PubMed Health⌕ Search

Biomedical subjects

J C Dunbar

Publications and source records attributed to J C Dunbar.

At least 73 records · Page 4Linked to original sources
PubMed1990

Platelet aggregation and disaggregation in the streptozotocin induced diabetic rat: the effect of sympathetic inhibition.

Alterations in platelet function have been observed in a number of diabetic states. Increased responsiveness to platelet-aggregating agents in diabetes associated with increased catecholamine production and/or turnover suggested that heightened sympathetic activity may contribute to this increased platelet aggregation response. To investigate this possibility, we made male Wistar-Furth rats diabetic with streptozotocin and treated them either with adrenergic inhibitors (clonidine, yohimbine, reserpine) or saline. After 2 weeks, arterial blood samples were collected in 3.8% sodium citrate or acid citrate dextrose (ACD). Platelet-rich plasma (PRP) was prepared, and platelet aggregation studies were conducted directly or conducted on washed platelets prepared from PRP collected with ACD. Platelet aggregation in response to ADP by PRP was reduced while the rate of disaggregation was increased in platelets from diabetic animals when compared to controls. However, platelet aggregation in response to ADP in washed platelets was increased in diabetic animals when compared to controls. Clonidine, reserpine and yohimbine significantly decreased the diabetes-induced increase in maximum aggregation. Thrombin-induced aggregation was not altered by diabetes or any of the treatments. The platelet size was increased in the diabetic animals and was decreased toward controls by clonidine, reserpine and yohimbine treatment. These studies suggest that diabetes increases platelet aggregation response in diabetic rats, and that blockage or suppression of adrenergic activity reverses or attenuates the diabetes-induced hypersensitivity to ADP.

Adenosine Diphosphate↗
PubMed1990

Cardiorespiratory response patterns elicited by microinjections of neuropeptide Y in the nucleus tractus solitarius.

A limited occipital craniotomy was conducted on anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of neuropeptide Y (NPY), a putative neuromodulator associated with catecholaminergic (CA) synapses, were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the posterior portion of the area postrema, an area of the NTS in which there is known to be a functional coexistence of cardiovascular and respiratory-related neuronal elements. This region of the caudal NTS in the rat is not only the principal site of termination of baro- and chemoreceptor afferents, but it also has profuse reciprocal connections with NPY-containing cardiorespiratory control regions in the hypothalamus and with other brainstem regulatory nuclei. Moreover, this same region of the rat NTS also shows very high densities of NPY binding sites. Cardiorespiratory responses were subsequently recorded for a 60-min test period following NPY administration. Microinjections of NPY, in the dose range of 10-100 pmol/rat, into the caudal NTS of intact rats produced significant dose-related reductions in mean arterial blood pressure, pulse pressure and minute volume. To a lesser extent, NPY microinjections also produced significant reductions in heart rate, respiratory rate and tidal volume. In a series of separate experiments, in an effort to ascertain the modulatory influences of rostral brain regions on these NPY-evoked, NTS-mediated cardiorespiratory response patterns, microinjections of NPY were made under identical anesthetic and experimental conditions in a group of rats wherein reciprocal connections between the NTS and rostral brain regions had been disrupted via supracollicular decerebration. In addition, since NPY microinjections were made into specific loci wherein afferent inputs from cardiopulmonary receptors are known to converge in the rat NTS, the effects of bilateral vagotomy on NPY-evoked, NTS-mediated cardiorespiratory response patterns were also examined in otherwise intact rats and under the same experimental conditions. The effects of NPY microinjections at the same dosage on NTS-mediated cardiorespiratory response patterns were subsequently compared among the intact, decerebrate and vagotomized rats. The results showed that whereas the hypotensive actions of NPY were not affected by decerebration, vagotomy significantly increased the magnitude of the hypotension elicited by NPY microinjections in comparison to the intact and decerebrate groups of rats. On the other hand, vagotomy abolished the NPY-evoked bradycardia which had a similar magnitude in both intact and decerebrate rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Elevated blood glucose is associated with poor outcome in the carbon-monoxide-poisoned rat.

