It has been shown that the monodeiodination of T₄ to either T₃ or rT₃ is an important step in T₄ metabolism. Moreover, recent studies reported that T₃ is converted further to either 3, 3'-T₂ or 3, 5-T₂ and rT₃ is converted to either 3, 3'-T₂ or 3', 5'-T₂. To evaluate the physiological significance of the sequential monodeiodination of T₄, several experiments were performed and the following results were obtained.
(1) Serum 3,, 3', 5'-T₂ and 3, 5-T₂ as well as T₄, T₄ and rT₃ concentrations were determined by RIAs in 81 normal subjects, aged 24-81 years. Although no significant relation existed between T4 levels and age, serum T₃ showed a significant inverse correlation with age. In contrast, no significant correlation was observed between rT₃ and age. Serum 3, 3-T₂, 3', 5'-T₂ and 3, 5-T₂ values all had significant inverse correlation with age. These findings suggest that sequential monodeiodinating activities of T₄ decrease with increasing age.
(2) The conversion of T₄ to T₃ was studied in normal, Graves' and neoplastic thyroid tissues. The T₃ generation in the thyroid tissue was dependent on the amount of tissue used, temperature and pH, suggesting the enzymatic nature of T₄ 5'-monodeiodinating activity in the thyroid. The conversion of T₄ to T₃ was observed in differentiated thyroid neoplasma and was markedly enhanced in Graves' thyroid tissues compared to that of normal thyroid tissues.
(3) The conversion of T₄ to T₄ was studied in the rat anterior pituitary, using paper chromatography. The T₃ generating activity from T₄ increased with an increase in the amount of tissue and was temperature- and pH-dependent. T₄ 5'-monodeiodinating activity was consistently, though minimally, detected in fetal rat pituitaries and increased after birth, reaching the maximum at 22 days. Serum TSH levels were markedly elevated in the fetus. They decreased after birth, reaching their nadir at 22 days. Thus, a reciprocal relation was observed between intrapituitary T₃ generating activity from T₄ and serum TSH levels in developing rats.
(4) The rT₃ generation from T₄ and 3, 3'-T₂ generation from T₃, representing T₄ or T₃ 5-monodeiodination, and the conversion of rT₃ to 3, 3'-T₂, representing rT₃ 5'-monodeiodination, were studied in the p2 fraction of rat brain homogenate. T₄ or T₃ 5-deiodinating activity was dependent upon the amount of the tissue, temperature and pH and was mainly found in synaptosomal fractions. Moreover, the conversion of rT₃ to 3, 3'-T2 was also dependent on tissue amount, temperature and pH. T₄ or T₃ 5-monodeiodinating activity was highest in the cerebral cortex and was far lower in the cerebellum, while rT₃ 5'-monodeiodinating activity was highest in the rat cerebellum and lower in the cerebral cortex. These findings suggest that two different deiodinases are present in the rat brain.
(5) Studies were undertaken to define the existence of specific T₃ binding sites in the synaptosomal fraction of the rat cerebral cortex. Scatchard analysis was compatible with the existence of two sets of high affinity T₃ binding sites, the higher affinity, lower capacity site and the lower affinity, higher capacity site. In contrast to nuclear T₃ receptors, the maximal binding capacity of the higher affinity synaptosomal T₃ binding sites was low in neonatal rats and increased thereafter to the levels of adult rats, coinciding with the

