Biomedical subjects
Publications and source records attributed to T Shibasaki.
The distribution of ovine corticotropin-releasing factor (CRF)-like immunoreactivity (CRFI) in the chicken retina was investigated by means of immunohistochemistry. The observations from frozen sections show that CRFI is localized in the stratified amacrine cells of the fourth sublayer . Whole-mount preparations revealed that these amacrine cells are moderately concentrated in the inferior part of the retina.
The distribution and projection of immunoreactive gamma-melanocyte-stimulating hormone (gamma-MSHI) in the rat brain was examined by indirect immunofluorescence using an antiserum against synthetic rat gamma-MSH. The present study confirmed the presence of gamma-MSHI neurons in the arcuate nucleus and further demonstrated that the n. commissuralis is a new gamma-MSHI neurons-containing site. We also found a gamma-MSHI fiber network in the hypothalamus, thalamus, amygdala, central gray matter of the midbrain and upper pons, and further demonstrated a much more extensive distribution of these fibers particularly in the medulla oblongata, an area previously thought not to contain gamma-MSHI structures. The present observation on the normal distribution of gamma-MSHI suggested the existence of two different systems: one is the arcuatofugal gamma-MSH system and the other n. commissuralis gamma-MSH system. Using experimental manipulations, we clearly established that gamma-MSHI fibers in the forebrain, diencephalon, midbrain and upper pons originate from gamma-MSHI neurons in the arcuate nucleus and those in the medulla oblongata from the n. commissuralis .
Appearance of immunoreactive corticotropin-releasing factor (CRF)-containing neurons was studied in developing hypothalamus of the rat by use of antisera against rat- and ovine CRF. These neurons were first recognized in the lateral and paraventricular nuclei on days 15.5 and 16.5 of gestation, respectively, when antiserum against rat CRF was employed. Antiserum against ovine CRF revealed the cells two days later exclusively in the latter nucleus. In both nuclei, the neurons increased in number with development. The neurons in the paraventricular nucleus appeared to project their immunoreactive processes to the median eminence via the periventricular and lateral pathways. In the median eminence, the immunoreaction with antiserum to rat CRF was first recognized in its anterior portion in the form of dots on day 16.5 of gestation but as beaded fibers in the external layer on day 17.5; these structures increased in amount with development in rostro-caudal direction. Although antiserum to ovine CRF was less potent in immunostainability than antiserum to rat CRF, it also revealed the beaded fibers in the median eminence on day 17.5 of gestation. Since evidence is available that the paraventricular nucleus is involved in corticotropin release, it is concluded that, in rats, the hypothalamic regulatory mechanism controlling the release of corticotropin initially appears on days 16.5-17.5 of gestation.
Twenty cases with spontaneous carotid-cavernous fistulas were followed up for periods ranging between 9 months and 9 years 8 months. In five cases, a temporary reappearance of symptoms was noted within 6 months after their regression. A complete regression of symptoms without reappearance for more than 6 months (between 6 months and 6 years 10 months) was noted in 18 cases, and a marked improvement was noted in one case. The regression of symptoms was usually delayed in patients less than 60 years old, in cases in which the symptoms developed slowly, and cases with three draining veins. According to these observations, noninvasive treatment is basically recommended in cases with spontaneous carotid-cavernous fistulas.
Distribution of substance P-, [Leu]enkephalin-, cholecystokinin-8-, neurotensin-, avian pancreatic polypeptide- and gamma-melanocyte stimulating hormone-like immunoreactive structures were investigated in the nucleus tractus solitarii of the rat by means of the indirect immunofluorescence method. The density of the immunoreactive structures varied markedly according to neuropeptides or subnuclei, with the medial and commissural nuclei containing the highest density. This suggests that the peptides examined play a role in cardiovascular function. However, as seen in the substance P- and [Leu]enkephalin-like immunoreactive structures, these peptides were widely distributed in the nucleus tractus solitarii in addition to the commissural and medial nuclei; a high density of immunoreactive fibers in the ventral, dorsolateral and intermediate subnuclei. In addition to the immunoreactive fiber plexus, a group of immunoreactive cells was also identified in the subnuclei mentioned above. These findings strongly suggest that substance P- and [Leu]enkephalin-like immunoreactive structures are involved not only in cardiovascular function but also in other functions such as respiration, at least in the rat. Finally, the present study demonstrated that the area postrema, particularly its lateral portion, contains various neuropeptide-like structures, both neurons and fibers, substance P-, [Leu]enkephalin-, cholecystokinin-8- and neurotensin-like immunoreactive neurons and fibers, and avian pancreatic polypeptide- and gamma-melanocyte stimulating hormone-like immunoreactive fibers.