Levine-prepared, unanesthetized rats exposed to 2400 and 2700 ppm carbon monoxide (CO) for 90 min were used to examine the effect of acute CO poisoning on plasma glucose and insulin concentrations, and neurologic dysfunction. Body temperature and mean arterial blood pressure fell progressively during CO exposure. Glucose rose during initial CO exposure, then declined: glucose increased again after 2 h of room air recovery. Neurologic deficit, behaviorally-assessed after 4 h of recovery, was strongly correlated (r = 0.71, P less than 0.001) with glucose increase during the first 2 h of recovery. Recovery hyperglycemia was, in turn, correlated (r = 0.69, P less than 0.001) with the fall in glucose during the second half of CO exposure. Neurologic deficit was also correlated, but less strongly so, with hypoglycemia during CO exposure. Failure to rapidly regain body temperature during recovery was correlated with the post-CO rise in glucose concentration and with increased neurologic deficit. Plasma insulin activity was depressed immediately following CO exposure, and increased during recovery. CO-induced hypothermia was greater at 2700 than at 2400 ppm CO, as were post-CO recovery hyperglycemia, neurologic deficit and mortality, while body temperature recovery was less complete. The results provide evidence of an association between neurologic deficit and general morbidity following acute CO poisoning and the magnitude of post-CO hyperglycemia.

Animals↗
PubMed1989

Beta cell desensitization to glucose induced by hyperglycemia is augmented by increased calcium.

Chronic hyperglycemia has been shown to induce a decrease in beta cell sensitivity to a subsequent glucose challenge. Calcium is a necessary cofactor in the insulin secretory process and glucose elevates cytoplasmic levels. This study was designed to study whether chronic exposure to different extracellular calcium and glucose concentrations would affect the islets' subsequent response to regulatory stimuli. Islets were isolated and cultured in TC 199 plus 10% beta calf serum, glucose (5.5 or 27.5 mM) and calcium (0.5, 2.5 or 4.0 mM) for 48 h. Following culture, the islets were harvested and incubated a second time in the presence of glucose and/or arginine, theophylline, and trifluoperazine (TFP). Some islets were used for insulin content, protein synthesis studies and/or CO2 production from labelled glucose. Islets cultured in a normal glucose environment with low or normal calcium concentration maintained the capacity to respond to a subsequent glucose or arginine challenge. However, islets cultured in a high glucose or high calcium medium failed to respond to a second glucose or arginine stimulus. Theophylline stimulated insulin secretion from both glucose-sensitive and non-sensitive islets, while trifluoperazine inhibited glucose-stimulated insulin secretion in previously sensitive islets and increased insulin secretion in previously non-sensitive islets. The different culture conditions did not alter insulin content, protein synthesis or glucose conversion to labelled CO2. We conclude that chronic exposure to high glucose decreases beta cell responsiveness to glucose and amino acids. Increased extracellular calcium augmented this response. However, the beta cell remained sensitive to theophylline-induced insulin secretion, while TFP paradoxically increased insulin secretion in the glucose-insensitive beta cells. Protein synthesis and glucose oxidation were not affected by culture conditions. Thus we suggest that the glucose-induced desensitization of the beta cells may be due to alterations in the calcium-dependent release mechanism.

Animals↗
PubMed1989

Regulation of the hepatic response to glucagon: role of insulin, growth hormone and cortisol.

