Eunice V. Flock

5-hydroxyindole metabolism in the brain after hepatectomy.

Abstract The concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) increased in the brain of dogs and rats after complete hepatectomy, the increases of 5-HIAA being greater than those of 5-HT. The increase in concentration of both 5-hydroxyindoles was much smaller than that of the precursor, tryptophan (Try). The demonstration of radioactive 5-HT and 5-HIAA in the brain of normal and hepatectomized rats after the intradiencephalic injection of l -Try-3- 14 C indicated that hydroxylation of Try occurred in brain in vivo . However, the intravenous injection of Try (33 mg/kg) resulted in definite increases in the concentration of 5-hydroxyindoles in the brain of normal rats and only marginal increases in the brain of hepatectomized rats. After intravenous injection of d , l -5-hydroxytryptophan, conversion to 5-HT was essentially similar in normal dogs and in dogs in coma after complete hepatectomy.

Current Experience in the Diagnosis of Pheochromocytoma

The pharmacological and biochemical tests available for the diagnosis of pheochromocytoma were evaluated among 28 patients with proved tumors and 148 other patients in whom the diagnosis was suspected. Of the biochemical tests on urine, determinations of total metanephrines (MN) and of vanilmandelic acid (VMA) were much less subject to false-positive results than was determination of catecholamines (CA). Since urinary MN values changed the most in tumor patients, MN determination is preferred as the current screening test. Of the pharmacological tests, the histamine test continues to be the most valuable, especially when combined with determination of plasma CA concentration. The phentolamine (Regitine) test has not proved to be of any distinct value as a primary diagnostic aid. Any of the chemical or pharmacological tests occasionally may give a false-positive result. The urinary output of excessive amounts of homovanillic acid (HVA) was an indication of the presence of pheochromocytoma with some features histologically similar to other neural crest tumors but was not an indication of malignancy. Reliable diagnosis of pheochromocytoma still must be based on multiple studies in an appropriate clinical setting.

Effect of Ethanol on 5-Hydroxytryptamine Turnover in Rat Brain

Summary In rats which had received an intoxicating dose of ethanol, the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain were not different from concentrations in brains of normal rats. The turnover of cerebral 5-HT, determined from rates of increase in concentration of 5-HT or of decrease in concentration of 5-HIAA after the administration of a monoamine oxidase inhibiter, was modestly decreased during ethanol intoxication.

Tryptophan Metabolism in the Brain of the Developing Rat

Publisher Summary It is known that only very small amounts of 5-hydroxytryptamine are present in the brain of the rat during early development and that monoainine oxidase activity in homogenates of the brain of the newborn is one third that is found in the young adult rat. Preliminary, experiments show that at this age, when only small amounts of 5-hydroxytryptamine is present, the concentration of tryptophan in the brain is considerably higher than in the adult. A study of changes in the concentration of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in relation to the concentration of the precursor amino acid, tryptophan, during the early development of the rat has been made. The concentrations of 5-hydroxytryptamine and its metabolite, 5-liydroxyindoleacetic acid, are related to the concentration of the precursor amino acid, tryptophan, during the early development of the rat and in the adult rat.

Pharmacologic and Chemical Tests as an Aid in the Diagnosis of Pheochromocytoma

Today pharmacologic and chemical tests are helpful in screening a relatively large number of patients for pheochromocytoma and are a definite aid to a correct diagnosis. No one test is infallible, and knowledge concerning the drugs used or the manner in which the blood and urine are collected, or both, is necessary to avoid a false-positive or false-negative result from the tests.

Metabolism of serotonin by the isolated perfused rat liver—effect of glucuronyl transferase deficiency or monoamine oxidase inhibition☆

Abstract The metabolism of 5-hydroxytryptamine-3- 14 C (5-HT, serotonin) was studied in isolated perfused rat livers when the monoamine oxidase pathway was inhibited by β-phenylisopropylhydrazine (JB 516) or the glucuronyl transferase pathway was deficient (Gunn rat livers). In all cases, 5-HT was cleared rapidly from the plasma by liver and platelets. In bile and in plasma in control perfusions (Sprague-Dawley livers), monoamine oxidase metabolites [chiefly conjugates of 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOH)] accounted for 29 per cent of the dose; conjugates of N -acetyl-hydroxytryptamine accounted for 12 per cent of the dose and 5-hydroxytryptamine glucuronide for 11 per cent. On addition of 2 mg JB 516 to the perfusate, the amounts of conjugates of 5-HT and N -acetyl-5-hydroxytryptamine increased and no radioactive 5-HTOH or 5-HIAA could be detected. Gunn rat livers produced less glucuronides, more sulfate conjugates and more free 5-HIAA compared to perfusion of Sprague-Dawley livers without JB516. The total amount of 5-HT metabolized was not reduced when a major metabolic pathway was either deficient or inhibited, because compensatory increases occurred in the amount metabolized by alternate pathways.

