Theophylline: potentiation of arginine-induced somatostatin release from the isolated rat pancreas.

Somatostatin's release from the isolated rat pancreas was studied using a perfusion technique. Arginine at a concentration of 19 mM produced a biphasic increase in somatostatin release from the perfused rat pancreas. Both first and second phases of somatostatin's increase are significantly higher in the presence of 1 mM theophylline than in the absence of the drug. These results indicate the possible inclusion of the adenylate cyclase--cyclic AMP system in the regulatory mechanism of rat pancreatic somatostatin secretion.

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.

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.

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.

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.

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.

Modulation by glucose and D-glyceraldehyde of glucagon and insulin secretion in the isolated perfused streptozotocin-treated rat pancreas.

In order to compare the effects of D-glyceraldehyde or glucose on glucagon secretion in insulin deficiency, the isolated streptozotocin-treated rat pancreas was perfused with arginine alone and arginine plus eigher glucose or D-glyceraldehyde. The glucagon secretion induced by arginine alone was not modified by pretreatment with streptozotocin, but the glucagon secretion induced by arginine plus either glucose or D-glyceraldehyde was less inhibited in the streptozotocin-treated pancreas. We conclude, therefore, that insulin deficiency may interfere with the metabolism of D-glyceraldehyde as well as glucose in the pancreatic A-cells, thus interfering with the inhibitory effect of glucose and D-glyceraldehyde of glucagon secretion.

The dual effect of alloxan modulated by 3-O-methylglucose or somatostatin on insulin secretion in the isolated perfused rat pancreas.

While alloxan treatment stimulated insulin secretion, alloxan pretreatment reduced arginine and glucose-induced insulin secretion in the isolated perfused rat pancreas. The transient insulin secretion by alloxan was inhibited by 3-O-methylglucose and somatostatin. Diminished insulin response to arginine and glucose induced by pretreatment with alloxan was restored by the addition of 3-O-methylglucose, whereas the addition of somatostatin did not improve the impaired insulin secretion. These results indicate that alloxan induced insulin secretion is not due to an uncontrolled leakage, but that the stimulatory and inhibitory action of alloxan on insulin secretion might be initiated by the binding of alloxan to the hexose transport site.

Epidemiological analysis on the mechanism of cigarette smoking as a risk factor in cardiovascular diseases.

To clarify the mechanism involved in the contribution of cigarette smoking to increased mortality in patients of cardiovascular diseases (CVD), blood pressure (BP), serum cholesterol (Chl), triglycerides (TG), obesity index (OI), hematocrit (Ht), hemoglobin (Hb) etc, were examined in male smokers and non-smokers among 2500 inhabitants of a farming village in Japan. Smokers were classified by age and by the number (n) of cigarettes smoked per day into mild smokers (1 smaller than or equal to n < 20), moderate smokers (20 smaller than or equal to n < 30) and heavy smokers (n larger than or equal to 30). Ht was increased with the number of cigarettes smoked and was significantly higher in heavy smokers than in non-smokers, in most all the age groups. BP, Chl, TG, OI, Hb etc, showed no significant quantitative relation to the number of cigarettes smoked. This increase in Ht in smokers may represent a risk factor in increasing the morality rate in CVD.

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.