direct cardiotonic action on the artrial muscle.