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In order to elucidate the role of hypothalamic amines in controlling the diurnal (D) and nocturnal (N) surges of prolactin (PRL) induced by cervical stimulation, chronological relationships between dopamine (DA), norepinephrine (NE) and serotonin concentrations in the hypothalamus and PRL concentrations in the anterior pituitary and plasma were studied in pseudopregnant (PSP) rats. In addition, the effects of diethyldithiocarbamic acid (DDC), an inhibitor of dopamine-β-hydroxylase, and DL-p-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, on two PRL surges were also investigated. Rats were made pseudopregnant by cervical stimulation performed at 10.00 h on estrus (Day 0). The concentrations of NE, DA and serotonin in the hypothalamus and PRL in the anterior pituitary and plasma were determined every two hours between 15.00 h on diestrus 1 and 13.00 h on diestrus 2 of the estrous cycle and during the corresponding periods of PSP. D- and N-surges of PRL in the PSP rats were clearly observed at 19.00 h on Day 1 and at 07.00 h on Day 2 of PSP, respectively. During the diestrus 1 and 2 stages of the estrous cycle, PRL concentrations in the anterior pituitary were consistently low and unvarying. In contrast to this, a marked increase in the concentration of PRL in the anterior pituitary was observed during the corresponding period of PSP, just after the D- and N-surges of PRL.
Hypothalamic NE concentrations increased during the D-surge of PRL in normal cyclic rats as well as in PSP rats, while in PSP rats, an additional increase in hypothalamic NE concentrations was observed during the initial stage of N-surge of PRL. Serotonin concentrations in the hypothalamus were significantly higher in PSP rats than in normal cyclic rats during the N-surge of PRL. DA concentrations in the hypothalamus significantly decreased during the D-surge of PRL in PSP rats, whereas those of PSP rats as well as normal cyclic rats markedly increased during the N-surge of PRL. These results suggest a possibility that these hypothalamic amines may have an important role on the occurrence of the D- and N-surges of PRL in PSP rats. DDC injected intraperitoneally (500mg/kg) at 12.00 or 21.00 h on Day 1 of PSP produced a dramatic decrease in NE concentrations in the hypothalamus. Under these conditions, initiation of both D- and N-surges of PRL was significantly suppressed, whereas the magnitude and peak time of each surge were the same as those of normal PSP rats. PCPA injected intraperitoneally (250mg/kg) at 12.00 h on estrus of PSP also produced a dramatic decrease in serotonin concentrations in the hypothalamus, but the N-surge of PRL was only partially suppressed. PRL concentrations in the anterior pituitary were normal in these DDC- or PCPA-treated animals during the time period observed.
These results suggest that hypothalamic NE and serotonin are not essential for the occurrence of D- and N-surges of PRL, but they have a facilitatory effect on hypothalamic neural mechanisms inducing PRL release in response to the cervical sitimulation.

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Plasma gastric inhibitory polypeptide (GIP), insulin, glucagon concentrations and blood glucose levels in response to the ingestion of 100 g glucose were measured in 5 patients with hyperparathyroidism in order to elucidate the effect of hypercalcemia on the release of these hormones. In addition, the effect of acute hypercalcemia on the release of these hormones in response to glucose ingestion was investigated in normal subjects. Fasting plasma GIP concentration in patients with hyperparathyroidism was significantly greater than the value in seventeen normal subjects. Significantly higher responses of plasma GIP and insulin were observed after the glucose ingestion in the patients with hyperparathyroidism as compared with the values in the normal subjects, and integrated GIP and insulin responses to the glucose ingestion for 120 min in the patients with hyperparathyroidism were significantly greater than the values in the normal subjects. On the other hand, plasma glucagon concentration after the glucose ingestion in the patients with hyperparathyroidism remained unchanged, although plasma glucagon concentrations after the glucose ingestion decreased significantly from the basal value in the normal subjects. Blood glucose levels after the glucose ingestion in two groups increased significantly from the basal value in the same manner. In nine normal subjects calcium infusion (4 mg/kg bolus injection followed by continuous infusion of 4 mg/kg/hr for 3 hr) caused a significantly high concentration of plasma calcium (11.5 13.0 mg/dl) from the basal value. Significantly higher responses of plasma GIP and insulin to the glucose ingestion were observed during calcium infusion as compared with the values during saline infusion. On the other hand, plasma glucagon concentration after the glucose ingestion was not significantly changed during calcium infusion in contrast with a significant decrease of plasma glucagon after the glucose ingestion during saline infusion. Consequently, calcium was considered to play a major part in the release of GIP and insulin. The characteristic response of plasma glucagon during calcium infusion was considered, at least in part, to protect the hypoglycemia caused by hyperinsulinemia.

