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When norepinephrine (NE) or epinephrine (E) is infused into a human subject, all but about 4% of the amine is metabolized to urinary 0-methylated and deaminated metabolites (1-4).The percentage excreted as each metabolite is fairly constant even in different individuals (1)(2)(3). This is in distinct contrast to the situation in patients with pheochromocytoma. In this disease patients with similar excretion values for free catecholamines may show up to tenfold differences in their excretion rates of metabolites (5). This implies that a pheochromocytoma may not be simply an endogenous source of circulating NE and E; catecholamine metabolism in these patients is more complex than traditional views would suggest. This paper describes a) the urinary excretion rates of NE and E and of their two major metabolites in 24 patients with pheochromocytoma, b) the NE and E content of the tumors of 23 of these patients, and c) the normetanephrine (NMN) plus metanephrine (MN) content of 9 tumors. An analysis of these data reveals certain correlations, not previously emphasized, between the size of the tumor, the rate of turnover of catecholamines within the tumor, and the pattern of catecholamine metabolites in the urine. We concluded that in some pheochromocytomas much of the catecholamine synthesized is degraded directly in the tumor before it ever reaches the circulation. This process may partially "protect" the patient from the cardiovascular effects of his tumor and thereby modify the clinical course of the disease.Materials and Methods Twenty-four hour urine specimens were collected in glass bottles containing 10 to 15 ml 6 N hydrochloric acid and were stored at -200 C or at 00 C. Portions of tumor were frozen on removal and stored at -200 C until the time of assay. Urine specimens and tumor samples shipped from outside hospitals were kept frozen on dry ice en route. Free urinary NE and E were determined fluorimetrically by a modification of the trihydroxyindole method (6). The mean recovery of NE plus E was 87%o; the results were not corrected for this small loss. Total NMN plus MN was determined by a modification of Pisano's method (5); no correction was made for an average recovery of 84%. This method measures the combined total of free and conjugated NMN plus MN but does not distinguish between these two 0-methylated amines. Urinary 3-methoxy-4-hydroxymandelic acid (vanilmandelic acid, VMA) was measured by the method of Pisano, Crout, and Abraham (7) ; the recovery in this procedure is quantitative.Tumors were assayed for NE and E by homogenizing 0.5 to 1.0 g of tissue in 10 ml cold 5% trichloroacetic acid, centrifuging to obtain a clear supernatant solution, and assaying this extract fluorimetrically. The tumor content of NMN plus MN was determined by preparing a 5% trichloroacetic acid extract as described above, adjusting its pH to 8.4 with 2 N ammonium hydroxide, and passing it over a 1.2-X 6-cm column of alumina to remove catecholamines. The effluent was then brought to pH 6.0 with 1 N acetic acid and carried th...

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The relation between the noradrenaline content of isolated guinea-pig atria and the rate-increasing action of tyramine was studied by the use of pretreatment with reserpine as a pharmacological tool for graded depletion of the noradrenaline stores. Reserpine was more potent in depleting the stores than in reducing the biological response to tyramine; 50% depletion had little effect on the response to tyramine; 50% reduction of the response to tyramine occurred when the noradrenaline content fell to about 10% of normal. Depletion of the store's of guinea-pig atria did not result in supersensitivity to noradrenaline. Exposure of heavily pretreated atria to 3 x 106 noradrenaline for 10 min (followed by repeated washing for 45 min) restored the response to tyramine to 70% of normal; it failed, however, to restore the noradrenaline content to the level expected from the experiments with reserpine alone. Restoration of the response to tyramine was accompanied by a small but significant increase in the noradrenaline content of the atria; a change in sensitivity to added noradrenaline did not occur. The results are consistent with the view that (a) the noradrenaline stores consist of two compartments the smaller of which is important for the action of tyramine, that (b) this smaller compartment can be at least partially refilled by exposure of the atria to noradrenaline, and that (c) there is no direct relationship between the noradrenaline content and the-sensitivity to noradrenaline in guinea-pig atria.It is well known that reserpine depletes the noradrenaline stores of peripheral organs (Carlsson, Rosengren, Bertler & Nilsson, 1957;Paasonen & Krayer, 1958;Burn & Rand, 1959) and abolishes the response of such tissues to tyramine and to stimulation of adrenergic nerves (Carlsson et al., 1957;Burn & Rand, 1958;Trendelenburg & Gravenstein, 1958). Tyramine is therefore generally assumed to exert its sympathomimetic effects through the liberation of noradrenaline from peripheral noradrenaline stores. Although various studies deal with the effects of pretreatment with graded doses of reserpine, they have been restricted either to the observation of -biological responses believed to be mediated through the liberation of noradrenaline (Fleming & Trendelenburg, 1961 ;Trendelenburg, 1961;Liebman, 1961;Waud, 1961 ;Liebman, Muskus & Waud, 1962) or to the determination of catechol amine content (Carlsson et al., 1957). Since no attempt has yet been made to correlate these two phenomena quantitatively, it is not known how TYRAMINE AND NORADRENALINE STORES much the noradrenaline stores must be depleted to reduce the sympathomimetic action of tyramine.Although it is well established that noradrenaline restores the response of reserpine-pretreated preparations to tyramine (Burn & Rand, 1958, 1960 and to nerve stimulation (Burn & Rand, 1958;Gillespie & Mackenna, 1961), restoration of the noradrenaline stores has been observed by some authors (Pennefather & Rand, 1960) but not by others (Muscholl, 1960).It was thus of interest to study ...

T HE -biochemical and pharmacologic properties of a-methyl-3,4-dihydroxy-DL-phenylalanine (DL-a-methyl-dopa) in man have been described in several reportsl-5 from this laboratory. These studies showed that, in addition to being a potent inhibitor of the decarboxylation of several aromatie L-amino acids, the compound has sedative and hypotensive properties. Thus, the agent has come to be looked upon as a potentially useful drug as well as an interesting bioehemical tool.The present report covers three phases of additional investigations: (1) further observations were made on the blood pressure lowering effects of the racemic (DL) form of the compound and preliminary data were obtained on its metabolism in man, (2) following resolution of the agent into its D and L isomers, these were tested comparatively and all activity was found to reside in the Lisomer, and (3) studies were initiated to evaluate the usefulness of L-a-methyl-dopa (Aldomet) as an antihypertensive agent. The conclusion is reached that Aldomet is a promising drug for the treatment of hypertension and has an interesting, albeit incompletely understood, mechanism of action.Materials and Methods ClinicalThe subjects were 52 patients with persistent primary hypertension; the age range was 32 to 67 years. Complications included: grade III retinopathy, nine cases; grade IV retinopathy, five cases; congestive heart failure, one case; and renal insuffieiency with azotemia, four cases. Twenty-eight of the patients were hospitalized and the others were studied as out-patients. All blood pressure measurements were by the arm cuffauscultatory technic. The protocols of individual studies are considered in the appropriate sections From the Experimental Therapeutics Branch,