New establishment of hypertensive diabetic animal models: neonatally streptozotocin-treated spontaneously hypertensive rats.

Hypertensive diabetic animal models have been developed by injecting streptozotocin (STZ) in neonatal stroke-resistant spontaneously hypertensive rats (SHRSR) and stroke-prone SHR (SHRSP) at the age of two days. After the treatment, the animals showed mild insulin deficiency and mild hyperglycemia at the age of three to four months. Diabetic nephropathy was produced particularly in STZ-treated SHRSR at the age of six months. The effect of neonatal STZ injection on hyperglycemia varied among normotensive Wistar-Kyoto rats (WKY), SHRSR, and SHRSP; SHRSR showed the highest glucose levels, SHRSP showed intermediate levels, and WKY was the lowest. All STZ-treated SHRSR showed glycosuria, while glycosuria was not observed in the treated SHRSP and WKY. Histologic study indicated that these strain differences were partly ascribed to differences in islet B-cell sensitivity to toxic effects of STZ. The development of hypertension was not accelerated in these SHRSR and SHRSP compared with respective nontreated controls. Since STZ-treated SHRSR develop mild diabetic symptom with hypertension and develop mild diabetic glomerulosclerosis, they are good models for studying vascular complications or other problems relating to the synergism between hypertension and diabetes mellitus.

Evidence for elevated levels of dopamine in the rabbit pulmonary and carotid artery.

Catecholamine levels in six arteries, two aortae, and atria of rabbits were determined by high-performance liquid chromatography (HPLC) coupled with electrochemical detection. An appreciable concentration of dopamine (DA) was found in the pulmonary and carotid arteries. The content in these two arteries was greater than 200 ng/g, although the mesenteric, celiac, renal, and femoral arteries had less than 55 ng/g. The ratio of DA to norepinephrine (NE) in the pulmonary artery was 32.2 +/- 6.3%, and that in the carotid artery was 9.0 +/- 3.8%. These values are equivalent to the ratio in the canine paw pad and kidney, which are considered to be innervated by a dopaminergic system among peripheral tissues. The presence of DA in the pulmonary artery was confirmed by gas chromatography and mass spectrometry. In addition, uptake and distribution of [3H]DA and significant enhancement of [3H]DA release by transmural stimulation in the pulmonary artery were observed. These results suggested the possibility of dopaminergic innervation in the rabbit pulmonary and, possibly, carotid arteries.

Effect of calcium antagonists on hypertension and diabetes in new hypertensive diabetic models.

Hypertension in diabetic patients is more common than in controls, contributes substantially to their increased cardiovascular morbidity and mortality, and should be treated as accurately as diabetes mellitus itself. The purpose of this study was to investigate the effect of calcium antagonists on hypertension and diabetes in hypertensive diabetic rats, which were newly established by neonatal injection of streptozotocin in spontaneously hypertensive rats. At the age of 6 months, hypertensive diabetic rats and control hypertensive nondiabetic rats were treated with hydralazine, diltiazem, or nifedipine for 2 months. In diabetics, antihypertensive therapy not only prevented the progression of nephropathy but also improved glucose metabolism by increasing insulin secretion. Calcium antagonists in this study reduced urinary protein excretion, and nifedipine relieved hypoalbuminemia. Hydralazine had no beneficial effect on urinary protein excretion. Calcium antagonists as compared to hydralazine decreased the heart weight. Calcium antagonists have a beneficial effect on cardiac hypertrophy. Good correlations have been found between kidney weight and blood pressure in hypertensive diabetic rats. It is suggested that blood pressure reflects increase in kidney weight in diabetic patients.

Rat fetal islets as a useful model for the study of insulin release failure.

To study the mechanism of imparied insulin secretion from rat fetal islets, the insulin responsiveness of islets from fetuses (day 21.5 of gestation) to a variety of secretagogues was compared with that of adult rat islets. Forskolin (30 microM)-induced insulin release from fetal and adult islets was 2.7-and 2.5-fold higher, respectively, than that from islets treated with 5.6 mM glucose alone. The effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) (200 nM) were also similar in fetal and adult islets. Thus, the responsiveness to forskolin and TPA showed no significant difference in adult and fetal islets. A synergistic effect of combinations of various insulin secretagogues was observed in adult islets; however, a weak synergistic effect was present with gliclazide plus TPA only in fetal islets. After islets were cultured in RPMI 1640 (containing 11.1 mM glucose), gliclazide-, forskolin-, and TPA-induced insulin release reached the levels obtained in adult islets. However, the synergistic effect of gliclazide and TPA disappeared after culture of the islets. These results suggest that the poor insulin secretion from fetal islets is not due to a defect in the activating system of either cAMP or C-kinase, but to the immaturity of the interaction of those messenger systems.