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The effects of calcium injection (3 mg/Kg/ 10 min) or oral calcium administration (calcium lactate 7.7g) on plasma iPTH and Nephrogenous cyclic AMP (NcAMP) were studied in 6 normal controls and 13 patients with primary hyperparathyroidism.
In the control subjects, plasma iPTH determined by a predominantly carboxyl-terminal antiserum was <0.3 ng/ml before and after both calcium loads, whereas 41-98% (mean 67%) of NcAMP was rapidly and uniformly suppressed to a level lower than the normal value.
In 2 patients with primary hyperparathyroidism, iPTH was clearly reduced from 8.0 to 4.6 ng/ml and 1.6 to 0.96 ng/ml, respectively, by the calcium load. However, in the other 7 patients with primary hyperparathyroidism who showed only a slight elevation of iPTH : <0.3-0.9 ng/ml, the reductions in iPTH were not detected after the calcium load : <0.3-0.7 ng/ml.
In contrast, 30-54% (1.02-3.85 nmol/dl GF, ) of NcAMP, which was greater than the diurnal variation, was suppressed after calcium injection in 5 patients with primary hyperparathyroidism (2 of 4 patients with urological, and 3 of 5 patients with chemical hyperparathyroidism). But NcAMP was not suppressed in all 4 patients with skeletal hyperparathyroidism including one with proximal renal tubular dysfunction whose basal iPTH was elevated markedly but reduced clearly by the calcium load.In general, suppression of NcAMP was followed by a decrease of phosphate excretion.
On the other hand, even in a patient with primary hyperparathyroidism whose NcAMP was not suppressed at all after the calcium injection, calcium infusion (15 mg/Kg/3 h) resulted in some (23%) decrease in NcAMP.
Oral calcium administration resulted in responses which were almost the same as those produced by calcium injection.
These results suggest that NcAMP provides a useful index in the parathyroid suppression test in patients with primary hyperparathyroidism, especially those who display a rather mild elevation of iPTH. This is not the case, however, in a few patients who show a marked elevation of iPTH and/or proximal renal tubular dysfunction.

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To evaluate the influence of hemodialysis on the determinations of iodothyronine concentrations, serum and plasma concentrations of thyroxine (T₄), 3, 5, 3'-triiodothyronine (T₃), 3, 3', 5'-triiodothyronine (rT₃), and 3, 3'-diiodothyronine (3, 3'-T₂), as well as total protein and non-esterified fatty acids (NEFA), were determined in 8 patients with chronic renal failure on hemodialysis. Serum samples were taken before the regular dialysis, and plasma samples during the dialysis were taken about 10 minutes after the beginning and just before the end of dialysis. T₄ was determined by competitive protein binding assay (CPBA) and radioimmunoassay (RIA), and T₃ rT₃ and 3, 3'-T₂ levels were determined by RIA.
Total protein concentrations were 7.0 ± 0.1 (mean ± SE) g/dl before the dialysis, decreased to 6.3 ± 0.3 g/dl about 10 minutes after the beginning of the dialysis, and then increased to 8.8 ± 0.4 g/dl at the end of the dialysis. Therefore, plasma NEFA and iodothyronine concentrations during dialysis were corrected by the protein concentration to avoid the effect of hemodilution or hemoconcentration.
Serum concentrations of T₄-RIA, T₄-CPBA, T₃ and rT₃ in patients with chronic renal failure were 6.4 ± 0.6 μg/dl, 6.9 ± 1.1 μg/di, 58 ± 4.9 ng/dl, and 16.8 ± 1.4 ng/dl, respectively; these values were all significantly lower than the normal controls. Serum 3, 3-T₂ concentrations (7.5 ± 0.7 ng/dl) were, however, significantly higher than the normal controls.
Plasma concentrations of T₄ determined by CPBA were markedly increased at the beginning of the dialysis (12.5 ± 1.2 μg/dl), whereas T₄-RIA levels were essentially constant during the dialysis. Plasma T₄ concentrations were not affected by the single dialysis. But plasma rT₃ concentrations were slightly decreased at the beginning and returned to the predialysis level at the end of the dialysis.
Plasma 3, 3'-T₂ concentrations were increased at the beginning of the dialysis (9.4 ± 1.0 ng/dl). Plasma NEFA concentrations were also increased at the beginning of the dialysis (from 510 ± 92 to 2453 ± 385 μM), and a positive correlation was observed between the increment of NEFA and that of T₄-CPBA or 3, 3'-T₂.
Furthermore, when more than 2 mM of sodium oleate was added to the pooled serum before the determinations of T₄ -CPBA, T₄ -RIA, T₃, rT₃ and 3, 3'-T₂, marked elevations of T₄-CPBA and 3, 3'-T₂ (RIA) levels were observed. T₃-RIA levels were also increased to the extent of 40% when sodium oleate was added to give the final concentration of 8 mM. No significant influences were observed on T₄-RIA and rT₃ (RIA).
These data confirm the previous report that NEFA falsely increase the T₄ concentrations as determined by CPBA in patients on hemodialysis and indicate that NEFA can significantly affect the T₃ and 3, 3'-T₂ concentrations determined by RIA.

