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M Berelowitz

Publications and source records attributed to M Berelowitz.

At least 73 records · Page 4Linked to original sources
PubMed1982

Release of somatostatin-like immunoreactivity from incubated rat hypothalamus and cerebral cortex. Effects of glucose and glucoregulatory hormones.

Somatostatin (SRIF) is localized in the hypothalamus, extrahypothalamic brain, and throughout the gastrointestinal tract. Release of gastrointestinal SRIF-like immunoreactivity (SRIF-LI) is under nutrient regulation but the effect of nutrients on neural SRIF-LI is unknown. The present studies examined the effects of glucose uptake and metabolism and hormones influencing glucose disposition on SRIF-LI release from medial basal hypothalamus (MBH) and cerebral cortex (Cx) incubated in Krebs-Ringer bicarbonate containing bacitracin. After a preincubation to achieve stable secretion, tissues were incubated for 20 min in 14 mM glucose (basal) and then, for 20 min in fresh medium with test materials. MBH SRIF-LI release was inversely related to medium glucose concentration with release in the absence of glucose (235+/-42 pg/MBH per 20 min) more than five times that in the presence of 25 mM glucose (46+/-4 pg/20 min). In the presence of 14 mM glucose MBH SRIF-LI release was stimulated above basal by agents interfering with glucose uptake including 3-O-methyl-d-glucose (42 mM; 70+/-5 vs. 42+/-3 pg/20 min, P < 0.05), phlorizin (50 mM; 351+/-63 vs. 29+/-2 pg/20 min, P < 0.001) or cytochalasin B (20 muM; 110+/-7 vs. 22+/-2 pg/20 min, P < 0.001). Inhibition of glucose metabolism by 2-deoxy-d-glucose resulted in dose-related stimulation of MBH SRIF-LI release (maximal at 28 mM; 201+/-28 pg/20 min vs. 32+/-4 pg/20 min, P < 0.001). Viability of MBH was unimpaired by incubation in the absence of glucose or following exposure to 2-deoxy-d-glucose as determined by retention of SRIF-LI responsiveness to stimulation by potassium (60 mM) or neurotensin (5 muM). In contrast, Cx SRIF-LI release was slightly inhibited by decreases in medium glucose and unaffected by inhibition of glucose uptake or metabolism. These results provide evidence for nutrient regulation of MBH but not Cx SRIF-LI release and may explain inhibition of growth hormone seen in the rat in response to hypoglycemia. Insulin (10 nM-1 muM) stimulated MBH but not Cx SRIF-LI release while glucagon was without effect. Our previous demonstration that MBH SRIF-LI release was stimulated by somatomedin-C, but not insulin at physiologic concentrations, is consistent with an action of insulin through the somatomedin-C receptor at the doses studied. Our studies indicate a regional specificity for the control of SRIF secretion within the brain and suggests the possibility of a role for hypothalamic SRIF in metabolic regulation.

3-O-Methylglucose↗
PubMed1982

The in vivo metabolism of somatostatin 28: possible relationship between diminished metabolism and enhanced biological action.

We have compared the metabolism of infused somatostatin 14 (SS14) and somatostatin 28 (SS 28) in anesthetized dogs. After iv infusion of either peptide, plasma SS-like immunoreactivity (SLI) coeluted from Bio-Gel P10 columns with the corresponding synthetic peptide marker. The hepatic extraction, renal extraction, MCR, and plasma half-life of plasma SLI and after SS28 infusion were 11.0 +/- 1.5%, 50 +/- 4.8%, 9.9 +/- 1.4 ml/kg.min, and 2.8 +/- 0.3 min, respectively. Corresponding values after SS14 infusion were 43.1 +/- 7.4%, 82.2 +/- 6.6%, 21.9 +/- 6.5 ml/kg.min, and 1.7 +/- 0.2 min. These differences between SS28 and SS14 were all statistically significant (P less than 0.05). When equimolar amounts of each peptide were given as bolus injections, both led to a significant reduction in portal venous blood flow. After the injection of SS14, the reduction in flow was short-lived and returned to baseline by 4 min. However, between 2-7.5 min after the injection of SS28, the reduction in blood flow was significantly greater than that induced by SS14, and returned to baseline only by 15 min. These studies indicate that the metabolism of plasma SLI is significantly slower during the steady state infusion of SS28 in pharmacological doses than after similar infusions of SS14. SS28 led to a more prolonged reduction in portal blood flow than SS14; this effect is probably due to its slowed metabolism. This suggests that further modification of the SS28 molecule may increase its therapeutic potential by slowing its in vivo metabolism.