Effect of chronic hyperprolactinemia induced by sulpiride on plasma dehydroepiandrosterone (DHA) in normal men.

In order to elucidate the relationship between plasma dehydroepiandrosterone (DHA) and sulpiride-induced hyperprolactinemia (of 60 day duration) in normal men, five normal men (aged 27-46) were administered daily 300 mg of sulpiride orally for 60 days to induce hyperprolactinemia. Plasma levels of prolactin, DHA and cortisol were measured by radioimmunoassay before sulpiride treatment, at day 14 and day 60 after initiation of the treatment. Plasma levels of prolactin after the administration rose significantly (P less than 0.001) to 71.6-95.3 ng/ml in four out of the five subjects compared with those of the controls. In the same four subjects the mean DHA values in plasma were elevated significantly (P less than 0.05) to 877 +/- 160 ng/dl from the mean baseline values (669 +/- 91 ng/dl). The elevated values remained during sulpiride treatment. Plasma levels of cortisol did not change significantly during sulpiride administration in all subjects. Our results suggest that sulpiride-induced hyperprolactinemia sustained at least 14-60 days in normal men stimulates the adrenal cortex to secrete DHA.

[Classification of asymptomatic autoimmune thyroiditis by thyrotropin-releasing hormone loading].

Thyrotropin-releasing hormone loading was performed on 91 patients with asymptomatic autoimmune thyroiditis. Four women had no response to this loading test and had high levels in serum total and free thyroxine (TT4, FT4) and in serum total and free triiodothyronine (TT3, FT3). These patients might be classified as subclinical hyperthyroidism (Group G). Twenty-four patients had normal levels of both basal and peak thyrotropin after loading and were classified as Group I. There were no significant differences between 45 controls (Group C) and Group I patients in serum thyroid hormone levels. Patients with normal basal and high peak levels of thyrotropin were included in Group II. The number of patients in this group was 53. The mean levels of basal and peak thyrotropin were 4.8 microU/ml and 39.6 microU/ml, respectively, and were significantly higher than in Group C and Group I (P less than 0.005). In 10 patients classified as Group III with high levels of both basal and peak thyrotropin, serum concentrations of TT4, FT4 and FT3 were significantly lower than in the other groups (P less than 0.025); however, significant differences in TT3 could not be seen among them. Serum cholesterol levels gradually increased from Group C to Group III. There were significant differences between Group C and Group II (P less than 0.05).

Natural killer cell activity against a variety of target cell lines in normal persons: NK-target sensitivity and effect of age and sex on NK levels.

Natural killer (NK) cells have been implicated as first line of defence mechanism for carcinogenesis in humans. A lot of studies of depressed NK activity in patients with malignancies have supported this. Two major problems, however, in these studies are the choice of normal controls and target cells. To study this problem, peripheral mononuclear cells (PBMC) of sixty-six normal subjects from young and elderly, males and females were tested for NK function against twenty target cell lines with a microcytotoxicity assay. The result was shown that no sex or age difference existed with respect to NK function, except for a slight but significant decreased in NK activity of young female to K562 target cells. Target cells were divided into four groups by their NK sensitivity, namely, high, moderate, low and refractory sensitive. In general, NK activity of healthy persons is considered to remain stable and polyspecific in our results.

Islet cell antibodies in the Japanese population and subjects with type 1 (insulin-dependent) diabetes.

Islet cell antibodies were studied in 1,112 non-diabetic adults, 473 normal school children and 162 Type 1 (insulin-dependent) diabetic patients in a Japanese population. The prevalence of islet cell antibodies was 0.5%, 0.4% and 32%, respectively. Most islet cell antibodies positive subjects with Type 1 diabetes had short duration of the disease. No patients who had over 10 years from the onset had islet cell antibodies. Six non-diabetic adults with islet cell antibodies were followed for 4 years. Only one with Hashimoto's thyroiditis showed a diabetic pattern in her oral glucose tolerance test. However, none developed overt insulin-dependent diabetes until 1984. Two out of these six subjects continued to be positive for both islet cell antibodies and antithyroid antibodies or antinuclear antibodies. Islet cell antibodies in the remaining four patients disappeared during the second year. It is difficult to predict the onset of Type 1 diabetes by islet cell antibodies in non-diabetic individuals because they may be transient.

Influence of chronic hyperprolactinemia induced by sulpiride on the hypothalamo-pituitary-testicular axis in normal men.

