Lordosis response in estradiol benzoate (EB)-progesterone (P) primed castrated female rats was studied after 4 types of deafferentation of the medial hypothalamus. Tests were started 4-5weeks after the brain surgery and ovariectomy. Anterior deafferentation (half-dome cut) at the level behind the suprachiasmatic nucleus (AD-I) and island isolation of the medial basal hypothalamus (MBH island) were highly effective to suppress lordosis response in EB-P primed females. However, the cuts placed dorsal (AD-II) or posterior (AD-III) to the AD-I were without apparent suppressive effect on the EB-P induced display of lordosis. These results suggest that the anterolateral fiber connection with the MBH may participate in lordosis facilitatory mechanisms in EB-P primed females. When reserpine (R) was injected instead of P to EB-primed rats, R effectively facilitated lordosis response in rats with or without the deafferentation (AD-I or MBH island). This suggests that the MBH is not necessary to facilitate lordosis in EB-R primed rats. The site of action of R in the central nervous system for facilitating lordosis may not be the same as that of P.

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The contents of insulin and C-peptide extractable with acid alcohol from the tail of the pancreas and insulinoma were investigated, using gel filtration in seven nondiabetics including two patients with insulinoma and eight diabetics. The gel filtration patterns of both C-peptide and insulin in pancreatic extract were fairly stable even after the pancreas had been left for 14 hrs in the room temperature. In non-diabetics except cases of insulinoma the content of insulin in pancreas ranged from 1.42 to 4.56U per gram and that of C-peptide from 8.76 to 25.63μg per gram wet pancreas. The proportion of proinsulinlike components (PLC) ranged from0.01to 2.04% of insulin plus PLC. In diabetics insulin content was low and ranged from 0 to 1.68 U per gram and that of C-peptide from 0 to 14.48μg per gram wet pancreas. In insulinoma, both insulin and C-peptide increased and PLC occupied 5.48 and 5.96%, respectively.

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Major hepatectomy in the dog induced a 50% decrease in peripheral serum glucose, all-fold increase in portal plasma glucagon and a 36-fold increase in the portal glucagon/insulin ratio 3hr after operation. Peripheral serum glucose levels were inversely correlated to the logarithmic value of portal plasma glucagon (r=-0.50, p<0.01) and that of the portal glucagon/insulin ratio (r=-0.85, p<0.01) for 1-6hr after operation. The ratio of peripheral to portal plasma glucagon was also inversely correlated to the logarithmic value of portal plasma glucagon (r=-0.59, p<0.01). In case of glucose infusion, plasma glucagon levels were not elevated after major hepatectomy.
The data suggest that glucose deficiency after major hepatectomy in the dog may cause hyperglucagonemia with an enhanced glucagon requirement.

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Oral glucose tolerance tests were performed under pentobarbital anesthesia in 43 male Wistar rats 2 to 18 months of age in order to determine if insulin and glucagon secretion are altered with aging.
Although any linear correlation was not demonstrated between aging and blood glucose, plasma insulin or glucagon levels, post-glucose levels of blood glucose were significantly suppressed and those of plasma glucagon were significantly elevated at 4 to 6 months of age. No significant difference was found between young (2 months of age) and aged rats (12 to 14 and 17 to 18 months of age) in either blood glucose or plasma insulin levels during oral glucose load. On the other hand, post-glucose plasma glucagon levels of the aged rats were significantly higher than those of the young ones. Furthermore, comparisons of various kinds of indices among the different age groups, such as insulinogenic index, insulin/glucagon and so forth during oral glucose tolerance tests also indicate the significant alteration of glucagon secretion during aging process.
It is concluded from the present data that glucose tolerance does not apparently deteriorate during aging process in rats but that glucagon responses to oral glucose administration are elevated with aging.

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The effect of a single i. v. injection of30, 50, and65mg of streptozotocin (Sz) per kg of body weight on blood glucose, plasma insulin and glucagon levels was studied in rats. Responses to glucose of these three parameters were also examined in rats one week after the administration of various doses of Sz alone, Sz with nicotinamide or with picolinamide. Nicotinamide, 500mg/kg, and picolinamide, 250mg/kg, were given i.p. 15min before the injection of 65mg/kg of Sz.
The triphasic pattern was observed after the injection of 65mg/kg of Sz not only in blood glucose and plasma insulin but also in plasma glucagon level fluctuations, the last of which showed a similar pattern to that of blood glucose responses. Further, the initial hyperglucagonemia had a delay of 2hr in onset, when treated with30and50mg/kg of Sz, respectively.
Oral glucose loading resulted in a significant increase of plasma glucagon levels in rats injected with 30 and 50mg/kg of Sz, respectively. The paradoxical rise of plasma glucagon and glucose intolerance was observed in rats given Sz with nicotinamide, and Sz with picolinamide, as well as in those given Sz alone, 65mg/kg, while there was no significant difference in insulin responses between the pretreated groups of rats and controls.
These results suggest that streptozotocin, even in a nondiabetogenic dose, has effect (s) on the A cell function, and that nicotinamide and picolinamide are active in protecting B cells against the cytotoxic effect, but they do not modify the effect of Sz on the A cell function.