Animals↗
PubMed1982

Sorting of pancreatic islet cell subpopulations by light scattering using a fluorescence-activated cell sorter.

Methods have been developed for the preparation of suspensions of viable rat pancreatic islet cells and their analysis and sorting in the fluorescence-activated cell sorter (FACS III or IV). Histograms of cell number versus light scattering in a near forward angle (1-15 degrees) demonstrated that viable islet cells produce a broad peak that is distinctly separated from the peaks generated by exocrine cells, erythrocytes, and nonviable cells. Electron microscopic examination and radioimmunoassay of hormone content in fractions collected across the peak showed that glucagon-containing (A) cells scatter less intensely and are concentrated within the left side of the islet cell peak, while somatostatin-containing (D) cells are localized to the far right side, indicating a higher intrinsic light scattering property of the D-cells. The more abundant insulin-containing (B) cells define the center of the islet cell peak. Sodium dodecyl sulfate slab gel electrophoresis and radioautography of 35S-methionine labeled cellular proteins confirmed that sorted cells are viable. Cells from the far left region contained increased amounts of labeled 18 Kd proglucagon and its 13-Kd and 10-Kd conversion intermediates, while cells from the right side were relatively enriched in labeled 12.4 Kd prosomatostatin. These results demonstrate that intrinsic light scattering alone can be used to prepare A- or D-cell enriched fractions from islets for biochemical analysis.

Animals↗
PubMed1981

Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary.

Somatomedin-C stimulates somatostatin release to a maximum of 390 percent of basal release during short-term (20-minute) incubation of rat hypothalamus. It has no effect on basal or stimulated growth hormone release from primary cultures of rat adenohypophyseal cells during a 4-hour incubation, but inhibits stimulated release by more that 90 percent after 24 hours. These findings suggest that somatomedin-C participates in the growth hormone negative feedback loop with an immediate effect on hypothalamic somatostatin and a delayed effect on the anterior pituitary.

Animals↗
PubMed1981

Acute effects of alloxan- and streptozotocin-induced insulin deficiency on somatostatin and glucagon secretion by the perfused isolated rat pancreatico-duodenal preparation.

The secretion of somatostatin and glucagon by the perfused rat pancreatico-duodenal preparation was examined in situ under control conditions and after the induction of acute insulin deficiency by alloxan or streptozotocin. A 10 min 0.625 mmol/l alloxan perfusion resulted in an immediate and transient increase in basal insulin and glucagon release and a slightly delayed and persistent increase in basal somatostatin secretion. The insulin responses to 16.7 mmol/l glucose, 1 mmol/l theophylline, and 19 mmol/l arginine alone or in combination were virtually eliminated by alloxan treatment. Somatostatin secretion in response to the stimuli was completely inhibited or markedly attenuated. The glucagon-suppressive effect of glucose was unaltered by alloxan and the stimulatory effect of arginine was enhanced. Addition of 1 microgram/ml porcine insulin to the perfusion medium did not modify the alterations in somatostatin and glucagon responses to arginine. Streptozotocin treatment 90 min prior to the onset of perfusion resulted in changes in somatostatin, glucagon, and insulin responses to glucose and arginine similar to those of alloxan. The present results are consistent with an effect of alloxan and streptozotocin on the D cell similar to that on the B cells, namely, interference with a glucose-mediated effect on hormone secretion.

Alloxan↗
PubMed1981

Effect of catecholamines on somatostatin secretion by isolated perfused rat stomach.

The secretion of somatostatin-like immunoreactivity (SRIF-LI) by the isolated perfused rat stomach was studied in response to stimulation by catecholamines. Gastric SRIF-LI secretion was significantly stimulated in a dose-dependent manner by norepinephrine at 10(-6) and 10(-8) M, and the effect of norepinephrine (10(-8) M) was attenuated by the addition of propranolol (10(-6) M) but not of phentolamine (10(-6) M). SRIF-LI secretion was also stimulated by dopamine at concentrations of 10(-4) and 10(-6) M but not at 10(-8) M. The effect of dopamine (10(-6) M) was not altered by the addition of haloperidol (10(-4) to 10(-7)) or metoclopramide (10(-4) M), and bromocriptine (10(-6) M) was without effect on SRIF-LI secretion. These results suggest that gastric SRIF-LI secretion is stimulated by a beta-adrenergic mechanism and raise the possibility that gastric somatostatin contributes to the inhibitory effect of norepinephrine on gastric acid secretion.

