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Biomedical subjects

M Rosenblatt

Publications and source records attributed to M Rosenblatt.

At least 163 records · Page 9Linked to original sources
PubMed1983

A parathyroid hormone inhibitor in vivo: design and biological evaluation of a hormone analog.

A synthetic analog of bovine parathyroid hormone (bPTH), [tyrosine-34] bPTH-(7-34)NH2, was found to inhibit parathyroid hormone action in vivo. When the analog and parathyroid hormone were infused simultaneously to rats at a molar ratio of 200 to 1, the analog inhibited the excretion of urinary phosphate and adenosine 3',5'-monophosphate. When infused alone at the same dose rate, the analog was devoid of agonist activity. The compound was prepared by following design principles developed for inhibitors of parathyroid hormone, and is believed to be the first antagonist of parathyroid hormone that is effective in vivo.

Amino Acid Sequence↗
PubMed1983

Parathyroid hormone: effects of the 3-34 fragment in vivo and vitro.

The biologically active fragment ofparathyroid hormone, consisting of residues 1-34, and its in vitro antagonist, fragment 3-34, were administered separately or in combination to chronically thyroparathyroidectomized dogs. These fragments were also studied in vitro with dog renal cortical membranes. Fragment 3-34 inhibited the stimulation of adenylate cyclase by fragment 1-34 in vitro, but had no agonist or antagonistic effects on renal phosphate transport in vivo.

Adenylyl Cyclases↗
PubMed1983

Prosomatostatin-specific antigen in rat brain: localization by immunocytochemical staining with an antiserum to a synthetic sequence of preprosomatostatin.

Using an antiserum to a 15-amino acid synthetic peptide corresponding to amino acids 63-77 of rat preprosomatostatin (rat somatostatin cryptic peptide, RSCP), we have compared the distribution of immunoreactive RSCP (IR-RSCP) with that of immunoreactive somatostatin-14 in the rat brain. IR-RSCP was present in neuronal cell bodies, processes, and axon terminals in the hypothalamic tuberoinfundibular system as well as in diverse regions of the central nervous system in an identical distribution to immunoreactive somatostatin. These observations indicate that in neurons the somatostatin prohormone or the NH2-terminal extension peptide of somatostatin-28 (or both) is stored and transported intracellularly along with somatostatin 14. In addition, the presence of IR-RSCP in nerve terminals suggests that this material may be secreted as a hormone or neuromodulator and may serve as a biologic marker of somatostatin secretion.

Amino Acid Sequence↗
PubMed1983

A multiresponse parathyroid hormone assay: an inhibitor has agonist properties in vivo.

Vitamin D-deficient rats subjected to thyroparathyroidectomy (TPTX) were used to evaluate in vivo the biological properties of native bovine parathyroid hormone (bPTH) and chemically synthesized fragments and analogues of the hormone on several parameters of hormone action: calcium and phosphorus fluxes, generation of cyclic adenosine 3',5'-monophosphate (cAMP), and the metabolism of 25-hydroxyvitamin D3 [25(OH)D3]. Vitamin D-deficient rats, after TPTX or sham operation, were intravenously infused with a nutrient containing 7.5 mM CaCl2 for 30 h. During the last 7 h, PTH or one of its analogues was infused intravenously at rates between 0.04 and 20 nmol/h. One hour after the start of the peptide infusion, tritiated 25(OH)D3 was injected. Urine was collected hourly for phosphate and cAMP determinations and, at the end of the experiment, blood was obtained to determine the relative accumulation of tritiated 1,25-dihydroxyvitamin D3 ([3H]1,25(OH)2D3). Infusion of bPTH-(1--84), bPTH-(1--34), human (h)PTH-(1--34), or [Nle8, Nle18, Tyr34]bPTH-(1--34) amide was accompanied by a comparable dose-dependent decrease in plasma phosphate and a dose-dependent increase in plasma calcium and [3H]-1,25(OH)2D3, and urinary excretion of phosphate and cAMP. An evaluation of [Nle8, Nle18, Tyr34]bPTH-(3--34) amide, a potent inhibitor of PTH action in vitro in the renal adenylate cyclase assay, revealed that the analogue possessed weak agonist properties in vivo. The analogue increased excretion of both cAMP and phosphate in the urine, decreased plasma phosphate levels, and increased the accumulation of [3H]-1,25(OH)2D3 in the plasma. This multiparameter model system should aid in the elucidation of the in vivo biological effects of PTH and its analogues.