The hepatic response to glucagon was investigated in five groups of animals: (1) controls; (2) excess growth hormone (GH; tumor-bearing); (3) streptozotocin-induced diabetic; (4) cortisol-treated, and (5) insulin-treated animals. Blood samples were collected from the animal models and hepatocytes were prepared and used for glucagon-binding studies and studies of total glucose production, gluconeogenesis and glycogen determinations. Glucagon binding was elevated in GH-tumor-bearing and cortisol-treated hepatocytes but lower in hepatocytes from diabetic animals. Basal total glucose production wash higher in hepatocytes from diabetic rats but not changed in hepatocytes from GH-tumor-bearing, insulin-treated or cortisol-treated animals. Glucagon significantly stimulated total glucose production in hepatocytes from control, insulin-treated and cortisol-treated but not diabetic and GH tumor models. Gluconeogenesis as evaluated by alanine conversion to glucose was significantly increased in hepatocytes from diabetic and cortisol-treated animals and was significantly lower in hepatocytes from GH-tumor-bearing animals. Glucagon failed to significantly stimulate gluconeogenesis in hepatocytes from diabetic and tumor-bearing animals. Hepatic glycogen content was significantly decreased in diabetic and GH-tumor-bearing animals but not changed in insulin-treated and cortisol-treated animals. We conclude that increased glucagon binding was not always correlated with an increase in glucagon-stimulated glycogenolysis, gluconeogenesis or increased sensitivity to glucagon. Persistent hyperinsulinism may effectively suppress glucagon- or cortisol-stimulated pathways.

Alanine↗
PubMed1988

Acute effects of S-carboxymethylated human growth hormone on insulin resistance in the obese (ob/ob) mouse.

Chronic treatment of ob/ob mice with growth hormone (GH) increases plasma insulin and blood glucose concentrations, and enhances insulin resistance in peripheral tissues. The purpose of the present study was: (1) to determine the length of time required for the development of increased circulating insulin concentration and adipose tissue insulin resistance in response to GH in the ob/ob mouse, (2) to examine the relationship between the rise in insulin concentration and the development of insulin resistance, and (3) to test whether the hormone derivative could enhance insulin resistance in isolated adipose tissue when added in vitro. Female ob/ob mice were injected intraperitoneally (ip) with either saline or 200 micrograms of S-carboxymethylated human GH (RCM-hGH), a diabetogenic GH derivative, which lacks significant insulinlike or growth-promoting activities. A threefold increase in plasma insulin concentration was observed three and six hours after RCM-hGH injection, but increased hyperglycemia was evident only after six hours. The in vitro stimulatory effect of insulin on [14C]glucose oxidation by parametrial adipose tissue was unchanged at three hours but suppressed six hours following administration of RCM-hGH. When the plasma insulin level of ob/ob mice was increased threefold by the administration of neutral protamine Hagedorn (NPH) insulin, the in vitro stimulatory effect of insulin on [14C]glucose oxidation by adipose tissue isolated from these animals was not altered, suggesting that insulin-induced receptor or postreceptor changes do not account for the increased insulin resistance produced by RCM-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1987

Amino acid sequence of guinea pig prostate kallikrein.

The primary structure of the major arginine esteropeptidase from guinea pig prostate has been deduced from automated Edman degradation of peptides generated by clostripain, cyanogen bromide, endoproteinase Lys-C, and Staphylococcus aureus V8 protease digestion of the protein. The esteropeptidase is a single polypeptide chain comprised of 239 amino acids and contains 2 apparent sites of carbohydrate attachment, Asn-78 and Asn-169. Both occur in consensus sequences for N-linked glycosylation sites. The esteropeptidase exhibits approximately 35% homology with trypsin including conservation of the catalytic residues and the aspartic acid which confers specificity toward basic amino acids. The sequence identity, however, extends to greater than 60% with the kallikrein family of serine proteases. In addition to the overall homology, the guinea pig enzyme displays a number of features characteristic of kallikreins including 10 conserved half-cystine residues, a C-terminal proline, and the "kallikrein loop". On the basis of this structural relatedness, the enzyme has been designed as guinea pig prostate kallikrein. In contrast to many of the kallikreins of other species and tissues, this enzyme does not contain any sites within the kallikrein loop sensitive to proteases that result in internal breaks in the polypeptide chain.

Amino Acid Sequence↗
PubMed1987

Role of glandular kallikreins as growth factor processing enzymes: structural and evolutionary considerations.

Hormones and growth factors are generally released from larger precursors by limited proteolysis. The causative agents remain poorly defined with respect to location and properties. One subset of proteases, the glandular kallikreins, have been implicated in a few cases, in part because of their specific association with mature forms of some hormones. However, limited distribution and low copy number in some species cast doubt on this hypothesis, and they may well play other physiological functions that remain to be elucidated.