Animals↗
PubMed1981

Effects of somatostatin on intestinal calcium transport in the rat.

The addition of somatostatin (SRIF) to rat descending colon in vitro increased the calcium secretory flux from serosa to mucosa (Js leads to m) and reduced tissue short-circuit current (Isc) but did not alter the absorptive flux from mucosa to serosa (Js leads to m). Js leads to m increased by 37% at 10(-9) M SRIF and by 48% at 10(-6) M. The response to SRIF was not altered by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and SRIF did not interfere with stimulation of calcium Jm leads to s by 1,25(OH)2D3. Removal of sodium from the buffer abolished the stimulation of Js leads to m by SRIF without reducing basal Js leads to m. Secretory fluxes of mannitol and calcium were strongly correlated in the presence and absence of SRIF, suggesting that SRIF stimulates a paracellular transepithelial pathway for calcium. In the duodenum, SRIF altered neither calcium Js leads to m nor Isc. In the ileum, calcium Js leads to m increased and Isc decreased, as in the colon, but only by 28 and 12%, respectively. The maximal change in calcium Js leads to m caused by SRIF in these three intestinal segments was negatively correlated with the tissue concentration of immunoreactive SRIF. These results suggest that intestinal calcium secretion could, in part, be regulated by intestinal SRIF.

Animals↗
PubMed1981

Hepatic and renal metabolism of somatostatin-like immunoreactivity. Simultaneous assessment in the dog.

The hepatic and renal metabolism of somatostatin-like immunoreactivity (SLI) was assessed simultaneously in an in vivo dog model. The hepatic extraction of this peptide was 29.4 +/- 2.3% and was similar for endogenous and infused exogenous SLI. The renal extraction was 62.3 +/- 5%. The renal clearance of SLI was significantly greater than that of inulin indicating that the peptide is handled by peritubular uptake from postglomerular blood in addition to glomerular filtration. In both organs SLI extraction was not saturable even at arterial concentrations in excess of 100 times physiological range. The overall metabolic clearance rate of SLI was 19.7 +/- 1.6 ml/kg per minute of which 32.7 +/- 4.6% was contributed by hepatic and 37 +/- 4.9% by renal uptake mechanisms. The plasma half disappearance time of exogenously infused SLI was 1.9 +/- 0.3 min. The studies indicate that in the dog, the liver and kidney are both major sites of SLI metabolism, together accounting for 70.0 +/- 8.7% of the metabolic clearance of the peptide.

Animals↗
PubMed1981

Effects of growth hormone excess and deficiency on hypothalamic somatostatin content and release and on tissue somatostatin distribution.

Considerable indirect evidence now exists to suggest that hypothalamic somatostatin (SRIF) is the physiological inhibitory regulator of pituitary GH release. To support this relationship further, we studied the effect of in vivo modifications of GH homeostasis on hypothalamic SRIF content and in vitro release in an attempt to document a feedback relationship between the two peptides. GH administration to normal rats resulted in increased hypothalamic SRIF concentration and release. GH deficiency, in contrast, resulted in decreased hypothalamic SRIF concentration and release. This effect appears to be, at least in part, a direct action of GH, since a dose-related stimulation of hypothalamic SRIF release was demonstrated in the presence of GH concentrations ranging from 10(-9)-10(-5) M. The lowest dose causing stimulation (10(-9) M) is well within the normal concentration range of plasma GH in the rat, suggesting that the effect may be physiological. Specificity of the effect is suggested by a much greater sensitivity of the medial basal hypothalamus than the septum and preoptic area to the effects of GH. The perturbations of GH homeostasis studied had no effect on extrahypothalamic neural or gastrointestinal SRIF concentrations, suggesting a different regulatory mechanism in these areas.

Animals↗
PubMed1980

Effect of ventromedial hypothalamic lesions on the secretion of somatostatin, insulin, and glucagon by the perfused rat pancreas.

