McC. Goodall

Biosynthesis of epinephrine and norepinephrine by sympathetic nerves and ganglia.

It is generally believed by the neurophysiologists that the sympathetic neurohormone is norepinephrine and not epinephrine as originally supposed. This concept of norepinephrine as the sympathetic neurohormone has evolved from much impressive circumstantial evidence; however, it has not been demonstrated that the biosynthesis of norepinephrine takes place in the sympathetic nerves and ganglia. This paper shows, through the use of labeled precursors, that the sympathetic nerves and ganglia synthesize norepinephrine in a systematic sequence from tyrosine and that this synthesis apparently terminates with norepinephrine rather than progressing to the formation of epinephrine.

Metabolism of dl-adrenaline-2-C14 in the human.

Summary A procedure is described which utilizes a combination of filter paper and ion exchange chromatography to separate the urinary metabolic products of adrenaline. After intravenous infusion of dl-adrenaline-2-C14 in 6 human subjects, 73 ± 5% of infused radioactivity was recovered in 24 hour urine. Radioactivity which appeared in urine was distributed among various metabolic products as follows: adrenaline, 4%, 3-methyl-O-adrenaline, 5%, 3-methyl-O-adrenaline conjugate, 42 ± 7%; 3-methoxy-4-hydroxymandelic acid, 27 ± 3%; 3, 4-dihydroxymandelic acid, 12 ± 4%; 2 unidentified fractions, 4%.

Increased Sympathetic Nerve Activity Following Resection of Coarctation of the Thoracic Aorta

Twenty patients who underwent resection of the thoracic aorta and six patients operated on for hiatial hernia, patent ductus, mitral insufficiency, or A-V fistula were studied to determine whether there was an increase in sympatho-adrenal medullary activity following resection. Daily 24-hour urine samples were collected from each patient and control, and outputs of noradrenaline (norepinephrine) and adrenaline (epinephrine) were determined. The preoperative outputs were similar in the coarctation group and the controls. Postoperatively, however, although noradrenaline was elevated in both groups, it was elevated more in the coarctation group and remained elevated for a longer period than in the control subjects. Both the subjects with coarctation and the controls had marked increases in urinary output of adrenaline after operation. In the coarctation arctation group, however, the increase was greater and extended for a longer period. The mechanism for increase in noradrenaline output seems to be directly ...

URINARY OUTPUT OF ADRENALINE, NORADRENALINE, AND 3-METHOXY-4-HYDROXYMANDELIC ACID FOLLOWING CENTRIFUGATION AND ANTICIPATION OF CENTRIFUGATION *

It has been shown that various forms of stress, i.e., thermal burn (1), muscular exercise (2), centrifugation (3-5), trauma (6) and so forth activate the sympatho-adrenal system and that this activation is manifested by an increase in the urinary output of adrenaline and noradrenaline. Furthermore, it has been demonstrated in the normal human that 3-methoxy-4-hydroxymandelic acid is one of the principal metabolic products of both adrenaline and noradrenaline (7-10). Hitherto, there have been no stress experiments correlating the urinary output of adrenaline and noradrenaline with that of 3-methoxy-4-hydroxymandelic acid. The experiments herein described not only demonstrate such a correlation but also show the effect of centrifugation and anticipation of centrifugation upon the urinary output of adrenaline, noradrenaline, and 3-methoxy-4-hydroxymandelic acid.

Dopamine (3-Hydroxytyramine) metabolism in parkinsonism

Three patients with idiopathic parkinsonism and six normal subjects were infused over a 4 hr period with 104.6 muc of dopamine-2-(14)C (3,4-dihydroxyphenylethylamine, 3-hydroxytyramine),(1) the immediate precursor in the synthesis of the sympathetic neurohormone, noradrenaline (norepinephrine). Urine was collected during the infusion period, 0-2 hr, 2-4 hr, 4-8 hr, 8-24 hr, and thereafter for 4 additional days. Using a technique herein described, the various metabolic and biosynthetic products of dopamine, including noradrenaline and its metabolic products, were separated, identified, and their radioactivity measured. The metabolic pattern of dopamine in the normal subject was compared to that of the three parkinsonism patients. The results indicate that in idiopathic parkinsonism there is a decrease in the recovery of free radioactive noradrenaline in the urine following an infusion of dopamine-2-(14)C and a slight shift toward dopamine metabolism. The latter is reflected by an increase in the following metabolites of dopamine: 3,4-dihydroxyphenylacetic acid and the conjugates of 3-methoxy-4-hydroxyphenylacetic acid, 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylethanol and dopamine.

Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia

Noradrenaline synthesis and metabolism of dopamine was evaluated in three patients with familial dysautonomia and compared with that of six normal subjects. Each patient and subject was infused with 104.8 muCi of dopamine-2-(14)C dissolved in 1000 ml of physiological saline. The urine was collected during the infusion period and at intervals thereafter. Using a specially designed flow monitor system, the various biosynthetic and metabolic products of dopamine were separated, identified, and their radioactivity measured. The results indicate that in familial dysautonomia the synthesis of noradrenaline is significantly decreased; this is reflected by a decrease in recovery of radioactive noradrenaline as well as various metabolic products of noradrenaline, i.e. 3-methoxy-4-hydroxymandelic acid (MOMA), normetadrenaline, and normetadrenaline conjugate. Concomitant with this decrease in noradrenaline synthesis, there was a shift towards dopamine metabolism as reflected by an increase in the recovery of primary and secondary dopamine metabolites; 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylacetic acid (HVA), 3-methoxytyrosine, and respective conjugates, etc. Whereas all dysautonomic patients showed the same general metabolic pattern as was expected, they varied in degree.

Dopamine (3-hydroxytyramine) replacement and metabolism in sympathetic nerve and adrenal medullary depletions after prolonged thermal injury

After severe thermal injury, the adrenal medulla and the sympathetic nerves can be partially or totally depleted of their adrenaline (epinephrine) and noradrenaline (norepinephrine). The purpose of this paper is to elucidate the rate at which dopamine-2-(14)C, a precursor of noradrenaline, is synthesized into noradrenaline and noradrenaline metabolic products, thereby giving some indication as to dopamines utilization, turnover, and possible use in treating such noradrenaline-adrenaline depletions. Three burned subjects, 3 wk postburn, were infused with 104.6 muc (872 mug) of dopamine-2-(14)C for 4 hr. Urine was collected at various hourly intervals for the 1st day, and thereafter for 4 days, assayed, and compared with the metabolism of dopamine in normal subjects. Methods for separating, identifying, and counting radioactivity of the various metabolic products of dopamine are described. Normally 87.6 +/-3.1% of the total radioactivity is recovered within 24 hr after an infusion of dopamine-2-(14)C, but in the three severely burned patients, this value was increased to 93.1, 97.3, and 97.5% in 24 hr. There was a marked decrease in the percentage of radioactivity recovered as noradrenaline in all collection periods, and in contrast to normal subjects, no radioactive noradrenaline was recovered after 24 hr. Concomitantly, there was an increase in radioactivity recovered as metabolic products of noradrenaline, reflecting a compensatory shift toward noradrenaline synthesis and utilization at the expense of the dopamine metabolic products. The results indicate that in the burned patients the infused dopamine-2-(14)C was rapidly synthesized into noradrenaline and then rapidly released and metabolized. From these results it seems evident that dopamine would be a useful adjunct in the treatment of sympathico-adrenal medullary depletion in burns.