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Insulin encapsulated in liposomes of various lipid compositions were prepared. The amount of insulin trapped in these liposomes increased in the order, negatively charged liposomes<neutral liposomes<positively charged liposomes. In positively charged liposomes, the amount of insulin trapped increased with increase in the amount of amphiphile stearylamine. Under the conditions tested, the highest insulin content (about 50%) was obtained with liposomes composed of phosphatidyl choline/cholesterol/stearylamine in a molar ratio of 7/2/2.25. These liposomes were stable on incubation for3hr at 37°C in solutions of pepsin, trypsin, and pancreatin, and after these incubations, a considerable amount of insulin was still associated with the liposomes. However, the liposomes released almost all the insulin into the medium on treatment with bile.
When the liposomes were administered orally to rats in the3rd phase of acute alloxan diabetes, reduction of the blood glucose level was observed in7of11animals the reduction persisted for several hours and was ranging from 30 to 75%.
In alloxan diabetic rats showing hyperglycemia for 3 to 6 months, the liposomes also increased the glucose tolerance in half the animals tested.

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Rats after adrenalectomy-testectomy showed a gradual increase in diencephalon 3-oxo-5α-steroid:(acceptor)Δ⁴-oxidoreductase (5α-reductase) activity for 3 days. The activity then returned near to the normal range on the 4th postoperative day. When rats were given testosterone propionate (TP) 3 days after adrenalectomy-testectomy, diencephalon 5α-reductase activity returned to the preoperative range 2hr after TP administration. Diencephalon 5α-reductase activity showed a highly significant increase (p<0.01) after a single administration of carbamazepine, reserpine, diazepam, phenytoin, phenobarbital or disulfiram. A significant increase (p<0.05) was also found after a single administration of methylphenidate, caffeine or methamphetamine. Plasma testosterone decreased concurrently after administration of all these agents, except diazepam. Diencephalon enzyme activity decreased significantly after repeated disulfiram administrations (p<0.01) but increased significantly after methamphetamine administrations (p<0.05). Plasma testosterone showed a tendency to decrease after repeated methamphetamine administrations but tended to increase after repeated disulfiram administrations.

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Thyroparathyroidectomy (TPTX) caused a significant increase in serum glucose and a corresponding fall in serum calcium in both fed and fasted rats. The increase in serum glucose, induced by TPTX, was markedly potentiated by a single intraperitoneal administration of calcium (2mg/100g BW) which caused a significant elevation of serum calcium in thyroparathyroidectomized rats. Parathyroid hormone (PTH; 20U/100g BW) administered subcutaneously to thyroparathyroidectomized rats, caused a significant decrease in serum glucose, but did not increase serum calcium. A single intraperitoneal administration of glucose (0.1g/100g BW) to sham-operated rats significantly increased both serum glucose and insulin. The rise of serum glucose produced by a glucose load was markedly potentiated by TPTX, but the increase in serum insulin was not promoted significantly. The administration of PTH decreased both serum glucose and insulin levels increased by a glucose load to thyroparathyroidectomized rats, in a dose-dependent manner. The administration of calcitonin (80MRC mU/100g BW) significantly prevented the effect of PTH to decrease serum glucose after a glucose load to thyroparathyroidectomized rats, and calcitonin increased serum insulin. These results suggest that the effect of PTH on serum glucose does not involve insulin secretion.