Amino Acid Sequence↗
PubMed1987

Metabolic basis for the diabetogenic action of growth hormone in the obese (ob/ob) mouse.

The ob/ob mouse responds predictably to chronic treatment with large doses of pituitary GH with marked hyperglycemia and decreased glucose tolerance. The purpose of the present study was to characterize the metabolic alterations produced by GH that lead to this diabetogenic response in the ob/ob mouse in order to determine whether this animal might serve as a useful model for the study of the cellular mechanisms involved in the diabetogenic action of GH. Female ob/ob mice were treated sc for 3 days with either saline or 200 micrograms/day S-carboxymethylated human GH (RCM-hGH), a diabetogenic GH derivative lacking significant growth-promoting or insulin-like activities. Six hours before the start of the experiment, the animals were given a sc injection of 2 micrograms dexamethasone and deprived of food. RCM-hGH treatment produced marked increases in fasting blood glucose and plasma insulin concentrations, but had no effect on plasma glucagon or serum insulin-like growth factor I levels. It had no effect on liver glycogen level or in vitro hepatic glucose production in the absence or presence of pyruvate and lactate added to the incubation medium. By contrast, the in vitro stimulatory effects of insulin on [14C] glucose oxidation by isolated soleus muscle or segments of parametrial fat were greatly attenuated by RCM-hGH treatment, without changes in rates of basal glucose oxidation. This change in peripheral tissue responsiveness to insulin does not appear to involve glucose transport, since the in vitro stimulation by insulin of 3-O-[14C]methylglucose transport into isolated diaphragm muscle was not altered by RCM-hGH treatment. Moreover, the RCM-hGH-induced reduction in adipose tissue responsiveness to insulin does not appear to be mediated by a reduction in insulin binding, since [125I]iodoinsulin binding to adipocytes isolated from RCM-hGH-treated mice was similar to that to cells from saline-treated animals. Interestingly, the reduction in responsiveness to insulin seen with segments of adipose tissue from RCM-hGH-treated animals was not found with isolated adipocytes prepared from such tissue by collagenase digestion. These results suggest that the hyperglycemia and glucose intolerance produced in ob/ob mice by chronic GH treatment result primarily from increased peripheral tissue insulin resistance. Therefore, the ob/ob mouse provides a useful model to elucidate the cellular mechanism(s) of this aspect of the diabetogenic action of GH.

Adipose Tissue↗
PubMed1987

The relationship between glucagon receptors and metabolic profile in two strains of rats: Wistar-Furth and Sprague-Dawley.

We studied glucagon and insulin binding to isolated hepatocyte receptors in Wistar-Furth (WF) and Sprague-Dawley (SD) rats, using 125I-labeled hormones. Hepatocytes from WF rats bound more glucagon than hepatocytes from SD rats. There were no differences in insulin binding. These observations prompted us to investigate other strain differences. Fasting and nonfasting serum glucose, glucagon, insulin, and growth hormone were measured. WF animals had a lower fasting glucose and higher fasting glucagon than SD animals, while SD rats had higher nonfasting insulin levels and a higher hepatic glycogen content. Total hepatic glucose production in response to glucagon (10(-8) M) was greater in WF than in SD rats, while glucagon-stimulated gluconeogenesis from alanine was the same in the two groups of animals. We concluded that the decreased glucagon binding does not play a significant role in the maintenance of serum glucose or in the gluconeogenetic response glucagon, and that neither these responses nor the serum glucagon levels appears to be correlated with the number of glucagon receptors. We conclude further that different animal strains of the same species may differ in their biologic responses.

Animals↗
PubMed1986

Immunologic and biologic evaluation of insulin degradation following prolonged storage in plastic syringes.