For elucidation of the effects of hyperprolactinemia on the hypothalamic-pituitary-testicular axis, five healthy men were exposed to sulpiride (300 mg/day by mouth); four among the five maintained hyperprolactinemia (71.6 to 95.3 ng/ml) for 78 days. Clomiphene citrate (CC), luteinizing hormone (LH)-releasing hormone, and human chorionic gonadotropin tests were performed before and after sulpiride treatment. The CC test, given as a measure of hypothalamic function, was carried out in each of the five volunteers before sulpiride treatment (control) and on days 14 (2 weeks) and 60 (2 months) of sulpiride administration. Each value of plasma LH stimulated by CC was integrated and expressed as a ratio of the integrated value obtained after administering CC at 2 weeks and 2 months to that from each control experiment. The mean ratio in the four subjects at 2 months (mean +/- standard deviation, 0.769 +/- 0.121) was significantly lower than that at 2 weeks (0.942 +/- 0.073; P less than 0.05) and before sulpiride treatment (1.000; P less than 0.01). Impairment of LH responses to CC by 2-month long sulpiride-induced hyperprolactinemia suggests that chronic hyperprolactinemia in men partly suppresses LH secretion by its inhibitory action on the hypothalamus.

Interrelationships between blood pressure, sodium, potassium, serum cholesterol, and protein intake in Japanese.

Interrelationships among blood pressure (BP), sodium (Na), potassium (K), dietary protein, and serum cholesterol level (Chol) were examined in 62% (1120) of 1818 Japanese inhabitants of both sexes aged over 30 years who lived in a rural village in Japan. Fasting single-spot urine specimens were collected in the morning to measure Na, K, urea nitrogen (UN), inorganic sulfate (SO4), and creatinine (Cr). The Cr ratios of Na, K, UN, SO4, Na/K, and SO4/UN were analyzed by multiple regression analysis to determine independent associations with BP together with age, obesity index, hematocrit (Hct), Chol, triglyceride (TG), and fasting serum glucose level (Glu). Except for Na/Cr in men, Na/Cr and Na/K were found to be independently and positively related to BP, particularly to systolic BP (SBP). In contrast, K/Cr and SO4/UN (an index related to the dietary score of sulphur-containing amino acids derived mainly from animal protein) were both negatively associated with SBP, and UN/Cr (an index of total protein intake) was positively associated with SBP in men. Chol was linked to BP negatively in men but positively in women. Age, obesity index, TG, and Hct were generally positively and significantly related to BP in both sexes. The results confirmed on epidemiological grounds the positive link of Na and the negative link of K to BP within a single population in Japan. They further suggest, although only in men, that there is a negative relationship of Chol and dietary animal protein with BP.

A population survey of pancreatic islet cell antibodies and antithyroid antibodies.

In a survey of one Japanese population, we detected pancreatic islet cell antibodies (ICA), antithyroid antibodies (ATA) and antinuclear antibodies (ANA). The prevalence of ICA was 6 out of 1125 cases, or 0.5%. ATA and ANA were detected in 8.9% and 1%, respectively. There were no cases of either type I or type II diabetes in subjects with ICA. But there was one case who had ATA and another with ANA. Serum samples from this population had been obtained once a year from 1979 and one case with neither ATA nor ANA was found positive for ICA in 1980. Identical tests for ICA were performed on 80 childhood diabetics as were carried out on type I diabetics. Pancreatic isles cell surface antibodies (ICsA), ATA and ANA were studied simultaneously. The prevalence of ICA in 80 cases was 36.3% and that of ICsA was 13.8%. 4 cases had both ICA and ICsA. The prevalence of ATA was 11.2% and that of ANA was 16.3%.

Antinuclear antibodies in childhood diabetics.

Antinuclear antibodies (ANA) were detected both in type 1 diabetic children and in control subjects. The incidence of ANA in eighty of these diabetics was 16.3%, as determined using two different substrates, human pancreas and human peripheral leucocytes. The incidence and the patterns in the detection of ANA were the same. Four hundred and seventy-three children and one thousand one hundred and twenty-five adults served as the controls. The incidence of ANA in non-diabetic children was 0.8% and that in one adult population was 1.1%. Therefore, the incidence of ANA in childhood diabetics was significantly higher. We studied autoantibodies in childhood diabetics, in normal children and in one adult population. Pancreatic islet cell antibodies (ICA) were detected in 29 out of 80 type 1 diabetics (36.3%) in two out of 473 normal children (0.4%) and in six cases in one population (0.5%). thyroid microsomal antibodies (MCHA) were detected in 9 out of 80 childhood diabetics and the incidence of MCHA in type 1 diabetics was significantly higher than in the controls.