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In order to assess further the mechanisms involved in insulin release, we prelabeled rat pancreatic islets of Langerhans by incubating either ⁴⁵Ca or [2-³H]adenine. When prelabeled islets were perfused with a glucose-free medium (the experiment with ⁴⁵Ca) and a medium containing 2.8mM glucose (the experiment with [2-³H] adenine) respectively, a constant rate of efflux of the radioactivity was established by 30min in each case. D-Glucose at 16.7mM concentration elicited a rapid efflux of ⁴⁵Ca and [2-³H] adenine derivatives ([³H]Ad) within 4 to 6 min after commencing the step-wise stimulation by glucose, concomitantly with insulin release. However, Lglucose and D-galactose little stimulated both ⁴⁵Ca and [³H] Ad release. Lanthanum chloride caused a burst peak of ⁴⁵Ca release in the absence of glucose. A rapid efflux of45Ca was caused by fi-D-glucose and D-glyceraldehyde to much lesser extent than by α-D-glucose.
The slowly rising concentration of glucose at 0.1mm/min of gradient level failed to elicit any rapid efflux of ⁴⁵Ca or [³H] Ad, although insulin release occurred in accordance with an increase in glucose concentration. Even when the gradient of glucose concentration was raised to 0.7mM/min, glucose failed to stimulate an efflux of [³H] Ad but the subsequent stimulation by 16.7mM glucose caused a rapid efflux of [³H] Ad concomitantly with the release of insulin. No rapid efflux of ⁴⁵Ca was observed under a slow-rise glucose stimulation until the gradient level of the glucose concentration was raised to 6.7mM.
Analysis of distribution of the radioactive adenine derivatives after incubation showed that the adenosine fraction had the highest radioactivity in the medium followed by the ATP, adenine and cAMP fraction in that order, and the ATP fraction had the highest radioactivity in the islet. The ratio of radioactivity in the cAMP fraction in the medium to the total count was the highest among all.
On the basis of these results, it was suggested that the discharge of [³H] Ad and ⁴⁵Ca might occur with the alteration of the membrane permeability induced by a rapid change of the glucose concentration, and that their discharge might perhaps link to the glucoreceptor mechanism directly controlling insulin release.

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The amount of free fatty acid in the mouse mammary gland continuously increased throughout pregnancy and lactation, while the amount of triglyceride which had been stored in the gland rapidly decreased after parturition. Higher lipolytic activity in the gland was observed in pregnancy than in nonpregnant and lactating animals. The optimum pH of the activities before and after parturition were about 6 and 7, respectively, and the activities did not decrease at high ionic strength in contrast to the ion dependent inactivation described in lipoprotein lipase. Incubation of the enzyme extract of the lactating mouse mammary gland at 50°C for 10min led to a remarkable increase in the lipolytic activity measured at pH6.0, suggesting the existence of either an inactive form of the lipase whose optimum pH is6.0or some heat sensitive inhibitor (s) or inactivator (s) of the enzyme in the lactating mammary gland. The triglyceride stored in the gland in pregnancy will be consumed within the first 3rd days after parturition, and the lipases play an important role in the decomposition of the triglyceride.

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To examine timed changes in the morphology of theca interna and granulosa cells of rabbit preovulatory follicles, mature female rabbits were injected with 100 IU per kg of human chorionic gonadotropin (hCG) and follicles larger than1mn in diameter were excised for light and electron microscopic studies before and 3, 6, 9 and 12hr after hCG injection. Spindle-shaped theca interna cells had been transformed into rounded cells with pronounced hypertrophy within9hr after hCG injection, and degenerative changes in cellular appearance with reduction in cellular density became apparent 12hr after hCG administration. Electron micrographs of thecal cells showed that the maximum proliferation of large mitochondria and the full development of smooth endoplasmic reticulum (sER) had occurred by6hr after hCG injection, while by 12hr after hCG administration abundant lipid droplets had accumulated and sER had decreased. These morphological changes in the theca interna cells indicate an activated endocrine function in the earlier stage followed by diminution in steroidogenesis in the later stage of the preovulatory interval. Although no appreciable changes was noted in granulosa cell histology in the first 6 hr after hCG injection, luteinizing changes proceeded9hr or more after hCG administration, as evidenced by the enlargement of cytoplasmic volume. A series of cytoplasmic modifications of granulosa cells leading to the formation of the fine structures characteristic of steroid-producing cells developed gradually in the earlier stage and rapidly in the final stage prior to ovulation, indicating differentiation of granulosa cells into lutein cells. It is concluded that the major cellular site of steroid biosynthesis in ovulating rabbit follicles may shift from degenerating thecal cells to luteinizing granulosa cells in the course of the preovulatory process.