The response of plasma growth hormone to synthetic growth hormone-releasing factor (hpGRF-44) administered intravenously was examined in normal men of various ages ranging from 20 to 75 years. Most of the subjects who were over forty years old had either no or much lower response of plasma growth hormone to hpGRF-44. In contrast plasma growth hormone increased markedly after hpGRF-44 injection in all men in their twenties and thirties. The mean peak level of plasma GH following hpGRF-44 administration was 29.6 +/- 20.4 (SD) ng/ml in men in their twenties, 30.2 +/- 26.5 ng/ml in their thirties, 9.7 +/- 5.2 ng/ml in their forties, 10.9 +/- 5.4 ng/ml in their fifties, 8.4 +/- 4.8 ng/ml in their sixties and 8.1 +/- 7.5 ng/ml in their seventies. These results suggest that somatotroph cells become less sensitive to growth hormone-releasing factor with aging.
Synthetic growth hormone-releasing factor (hpGRF-44) (100 micrograms) was administered intravenously to ten acromegalic patients. The time when the peak of plasma GH occurred as well as the magnitude of the response were highly variable among these ten patients. From the GH response patterns the ten acromegalic patients were tentatively classified into three groups: (1) those highly GRF-dependent whose GH level increased to four times basal, (2) those moderately GRF-dependent whose GH level rose to less than two times basal and (3) those GRF-resistant whose GH level did not change. These data suggest that there may be differences in the GRF-receptor system in pituitary adenomas causing acromegaly.
Synthetic human pancreatic GRF (hpGRF-44) was administered as an iv bolus to 28 normal children with short stature and 27 patients with GH deficiency. After a dose of 1 or 2 micrograms hpGRF-44/kg BW, mean plasma GH levels peaked at 15 and 30 min, respectively, with corresponding values of 30.1 +/- 4.7 and 33.2 +/- 3.7 ( +/- SE) ng/ml in normal but short children. The overall plasma GH response was greater than that of other GH stimulation tests such as insulin-induced hypoglycemia, glucagon-propranolol or L-dopa administration. Plasma LH, FSH, TSH, PRL, and cortisol levels were not altered by hpGRF-44 injection. Sixteen of 27 patients with GH deficiency did not respond to a 2 micrograms/kg BW hpGRF-44. However, plasma GH increases to greater than 5 ng/ml occurred in the remaining 11 patients. Their GH levels reached peaks between 15 and 90 min, with values ranging between 5.8 and 17.8 ng/ml. Two of these responding patients were infused iv with hpGRF-44 at 2.5 micrograms/min for 90 min after receiving an iv bolus injection of 2 micrograms/kg BW. Their plasma GH levels increased and remained near peak values throughout the infusion period. However, no increase in plasma GH levels occurred after a second bolus injection of hpGRF-44 given at the end of the infusion. These results suggest that hpGRF-44 is useful for the diagnosis of GH deficiency in individuals with short stature and that some patients with GH deficiency, diagnosed on the basis of established tests, have GH responses to hpGRF-44.
A specific RIA for human pancreatic tumor GH-releasing hormone [hpGRH(1-44)NH2] was developed using an antiserum which recognizes the region (Met27-Leu44)NH2 of hpGRH(1-44)NH2. This RIA was used to measure GH-releasing hormone-like immunoreactivity (GRH-LI) in various human tissue extracts. The highest concentration of GRH-LI was detected in extract of pituitary stalk with moderate amounts found in hypothalamus and optic chiasm but none in the cerebrum, cerebellum, medulla oblongata, spinal cord, and anterior pituitary. In peripheral organs appreciable quantities of GRH-LI were found in the pancreas, whereas extracts of thyroid, lung, stomach, duodenum, ileum, colon, adrenal, and kidney contained very low concentrations of GRH-LI. No GRH-LI was detected in liver and spleen extracts. Gel permeation chromatographic analysis of the tissue extract from the hypothalamus revealed only one peak which eluted at the same position as that of 125I-hpGRH(1-44)NH2. Similar analysis of an extract from the optic chiasm showed one peak at the same position as that of 125I-hpGRH(1-44)NH2 and another peak which eluted after hpGRH(1-44)NH2. In contrast, an extract from the pancreas contained only one peak which eluted before 125I-hpGRH(1-44)NH2, indicating a possible precursor form of hpGRH(1-44)NH2. Limited trypsin digestion of the GRH-LI material from the pancreas, followed by gel permeation chromatographic analysis, yielded a major peak eluting at the same position as that of 125I-hpGRH(1-44)NH2. These results suggest that the GRH-LI detected in the hypothalamus most likely corresponds to hpGRH(1-44)NH2 in structure and that the GRH biosynthesized in the hypothalamus is transported to the stalk median eminence and stored there for release into the portal vessels.