Animals↗
PubMed1983

Dynamics of cortisol and endorphin responses to graded doses of synthetic ovine CRF in sheep.

Corticotropin-releasing factor (CRF), recently isolated from sheep hypothalami, has been shown to stimulate secretion of ACTH and beta-endorphin in vitro, and in vivo in rat and man. In previous reports, responses to ovine CRF were studied in heterologous bioassay systems where the ovine sequence was likely to act as a CRF analogue. We administered synthetic ovine CRF to sheep to assess the dynamics of endorphin and cortisol responses. Graded doses of CRF caused a rapid increase in immunoreactive beta-endorphin (iB-E) within 2 min of iv administration, followed by a cortisol response which was maximal 15 min after the iB-E peak. Doses of CRF in excess of 10 micrograms did not increase the magnitude of the peak iB-E response but did prolong the duration of the plasma beta-endorphin rise. Ovine CRF is an extremely potent and rapidly-acting hypothalamic peptide in vivo when assayed in a homologous system.

Animals↗
PubMed1983

Corticosteroidogenesis and adenosine 3', 5'- monophosphate production by the amino-terminal (1-34) fragment of human parathyroid hormone in rat adrenocortical cells.

Several studies have revealed a variety of interactions between PTH and ACTH. The existence of a significant area of homology in the bioactive regions of the two molecules has been proposed as a possible reason for such interactions. To clarify the relationship, corticosteroidogenic and cAMP accumulative effects of bovine PTH (bPTH 1-84), its amino-terminal fragment (bPTH 1-34), and the amino terminal fragment of human PTH (hPTH 1-34) were compared with ACTH 1-39 by determining their dose-response characteristics in collagenase-dissociated adrenocortical cells from rats. bPTH 1-84 and bPTH 1-34 (10(-8)-10(-5)M) did not alter steroid production of the cells nor did 10(-6)M bPTH 1-34 affect the steroid response curve to ACTH 1-39. However, the degree of steroidogenesis elicited by hPTH 1-34 over the dose range 3.3 X 10(-7)-3.3 X 10(-5)M was the same as that elicited by ACTH 1-39 over the range 10(-11)-10(-9) M. cAMP generation with hPTH 1-34 was maximal at 10(-4) M but the correlation between the steroid and cAMP responses with ACTH 1-39 was noticeably different from that with hPTH 1-34. In experiments with ACTH 6-24 (a competitive inhibitor of ACTH 1-39), both steroid and cAMP responses to hPTH 1-34 were greatly reduced. Oxidized hPTH 1-34 did not elicit any steroid production nor did several other peptide hormones (arginine vasopressin, angiotensin II, calcitonin, insulin, GH) at 10(-5) M. These observations indicate that hPTH 1-34 can exert a direct and specific effect on rat adrenocortical cells revealing the peptide as a full agonist for steroid production in this system. We suggest that it is a combination of sequence homology and conformational structure which permits hPTH 1-34 to interact with, and elicit its response through, the receptor for ACTH 1-39.

Adrenal Cortex↗
PubMed1982

Endotoxin-stimulated opioid peptide secretion: two secretory pools and feedback control in vivo.

Small doses of endotoxin evoked a dramatic biphasic response of opioid peptide secretion into blood in sheep. The first phase began within minutes and coincided with a brief hypertensive response to endotoxin well before the appearance of fever or hypotension. The ratio of beta-endorphin to beta-lipotropin fell abruptly at the onset of the second phase of release, suggesting early depletion of a pool rich in beta-endorphin and subsequent emergence of a pool rich in unprocessed precursor. The concentration of cerebrospinal fluid opioids increased tenfold during the second phase. Naloxone administration augmented endotoxin-induced opioid secretion in both early and late phases, suggesting a short-loop feedback regulation of stress-induced endorphin secretion.

Animals↗
PubMed1982

Proliferative capacity of murine hematopoietic stem cells in vitro.