Somatostatin, insulin, and glucagon secretion by the perfused pancreas were studied in adult female rats 10 days after ventromedial hypothalamic (VMH) lesions and in sham operated controls to assess the role of their hypothalamic control. Insulin secretion was significantly greater in VMH-lesioned rats both under basal conditions and after stimulation by theophylline and arginine plus theophylline. Basal glucagon secretion was greater in VMH-lesioned rats as was the glucagon response to theophylline alone and in combination with arginine. Basal somatostatin secretion with similar in VMH and control rats but somatostatin secretion induced by theophylline and by arginine plus theophylline was significantly increased in VMH-lesioned rats. Both the pancreatic content and concentration of somatostatin were increased in VMH-lesioned rats. These results indicate the presence of hyperresponsiveness of A, B, and D cells following VMH destruction and provide new evidence for a role of the hypothalamus in the regulation of pancreatic somatostatin secretion.

Animals↗
PubMed1980

Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly.

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.

Acromegaly↗
PubMed1980

The effect of alterations in the pituitary-thyroid axis on hypothalamic content and in vitro release of somatostatin-like immunoreactivity.

The role of somatostatin (SRIF) in the regulation of thyroid homeostasis was studied by measuring hypothalamic SRIF-like immunoreactivity (SRIF-LI) content and in vitro release in hypothyroid (T3-treated and untreated), euthyroid, and T3-treated normal rats. Hypothalamic SRIF-LI content was decreased in hypothyroid rats and was restored to euthyroid levels by T3 treatment. SRIF-LI release from hypothalami of hypothyroid rats was decreased compared to that in euthyroid controls under basal and stimulated (60 mM K+ or 10(-6) M dopamine) in vitro conditions. The release of SRIF-LI from hypothalami of hypothyroid rats treated with T3 was restored to euthyroid levels. The release of SRIF-LI from normal rat hypothalami was unaffected by TRH or TSH but was stimulated by T3. These results suggest that T3 exerts its negative feedback effect on pituitary TSH release via stimulation of hypothalamic SRIF release as well as by a direct pituitary effect, and that the elevated TSH levels seen in primary hypothyroidism may result in part from a decrease in the tonic inhibitory effect of hypothalamic SRIF. Pancreatic, but not antral or colonic, SRIF-LI was increased in hypothyroid rats, and the levels were reduced by T3 treatment. The changes cannot be explained by alterations in food intake and may represent primary effects of the hypothyroid state.

Animals↗
PubMed1980

Somatostatin-like immunoreactivity in transplantable medullary carcinoma of rat thyroid: partial chromatographic and biological characterization.

Somatostatin-like immunoreactivity (SRIF-LI) has previously been demonstrated immunohistochemically in rat thyroid parafollicular cells. Studies were therefore performed to determine whether SRIF-LI was present in a transplantable medullary carcinoma of the thyroid (MCT) in the WAG/Rij strain of rat. SRIF-LI was found in MCT in significantly higher concentrations than in normal thyroid tissue. Thyroid and MCT SRIF-LI showed parallelism with the synthetic SRIF and RIA displacement curves and coeluted with synthetic SRIF on immunoaffinity chromatography. On gel filtration, thyroid SRIF-LI and the major peak of MCT SRIF-LI coeluted with synthetic SRIF. SRIF-LI of a larger molecular size was also present in the MCT. MCT and thyroid SRIF-LI coeluted with synthetic SRIF on high pressure liquid chromatography. MCT SRIF-LI purified by affinity chromatography was equipotent to synthetic SRIF in inhibiting dibutyryl cAMP-stimulated GH release by rat pituitary cells in monolayer culture. Serum SRIF-LI was elevated in tumor-bearing rats and showed characteristics similar to those of MCT SRIF-LI and synthetic SRIF on affinity and high pressure liquid chromatography (HPLC). Tumor-bearing rats showed diminished secretion of insulin after orally administered glucose and impaired secretion of GH in response to pentobarbital compared to normal control rats. The results indicate that SRIF-LI is produced in excessive quantities by a transplantable rat MCT and impairs the secretion of GH and insulin. The immunological, chromatographic, and biological properties of MCT SRIF-LI suggest that it is indistinguishable from synthetic SRIF.

Animals↗