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A 34-year-old female complaining of numbness and weakness of the extremities was examined. Consanguineous marriage was contracted between mother and father. She was of short stature (149 cm), and her blood pressure was normal (118/60 mmHg). Her serum potassium concentration had decreased to a level between 2.5 and 3.2 mEq/L, and hypokalemic alkalosis was present. Potassium clearance had increased and urinary concentrating capacity was impaired. Plasma renin activity was high at 25 ng/ml/hr but plasma aldosterone concentration was normal. Hypertensive response to angiotensin II (50 ng/kg/ min) was weak but improved to nearly the normal value after the administration of indomethacin for 17 days at a dose of 50 mg/day. A slight elevation in blood pressure was observed during the infusion of norepinephrine (250 ng/kg/min). A decrease in blood pressure was observed during the infusion of 1-sarcosine, 8-isoleucine angiotensin II (600 ng/kg/min) with concomitant increase of plasma renin activity. Twenty-four hour urinary excretion of prostaglandin E decreased somewhat (225-252 ng/day), and hyperplasia of the juxtaglomerular cells and increased JG index were demonstrated in the biopsy specimens of the right kidney. From these findings, the present case was diagnosed as Bartter's syndrome.
Although mild enlargement of the sella turcica was found in skull x-ray films, no abnormalities in pituitary function were demonstrated.
Other unusual complications, i.e. hyperlipidemia (type II, β-dominent) and abnormal configuration of peripheral erythrocytes, were demonstrated. Phospholipid composition of the erythrocyte membrane was normal. The fluidity of plasma VLDL examined by electron spin resonance was increased.
Hypokalemia and hyperreninemia were improved through the administration of indomethacin. However, because of headache as an adverse effect, further administration could not be accepted. The patient's complaints were resolved by the rectal application of indomethacin with oral administrations of spironolactone and triamterene.
Changes in serum lipid levels did not occur with the above mentioned treatment. α-tocopheryl nicotinate lowered the levels of serum lipids and normalized the configuration of peripheral erythrocytes. But increased fluidity of plasma VLDL remained, and phospholipid composition of erythrocyte membrane was also unchanged.
The relationship between the rare complications mentioned above and the pathophysiology of Bartter's syndrome is still obscure.

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This study was made to investigate the mechanisms of the changes in serum potassium during a period of insulin-induced hypoglycemia.
The following experiments were performed :
I) A relationship was observed between the amount of insulin dosage and the levels of serum potassium, blood sugar, and plasma cyclic AMP or plasma cyclic GMP in normal controls and rats. In humans, regular insulin (0.025-0.15 U/kg) was injected intravenously, and blood samples drawn at intervals were used for estimation. Regular insulin (0.1-1.0 U/kg) was injected into Wistar strain male rats and blood was drawn at intervals.
II) A relationship was observed between those items mentioned above in patients with thyroid diseases or diabetes mellitus. They were injected with regular insulin (0.1 U/kg).
III) An effect of spironolactone was observed on the levels of the above mentioned items. Regular insulin (0.075 U/kg) was injected into normal controls after the ingestion of spironolactone.
IV) An effect of non-selective β-blocker was observed on the levels of the above mentioned items. Regular insulin (0.1 U/kg) was injected into normal controls and patients with hyperthyroidism after the ingestion of 20 mg of propranolol.
The results obtained were as follows :
1) There was a significant logarithmic dose-response relationship between insulin dose and maximum per cent decrease in serum potassium, and maximum per cent increase in plasma cyclic AMP. (p<0.02-0.01)
2) A significant positive correlation was observed between the maximum per cent decrease in serum potassium and the maximum per cent increase in plasma cyclic AMP during the period of insulin-induced hypoglycemia. (p<0.001)
3) The changes in serum potassium and plasma cyclic AMP were significantly greater in patients with hyperthyroidism who were possibly in a hyperdynamic β-adrenergic circulatory state, and these changes were smaller in patients with hypothyroidism than in the normal controls. When their thyroid functions were normalized by the treatment, the changes in serum potassium and plasma cyclic AMP behaved in the same manner as those in the normal controls.
4) Spironolactone had no effect on any change observed in this study.
5) Neither per cent decrease of serum potassium nor per cent increase of cyclic AMP were influenced by propranolol at 15 minutes, but they decreased 30 minutes after the insulin injection.
These results may indicate that a decrease of serum potassium levels during the period of insulin-induced hypoglycemia in both the early and late phases is caused by different mechanisms. The change in serum potassium was accompanied by an increase of plasma cyclic AMP, and furthermore this change was inhibited by β-blocker. It was suggested that β-adrenoreceptor plays a role in a decrease of serum potassium, especially 30 minutes after a injection of insulin.

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