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Intravenous infusion of somatostatin in mongrel dogs caused a significant decrease in the peripheral plasma renin activity (PRA) enhanced by pentobarbital sodium anesthesia or furosemide treatment. However, the inhibitory activity vanished within 10min after termination of somatostatin infusion. Intrarenal arterial infusion of somatostatin decreased furosemide-enhanced PRA in renal vein by 24.0%, 16.6% and 8.6% in dose of 0.1, 0.5 and 1.0μg, respectively. On the other hand, high doses of the peptide (50-200μg) failed to decrease. The changes in PRA occurred in the absence of any alteration in blood pressure during the intravenous infusion under furosemide treatment.
In an in vitro study, the addition of somatostatin in doses of 0.01 and 0.05μg suppressed the renin release in dog renal cortical cell suspension by 74.3% and 53.6%, respectively. Therefore, in both intrarenal arterial infusion and the cell suspension system, somatostatin was increasingly effective in decreasing renin release towards the lower end of the dose range tested.
These results suggest that the effect of somatostatin on hyperreninemia may involve an inhibition of renin release at the cell level in the kidney.

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The effects of alloxan on glucose oxidation and the protection by anomers of D-glucose from alloxan inhibition of glucose oxidation in the pancreatic islets were investigated using in vitro incubation of rat isolated islets.
The pretreatment by alloxan (5-30mg/dl) for 6 minutes inhibits significantly ¹⁴CO₂ formation from ¹⁴C-U-D-glucose (10mM) and the addition of a-anomer of D-glucose (8.3mM) to alloxan (20mg/dl) completely reverses alloxan inhibition of glucose oxidation.
These findings seem to be incompatible with the recent view that alloxan acts at the glucose receptor on the plasma membrane of pancreatic β-cells without affecting glucose metabolism in the pancreatic islets.

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Intracisternal injection of bethanidine in rats decreased brain norepinephrine turnover without affecting its endogenous level, and increased both cardiac norepinephrine turnover and serum corticosterone level. A negative correlation was observed between brain norepinephrine turnover rate and serum corticosterone level. On the other hand, when cardiac norepinephrine turnover was suppressed by intraperitoneal injection of bethanidine, serum corticosterone did not change significantly. Next, ether inhalation was added after intracisternal injection of bethanidine. Then, serum corticosterone increased more even when brain norepinephrine turnover was suppressed only slightly. These data may indicate that serum corticosterone increases by selective decrease in brain norepinephrine turnover via the humoral route; from the hypothalamus down to the adrenal cortex.
Inversely, intracisternal injection of corticosterone increased brain norepinephrine turnover.
These results suggest that brain norepinephrine may play an inhibitory role in the tonic regulation of CRF-ACTH secretion in the higher center than the hypothalamus and there may be a closed-loop feedback system between brain norepinephrine and serum corticosterone.

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Effects of an orally active angiotensin I-converting enzyme inhibitor, SQ14225, on the actions of angiotensin I (AI) infused intravenously for 120 to 390 min were studied in 5 normal men. When 20ng/kg/min of AI infusion was started immediately after a single oral administration of 100 mg of SQ14225, a significant rise in blood pressure (BP) was observed for the first 15 min, but BP began to fall from 17 min and returned to the pretreatment level at 45 min. This BP level continued at least to 120 min and in one subject to 180 min. In this subject BP began to rise again from 185 min and reached the level of 15 min at 390 min. Plasma Al level increased gradually from 45 min. At 15 min plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased, but then PRA began to increase and PA began to decrease. At 120 min the values of PRA and PA were similar to the pretreatment values. In one subject plasma AI and PRA began to decrease and PA began to increase after 120 or 180min. On the other hand, in the 5 men sole AI infusion caused a continued BP rise, PRA decrease and PA increase, and sole SQ14225 administration caused increases in plasma AI and PRA and a decrease in PA b ut no BP change. From these results it was concluded that complete blockade and partial inhibition of AI conversion by 100mg of oral SQ14225 lasted for about 2.5 and 6.5hr, respectively and that BP rise, PRA suppression and aldosterone stimulation after AI infusion were entirely due to the actions of angiotensin II converted from AI.

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The effects of chlorpromazine (CPZ) and estradiol benzoate (EB) on serum prolactin (PRL) levels were studied in gonadectomized male and female rats. In both sexes CPZ (25mg/kg body weight) produced an elevation of PRL when measured 2hr after the injection, but the elevated levels were higher in ovariectomized rats than in orchidectomized rats. These results reconfirm a sexual difference in the regulatory mechanism of PRL secretion in response to the dopamine receptor blocker. Pretreatment with 5μg EB 48hr before CPZ injection abolished this sexual difference in serum PRL concentration.

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