Insulin potency during storage in plastic disposable syringes for short periods of time is a concern of diabetics as well as syringe manufacturers. Previous studies have indicated that leaching of organic materials from rubber gaskets may have cytotoxic effects. The purpose of this study was to evaluate the immunologic and radioreceptor degradation of insulin storage in commercial plastic syringes. Insulin syringes were filled with insulin and stored at 4 degrees C for 2 weeks. Immunologic potency was assessed by radioimmunoassay while biologic potency was evaluated by binding to hepatic insulin receptors. Recoverable insulin was measured on days 1, 3, 7, and 14 and compared with highly purified porcine insulin. Insulin content of samples stored in all three plastic syringes showed no statistically significant (p less than 0.05) loss of immunologic or biologic potency for 2 weeks compared with stock controls. Lente insulin gave more variability in storage in the radioimmunoassay, possibly due to settling, and was less effective in displacing labeled insulin in the radioreceptor assay. We conclude that premeasured insulin may safely be stored in plastic disposable syringes under selected conditions, especially in blind and handicapped diabetic patients, for 2 weeks.

Drug Stability↗
PubMed1985

Nerve growth factor biosynthesis: isolation and characterization of a guinea pig prostate kallikrein.

Guinea pig prostate contains one major soluble esteropeptidase activity. The protein has been purified and characterized and found to be a glycoprotein comprised of a single polypeptide chain. The molecular has a similar Km for lysine and arginine synthetic substrates, although the Vmax for arginine is much greater than that for lysine. Amino-terminal sequence analysis has also revealed a marked degree of homology to mouse gamma-nerve growth factor (NGF) and the kallikrein family of serine proteases. In contrast to gamma-NGF, however, the guinea pig enzyme does not appear to form stable complexes with beta-NGF.

Amino Acid Sequence↗
PubMed1985

Cardiomegaly and haemodynamics in rats with a transplantable growth hormone-secreting tumour.

To investigate cardiovascular changes in experimental acromegaly, a growth hormone-secreting tumour (MtT-W-15) was implanted in adult female rats. Somatic and tumour growth occurred steadily during the 8 week study period, as did an increase in serum growth hormone titre. Weight of left ventricle and right ventricle increased directly with tumour growth, both on an absolute basis and when compared with normal rats of equal body weight. Atrial weight also increased substantially. Haematocrit declined sharply at first, and more slowly later with increasing tumour weight. Haemodynamic measurements were made on these animals at two stages of tumour growth using an anaesthetised open-chest preparation. Cardiac index (per g body wt), stroke index, stroke work, left ventricle +dP/dtmax, and dF/dtmax of aortic flow were greatly elevated in rats with the largest tumours (longer duration), and to a lesser extent in those with smaller tumours (shorter duration). Systemic peripheral resistance and heart rate were depressed. Ventricular weight increased non-linearly with increases in cardiac index. Cardiac output, stroke volume, stroke work and dF/dtmax normalised per g left ventricle weight were also elevated. Splenomegaly accompanied tumour growth; however, splenectomy of tumour-bearing animals failed to prevent development of anaemia and cardiomegaly. While a direct effect of elevated growth hormone provides the best explanation for development of cardiomegaly in this model, volume work overloading due to anaemia and water retention may be a contributory cause.

Acromegaly↗
PubMed1985

Increased glucagon receptors in chronically hypersomatotrophic and hyperglucagonemic rats.

The effect of increased levels of growth hormone on glucagon binding by isolated hepatocytes and on the cellular cyclic AMP response to glucagon was evaluated in rats bearing growth hormone-secreting tumor (Mt-T-W15) and in rats treated with rat growth hormone. An increased binding, due to an increased number of receptors, was observed in both groups of animals. Glucagon binding did not correlate with plasma glucagon levels, suggesting a failure of down regulation, possibly due to an effect of growth hormone and insulin on the number of receptors. Tumor-bearing and growth hormone-treated rats had larger hepatocytes so that, when hormone binding was expressed in terms of square micrometer of membrane surface, it appeared decreased. When the tumor was removed the increase in the number of glucagon receptors per cell persisted, even though the average cell size returned toward normal. It is suggested that this retention of the receptors may have been the result of continuing hyperinsulinism. Basal cAMP levels were elevated in hepatocytes of tumor-bearing and growth hormone-treated animals, possibly due to cell hypertrophy. On the other hand, the maximum cAMP response to glucagon was not altered by the experimental procedures. A negative effect of insulin on cAMP accumulation may explain this apparent paradox. Indeed, hepatocytes isolated from rats following tumor removal, but with continuing hyperinsulinemia, had a lower maximum cAMP response, even though the glucagon binding per cell or per unit of cell surface was increased.