Large numbers of granulocytes can be collected repeatedly from the supernatant medium of long-term cultures of mouse bone marrow cells. A constant relationship was found between the number of adherent hematopoietic stem cells and the lifetime cell production per culture. The data indicate that there is a limit to the proliferative capacity of normal and of irradiated stem cells. A similar limitation was found in the production of marked granulocytes from clonal cultures of "beige" C57 (bg/bgJ) stem cells placed in limiting dilutions into stromal culture layers.

Animals↗
PubMed1982

Retreatment of retinoblastoma with external beam irradiation.

A retrospective review of cases on file at the Ophthalmic Oncology Center of New York Hospital-Cornell Medical Center, New York, was undertaken to examine the effectiveness of a second course of radiotherapy on retinoblastoma. One hundred four patients were found to have been treated with at least two courses of external beam irradiation to one eye. All but one of the cases were bilateral, the other eye with more advanced disease having been previously enucleated. At the time the decision was made to repeat radiotherapy, 15 eyes could be classified group I, II, or III. Twelve (80%) of these eyes survived. Of the 89 eyes that showed more advanced growth (group IV or V), only two (2.2%) survived. In all, 14 of the 104 eyes wer saved--nine with useful (macula) vision, five without. Second nonocular tumors developed in 18 patients (22.8% of those who survived retinoblastoma itself). There appears to be no increased risk of second tumors from the second course of irradiation.

Child, Preschool↗
PubMed1982

In vitro studies on an antagonist of parathyroid hormone [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide.

1 The actions of parathyroid hormone (PTH) are antagonized in vitro by the peptide [Nle-8, Nle-18, Tyr-34]-bPTH-(3-34)amide, an analogue of PTH. In this paper, the actions of the inhibitory peptide were investigated in vivo. 2 Native parathyroid hormone (bPTH-(1-84)), administered i.v. (0.17-1.51 nmol in volume of 0.3 ml) to 7 day old chicks produced hypercalcaemia but administration of the analogue in doses up to 173 nmol was ineffective in this respect. 3 The analogue failed to antagonize the hypercalcaemia produced by bPTH-(1-34) when injected, in 10 fold molar excess, 2 min before or simultaneously with bPTH-(1-34). 4 Normocalcaemia was restored in parathyroidectomized rats by intravenous infusion of bPTH-(1-84) at 32 pmol kg-1 h-1. Addition of the analogue to the infusion fluid in a 200 fold molar excess did not affect the concentrations of calcium and phosphate in the plasma, cyclic adenosine 3',5'-monophosphate (cyclic AMP) in the urine or phosphate clearance but produced a significant (P less than 0.05) rise in urinary calcium clearance. 5 The results suggest that the peptide [Nle-8, Nle-18, Tyr-34]-bPTH-(3-34)amide does not antagonize the actions of PTH in vivo and demonstrate an important dichotomy between in vitro and in vivo biological properties of the PTH analogue.

Animals↗
PubMed1981

Sulfur-free parathyroid hormone analogues containing D-amino acids: biological properties in vitro and in vivo.

Three sulfur-free analogues of bovine parathyroid hormone (bPTH) containing D-amino acids were synthesized by the solid-phase method and their biological properties compared in an in vitro bioassay (rat renal adenylate cyclase assay), a receptor assay for parathyroid hormone (PTH) (canine renal membranes), and an in vivo bioassay (chick hypercalcemia assay). The analogue [Nle8,Nle18,D-Tyr34]-bPTH-(1-34)-amide, which was found to be more than 4 times as potent in vitro as unsubstituted PTH, is the most potent analogue of PTH yet synthesized. The enhanced potency was largely attributable to increased affinity for the PTH receptor. In vivo, however, this analogue was only one-third as potent as bPTH-(1-34). Cumulative evidence suggests that the nearly 15-fold decline in the relative potency when the compound was assayed in vivo is due to the substitution of norleucine for methionine. The other analogues, [D-Val2,Nle8,D-Tyr34]bPTH-(1-34)-amide and [D-Val2,Nle8,Nle18,D=Tyr34]bPTH-(2-34)-amide, were only weakly active in vitro and in vivo, indicating that substitution with D-amino acids at the NH2 terminus of PTH causes markedly diminished receptor affinity. In fact, the placement of a D-amino acid at the NH2 terminus is more deleterious to biological activity than is omission of amino acids at positions 1 and 2.

Adenylyl Cyclases↗