Biomedical subjects
Publications and source records attributed to M Shino.
The synthesis of trans-3,4-bis-(3,4-dihydroxyphenyl)pyrrolidine by the Michael reaction of esterenolate with nitro olefin is described. This compound was expected to be the agonist toward dopamine (DA1) receptor with equipotent affinity and to be more selective than dopamine itself.
Pharmacokinetic parameters of E4101,(-)-(3R,4R)-3-(2-chloro-3-hydroxyphenyl)- 4-(3,4-dihydroxyphenyl)-pyrrolidine hydrochloride, in plasma were determined in conscious beagles. E4101 was extracted from plasma using a Bond Elute C18 cartridge and determined by HPLC connected to a reverse phase ODS column and an electrochemical detector. After an i.v. administration of 1 mg/kg, the plasma level of E4101 decreased according to the three compartment model. The half lives of the alpha, beta and gamma phases were 1.3, 8.1 and 27 min, respectively. The mean residence time (MRT) and total clearance were 14.5 min and 78 ml/min/kg, respectively. When 3 mg/kg of E4101 were administered orally under fasting, E4101 in plasma reached the peak (Cmax: 22.4 ng/ml) 45 min after administration. The bioavailability was 3.6%. When 3 mg/kg of E4101 in combination with 15 mg/kg of ascorbic acid was orally administered in capsule, the area under concentration curve (AUC) was increased 7-fold compared with that in a matched control study. A combination with 15 mg/kg of tartaric acid, citric acid, L-aspartic acid or L-cysteine also increased the AUC, byt they were less effective than ascorbic acid. When 10 mg/kg of E4101 in combination with 25 mg/kg of ascorbic acid as a sustained-release dosage form using oily somisolid matrix orally administered to non-fasted beagles, the duration of effective plasma concentration (2 ng/ml plasma in i.d. administration) was 8.4 +/- 1.0 hr (mean +/- SE, n-4). The Cmax was 16.2 +/- 2.5 ng/ml.
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Three monoclonal antibodies (Ig G1 type) to particulate guanylate cyclase from porcine kidney cortex have been produced by fusing spleen cells from immunized BALB/c mouse with P3X63 myeloma cells. The antibodies were detected by their ability to bind immobilized antigen and by immunoprecipitation of enzyme activity. After subcloning by limiting dilution, hybridomas were injected intraperitoneally into mice to produce ascitic fluid. The antibodies recognized a 180,000 dalton protein in Lubrol-PX extract of porcine kidney cortex membrane, and when immobilized on Sepharose 4B, they co-precipitated both [125I]human atrial natriuretic peptide (ANP)-receptor complex and guanylate cyclase activity. The antibodies caused a greater increase in generation of cGMP than that of ANP.
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Digital processing method using the scanning-densitometer with microcomputer provides a useful description system. It draws attention to the usefulness of local lattice averaging in clarifying images of periodic structures in crystals as well as crystalloids and para crystalline arrays in biological specimens. Digital processing of lattice images in crystal structures from the selected diffraction spots is successfully developed to the structural analysis of evaporated gold, graphitized carbon and human tooth enamel of hydroxyapatite. Furthermore, known microbody crystalloids in enzyme and icosahedral capsids in virus are confirmed and clarified by the procedure of selecting diffraction spectra transformed from the information taken with high resolution electron micrographs. The processed results can provide significant improvements in structural analysis of an electron micrograph.
Female Sprague-Dawley rats were hypophysectomized and the anterior pituitary gland was immediately placed under the kidney capsule. For 1 week after surgery, groups of pituitary autograft-bearing animals were treated with twice-daily injections of estradiol 17 beta (E), progesterone (P), estradiol 17 beta and progesterone (EP), or luteinizing hormone-releasing hormone (LRH). Within 2--4 hours following the last injection, the pituitary grafts were removed and placed into organ culture. They were maintained in culture with or without added LRH (10(-7) M) for 1 hour at 37 degrees C. The culture media were then frozen for later radioimmunoassay of FSH and LH. The tissues were kept in culture for an additional 24 hours, at which time they were fixed and prepared for immunocytochemistry or electron microscopy. Results showed that treatment of the animals with E, EP, or LRH enhanced the release of FSH and LH into the culture media, and that the release of these hormones was increased further by acute incubation with LRH. The ultrastructure of the gonadotrophs was well maintained by treating the animals with E or the combination of E and P or with LRH. Graft tissue from animals treated with LRH, which was incubated subsequently for 24 hours with LRH, showed the best maintenance of gonadotroph morphology. This experimental procedure should be useful for obtaining gonadotrophs for use in establishing gonadotroph cell lines.
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We recently established a clone (2B8) of normal rat prolactin cells that secretes only prolactin into the medium. When grown in the presence of thyrotrophin-releasing hormone (TRH), estradiol (E2) or arginine vasotocin (AVT), the cells show increased production of prolactin. Subclones of single cell origin were developed from 2B8 cells exposed for 1 week to TRH, E2 or TRH plus E2. These subclones differ in their response to TRH, E2 or AVT and therefore may possess different receptors for these hormones.
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The effect of active and passive immunization with luteinizing hormone-releasing hormone (LHRH) on serum LH and follicle-stimulating hormone (FSH) levels and the ultrastructure of the pituitary gonadotrophs was investigated in castrated male rats. Two weeks after castration, the animals were immunized with Glu1-LHRH conjugated with human serum albumin (hSA), immunized with hSA only, or left uninjected. Immunogens were administered every 2 weeks. Four weeks after the initiation of immunization with hSA-Glu1-LHRH, 2 out of 4 rats showed parallel decreases in serum LH and FSH levels associated with a rise of serum antibody titer to LHRH. Serum LH and FSH levels remained suppressed throughout the experiment in these rats. On the other hand, both LH and FSH levels in hSA-immunized rats or non-immunized rats remained elevated, and typical castration cells containing large vacuoles were found in the pituitary. Although castration cells existed in the pituitary of rats which produced antibody to LHRH by active immunization, these cells were markedly degranulated, and secretory granules were scarce in the cytoplasm. In another experiment, rats were injected iv with one ml sheep anti-LHRH gamma-globulin (anti-LHRH) or normal sheep gamma-globulin (NSG) every 2 days for 3 weeks, starting one day after castration, when serum LH and FSH levels were already elevated. All the animals which received anti-LHRH showed a decrease in both serum LH and FSH levels, which remained low throughout the study, in a range comparable to those in intact normal male rats. On the other hand, in the animals which received NSG, both LH and FSH levels remained high or increased further throughout the experiment, and the pituitary contained numerous castration cells. Castration cells were completely absent from the pituitaries of rats treated with anti-LHRH, suggesting that castration cells are formed as a result of increased secretion of LHRH. Some FSH gonadotrophs in these castrated rats were atrophic. It was difficult to distinguish the LH gonadotrophs in rats which were either actively or passively immunized with LHRH; however, they seem not to have contributed significantly to the development of castration cells. In any case, antibody to the LHRH decapeptide drastically affected both LH and FSH cells, providing additional evidence for the concept that LHRH represents the physiological LHRH and FSHRH.
Some aspects of the kinetics of emiocytosis of secretory granules were investigated in pituitary prolactin cells of lactating female rats. Most of the emiocytotic events were directed towards those areas of the cells which were covered with a basal lamina. Diameters of the secretory granules within the emiocytotic pockets and of the openings of the pockets to the exterior were measured. An inverse relationship between the size of the granule and the diameter of the foramen was noted. A mechanism is proposed relative to the processes involved in the release of secretory granules from prolactin cells.
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