In a multi-center study, nifedipine (Bay a 1040, Adalat) (10 mg capsule) was administered, in liquid form and via sublingual route, to 22 cases who were diagnosed to have clinically severe systolic hypertension, and the depressor effect of the treatment was studied over a period of 4 h. In patients of "emergent" admission (cerebral hemorrhage n = 8, cerebral thrombosis n = 4, subarachnoid hemorrhage n = 1, renal failure n = 6, essential hypertension n = 3), 3 bouts of blood pressure measurement at intervals of 10-15 min during the control period were carried out. In case of systolic blood pressure higher than 200 mmHg, at least one time, nifedipine at a dose of 10 mg was sublingually administered. Thereafter, blood pressure and pulse rate were recorded at intervals of 15 min up to the end of the first one hour, then at intervals of 30 min up to the end of 4 h. Results were as follows. In terms of the average values for all cases, blood pressure fell to near lowest levels by the end of about 30 min after the administration and it stayed at near lowest levels up to the end of 120-240 min. During this period of time, pulse rate remained substantially unchanged. In terms of the pattern of the blood pressure fall, all cases could be classified generally into two types, namely (a) the "dip" group (7 cases) in which blood pressure fell to the lowest level to form a "dip" and remained below the control level, although it showed a trend to return to control level for 4 h and (b) the "flat" group (15 cases) in which blood pressure declined gradually for about 1 h and, then, remained low or below the control level, although it showed a trend to return to control level throughout the rest of the observation period of 4 h.
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The concentrations of sulfur-containing amino acids (taurine, methionine, cystine, cystathionine, homocystine) in lumbar CSF from patients with consciousness disturbances and controls were measured, and it was investigated whether there was any correlation between the sequential changes of these amino acid concentrations and of the level of consciousness. In all patients, thyrotropin-releasing hormone (TRH) was administered and the changes of levels of consciousness and amino acid concentrations were followed before and after administration. The concentrations of taurine and cystathionine from the patients were significantly lower, and methionine and cystine significantly higher than those from the controls; they returned to the control values in parallel with improvement of consciousness level. Homocystine was not detected in either patients or controls. These results suggest that the alteration in the level of consciousness is associated with distortion of sulfur-containing amino acid metabolism within the central nervous system, at least in the CSF.
The response of pituitary adenomas obtained surgically from patients with Cushing's disease of Nelson's syndrome to synthetic ovine corticotropin-releasing factor (CRF), vasopressins, somatostatin-28, dexamethasone, 3-isobutylmethylxanthine or high [K+] was examined in vitro by measuring the amount of pro-opiomelanocortin (POMC)-derived peptides secreted into the culture medium. CRF did not stimulate the secretion of adrenocorticotropin-, beta-endorphin-, or gamma 3-melanotropin-like peptides from the pituitary adenomas at concentrations ranging from 1 x 10(-13) M to 1 x 10(-7) M whereas vasopressins, 3-isobutyrl-methylxanthine and high [K+] increased, while somatostatin-28 and dexamethasone suppressed, the secretion of these POMC-derived peptides. These findings suggest that either the pituitary ACTH-producing tumors have lost their receptors to CRF or their post-receptor mechanism to CRF is not functional.
Direct effects of cyproheptadine, reserpine, synthetic ovine corticotropin-releasing factor (CRF), dexamethasone, and lysine-8-vasopressin (LVP) on the secretion of immunoreactive ACTH and beta-endorphin from the adenoma and the nonadenomatous tissue of patients with Cushing's disease were examined using a superfusion system. Cyproheptadine and reserpine (10(-9)-10(-7) M of each) suppressed immunoreactive ACTH and beta-endorphin secretion from both tissues. CRF (10(10)-10(7) M) stimulated the secretion of both peptides from the nonadenomatous tissue, but only a high dose of CRF could stimulate the secretion of these peptides from some adenomas. Such CRF-induced secretion was partially suppressed by dexamethasone. LVP (10(-9)-10(-7) M) stimulated peptide secretion from both types of tissue. These results suggest direct inhibitory effects of cyproheptadine and reserpine on the secretion of these peptides from the pituitary of patients with Cushing's disease, a different stimulatory mechanism of LVP from that of CRF in these tissues, and low sensitivity of the adenoma to CRF.
Corticotropin-releasing factor (CRF) tests were performed in normal subjects and patients with hypothalamic-pituitary-adrenal disorders. In normal subjects, after iv administration of 500 micrograms synthetic ovine CRF, plasma ACTH rose significantly to approximately 3.6 times the basal level at 30-60 min and cortisol reached a peak of 2.3 times the basal level at 60-90 min, whereas aldosterone peaked at 1.6 times the basal level at 60 min. Injection of 100 micrograms CRF in normal subjects also caused a significant increase in plasma ACTH and cortisol levels but only a slight increase in aldosterone. However, the total hormone released and their peak levels were lower than those elicited by the 500-microgram dosage. In patients with Cushing's disease, although the basal and peak levels of plasma ACTH and cortisol induced by administration of CRF were variable, the ratios of increase for the two hormones elicited by CRF were lower than those in normal subjects, especially for cortisol. In patients with Cushing's syndrome due to an adrenal adenoma, basal levels of ACTH were markedly suppressed and plasma ACTH and cortisol did not rise after CRF. In patients with isolated ACTH deficiency or Sheehan's syndrome the basal level of plasma ACTH was less than 5 pg/ml and no change in plasma ACTH occurred after injection of CRF. In patients with Nelson's syndrome or Addison's disease the basal levels of ACTH were extremely elevated but infusion of CRF increased plasma ACTH to even higher levels.