Animals↗
PubMed1984

Glucagon secretion by dispersed alpha cell enriched islets from streptozotocin treated hamsters in perifusion.

Streptozotocin (70 mg/kg) was administered intravenously to female Syrian hamsters. The hamsters received insulin (5U/animal/day). Insulin treatment was withdrawn 3 days before sacrifice in one group, while another group was maintained on insulin until sacrifice. Ten to 14 days following streptozotocin administration the animals were killed, and the pancreatic islets isolated and subsequently dispersed. Islet DNA content was decreased while the glucagon content was elevated by streptozotocin treatment. The glucagon secretory responsiveness of the dispersed alpha cells of control animals was stimulated by glucopenia and decreased by glucose. Alpha cells of streptozotocin hamsters were not only suppressed but were actually stimulated by high glucose concentrations. Treatment with insulin in vivo but not in vitro, resulted in a restoration of the alpha cells responsiveness to glucose suppression. Dispersed alpha cells from control and streptozotocin treated animals were stimulated by arginine. Basal and total glucagon secretion was greatest in dispersed alpha cells from streptozotocin treated animals. We concluded: that the paradoxical response of alpha cells to glucose noted in diabetes is not due to short term insulin deprivation or the lack of morphologic contact with beta cells; that the alpha cells require and insulin stimulated islet metabolite and extra islet materials to respond appropriately to glucose; and that the alpha cells response to arginine is mediated independently of glucose regulation.

Animals↗
PubMed1984

Glucagon binding to liver membranes of Mt-T-W15 tumor-bearing and hypophysectomized rats. A possible role for insulin and growth hormone.

To assess the effect of the endocrine environment and, more specifically, of growth hormone and insulin on glucagon receptors, we studied 125I-glucagon binding to liver membranes in five groups of rats: (1) controls, (2) streptozocin (STZ)-treated, (3) tumor-bearing (growth hormone-producing, Mt-T-W15), (4) STZ-treated tumor-bearing, and (5) hypophysectomized rats. Glucagon binding was decreased in tumor-bearing, hypophysectomized, and STZ-treated rats. Basal and glucagon-stimulated cAMP levels were determined in isolated hepatocytes. The basal cAMP levels were increased in STZ-treated, tumor-bearing, STZ-treated tumor-bearing, and hypophysectomized animals. All groups responded and produced more cAMP in response to glucagon stimulation, although the maximal response was greater in STZ-treated, tumor-bearing STZ-treated, and hypophysectomized groups than in the controls. Our data confirm that hyperglucagonemia downregulates the hepatic glucagon receptors and suggest that insulin and growth hormone may play a stimulatory role in their regulation. The results also suggest that the downregulation of glucagon receptors is not directly correlated to the basal or glucagon-stimulated cAMP levels.

Animals↗
PubMed1984

Nerve growth factor: mechanism of action.

Although the detailed mechanism of action of NGF as it occurs in vivo still requires considerable clarification, a model in which NGF is generated by end organs of responsive neurons and interacts with these neurons to provide trophic stimulation and maintenance of viability seems highly plausible. The demonstration of NGF synthesis by these cells, including the details of the process, is required, and information regarding the events following the formation of the hormone-receptor complex at the plasma membrane must be obtained. However, the contribution of internalization and the possible role of the internalized receptor as a second messenger for generating the long-term effects of the hormone are particularly appealing. Any findings with NGF will almost certainly provide additional important insights into other polypeptide growth factors, particularly those substances found in the neurotrophic subset.

Affinity Labels↗