Effects of Ethanol on Glucose Utilization in Rat Brain

Summary Signs of impairment of utiliztion of glucose in rat brains at 2 1/2 hr after administration of ethanol included increased glucose ratios for cerebrum/blood and hind-brain/blood in fed and fasted rats, decreased concentrations of lactate in cerebrum and hindbrain in fed rats, higher percentages of brain 14C in glucose at 15 min after injection of glucose-U-14C, and decreases in blood glucose equivalents in the combined glucose metabolites in cerebrum and hindbrain of fed and fasted rats. Glucose uptake in cerebrum and hindbrain was lower in rats given ethanol by stomach tube (fed or fasted) than in control rats. Glucose uptake was normal in fed rats given ethanol intraperitoneally, but they had increased blood glucose concentrations. However, in these rats with the greater supply of blood glucose the greatest decreases in blood glucose equivalents of brain glucose metabolites were found. Significant decreases were found in aspartate, glutamate, glutamine, and γ-aminobutyrate (GABA). Effects of fasting in control rats included decreased concentrations of glucose in blood, of lactate and GABA in both cerebrum and hindbrain, and of glycine in hindbrain.

Metabolic pathways of tetraiodothyroacetic acid, triiodothyroacetic acid, tetraiodothyropropionic acid and triiodothyropropionic acid☆☆☆

Abstract Major metabolic pathways for l -thyroxine and l -3,5,3-triiodothyronine involve removal of an iodine atom from the benzene ring with the side chain and thus inactivation of these hormones. Conjugates of the products 3,3,5-triiodothyronine and 3,3-diiodothyronine are excreted in the bile of dogs with livers but accumulate in the blood and urine of dogs without livers. Analogs of the thyroid hormones labeled with 131 I in the 3 or 5 position were studied in dogs with biliary fistulas and in hepatectomized dogs. In dogs with biliary fistulas tetraiodothyroacetic acid was metabolized much more slowly than was thyroxine ; much less 131 I was excreted in bile or urine. Large amounts of unchanged tetraiodothyroacetic acid with smaller amounts of 3,3,5-triiodothyroacetic acid were found in the blood. Tetraiodothyropropionic acid was partially deiodinated to 3,3,5-triiodothyropropionic acid which accumulated in the blood as the amount of unchanged tetraiodothyropropionic acid decreased. Both of these compounds of propionic acid were excreted in bile as glucosiduronides. 3,5,3-Triiodothyroacetic acid and 3,5,3-triiodothyropropionic acid were rapidly cleared from the blood and excreted in the bile chiefly as glucosiduronides, with small amounts of the ethereal sulfate conjugates of 3,3-diiodothyroacetic acid and 3,3-diiodothyropropionic acid. In dogs without livers, the sulfates of these 3,3-diiodo-compounds were found in larger amounts in both blood and urine, but the major metabolites appeared to be sulfoconjugates of 3-monoiodo-derivatives.

Effect of Ethanol on γ-Aminobutyric Acid (GABA) and Other Amino Acids in Rat Brains∗

Summary The concentration of GABA was less in the hindbrain (in both the cerebellum and brain stem) than in the cerebrum of normal rats not given alcohol (control rats). Smaller amounts of the immediate precursor of GABA, glutamate, and its metabolites, glutamine and aspartate, were also found in the hindbrain than in the cerebrum. Administration of intoxicating doses of alcohol had no effect on the concentration of GABA in the hindbrain but produced small decreases in the concentrations of glutamate and aspartate.

Effect of methyldopa on the metabolism of catecholamines and tryptophan in metastatic pheochromocytoma: Report of two cases∗

Abstract The oral administration of methyldopa produced a transient reduction in excretion of vanilmandelic acid (VMA) and of metanephrine (MN) and normetanephrine (NMN) in a patient with metastatic pheochromocytoma. In another, similar patient, the amount of VMA excreted after an injection of histamine was markedly reduced by methyldopa therapy. The blood pressure was decreased in both, and this reduction persisted, unrelated to the alterations in urinary concentrations of VMA or of MN and NMN. Methyldopa did not prevent the spontaneous paroxysms apparently due to release of catecholamines in the patient in whom these were an almost daily occurrence but did interfere with the pressor response to histamine. The decarboxylation of tryptophan was not inhibited in either patient. It was concluded that methyldopa transiently inhibited decarboxylation of aromatic amino acids, but that the hypotensive properties more probably were related to interference in the storage or release of catecholamines. Methyldopa holds some promise as an effective agent for reducing blood pressure in patients with continuously secreting pheochromocytoma and by so doing, preventing the complications due to persistent hypertension. Methyldopa interferes with the determination of catecholamines in blood and urine by fluorometry. It persists in the urine for about four days after administration is discontinued. It also interferes with the performance of a histamine test. This interference should be considered when pharmacologic studies and determinations of plasma and urinary catecholamine content are used in the investigation of patients for pheochromocytoma. In patients with pheochromocytoma, the excretion of catecholamines, VMA, and MN and NMN varies considerably from day to day and from patient to patient. No single test can be relied on to exclude this tumor, but the results of all tests must be considered along with those of pharmacologic studies.