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Biomedical subjects

N Kaiser

Publications and source records attributed to N Kaiser.

At least 55 records · Page 3Linked to original sources
PubMed1994

Influence of the xanthine derivative denbufylline and the anti-inflammatory agent nabumetone on microsomal free radical production and lipid peroxidation in rat liver.

The influence of denbufylline, nabumetone and its main metabolite BRL 10,720 on iron stimulated lipid peroxidation (LPO), cytochrome P 450 dependent H2O2 and chemiluminescence (CL) production was investigated in rat liver microsomes in vitro (10(-5)-10(-3) M) and in vivo after treatment of rats (5-300 mg/kg b.m. orally on three consecutive days). In rat liver slices the release of thiobarbituric acid reactants (TBAR) was measured after 1 hour of incubation with the drugs. Denbufylline, nabumetone and BRL 10,720 exerted a significant inhibition of iron stimulated LPO in vitro. Nabumetone showed the strongest antioxidative activity, which was also seen in liver slices. These antioxidative effects were not found after in vivo treatment of rats. Denbufylline (10(-3) M) additionally inhibited H2O2 formation and the luminol and lucigenin amplified CL in vitro. Unexpectedly, nabumetone increased H2O2 formation both in vitro and in vivo, but in vitro only lucigenin amplified CL. BRL 10,720 increased microsomal H2O2 production in vivo. Moreover, BRL 10,720 enhanced CL in vitro and in vivo significantly, which is interpreted as an increase of the production of superoxide anion radicals and other reactive oxygen species such as H2O2, but lipid peroxidation in liver microsomes was not enhanced. These results suggest that denbufylline, nabumetone and BRL 10,720 in contrast to the in vitro effects did not exert antioxidative activities after treatment of rats. On the contrary, BRL 10,720 was found to support the formation of reactive oxygen species in liver microsomes.

Animals↗
PubMed1994

Familial hyperinsulinism maps to chromosome 11p14-15.1, 30 cM centromeric to the insulin gene.

Familial hyperinsulinism (HI) is the most common cause of persistent neonatal hyperinsulinaemic hypoglycemia. Linkage analysis in 15 families (12 Ashkenazi Jewish, 2 consanguineous Arab, 1 non-Jewish Caucasian) mapped HI to chromosome 11p14-15.1 (lod score = 9.5, theta = 0 at D11S921). Recombinants localized the disease locus to the 6.6 cM interval between D11S926 and D11S928. In Jewish families, association (p = 0.003) with specific D11S921/D11S419 haplotypes suggested a founder effect. This locus, which is important for normal glucose-regulated insulin secretion, represents a candidate gene for studies of other diseases of beta-cell dysfunction including non-insulin-dependent diabetes mellitus (NIDDM).

Chromosome Mapping↗
PubMed1994

Hyperproinsulinemia and insulin deficiency in the diabetic Psammomys obesus.

Patients with noninsulin-dependent diabetes mellitus exhibit increased proportions of plasma proinsulin and proinsulin conversion intermediates. We used hyperinsulinemic diabetic and nondiabetic Psammomys obesus to study the possible relationship between steady state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and pancreas. Insulin-like peptides were separated by reverse phase HPLC and identified by pulse-chase experiments. A marked increase in the proportions of proinsulin and proinsulin conversion intermediates in the plasma and pancreas of diabetic nonfasted Psammomys was associated with 90% reduction in insulin stores of the pancreas. After a 16- to 20-h fast, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio was normalized. In contrast, nondiabetic Psammomys showed only 50% reduction in pancreatic insulin stores under nonfasting conditions, with no change in the proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, the pancreatic capacity for storage of insulin may be limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycemia, which may in itself further exacerbate pancreatic dysfunction.

Animals↗
PubMed1993

Replication of adult pancreatic-beta cells cultured on bovine corneal endothelial cell extracellular matrix.

A valuable system has been developed to study replication of adult beta cells. Isolated islets from adult rats were partially dispersed and plated on dishes coated with extracellular matrix from bovine-corneal endothelial cells. Within 24 h islet cells attached to the matrix and formed a monolayer. The proportion of insulin-, glucagon-, and somatostatin-containing cells in the cultures was characteristic of whole islets. Function of beta cells was assessed by measuring glucose-stimulated insulin release. Insulin release from 7-day-old cultures increased 19-fold after a 16.7 mM glucose challenge indicating that beta-cell function was normal. Cellular replication in the cultures was assessed using the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU). BrdU incorporation was noted in insulin-, glucagon-, and somatostatin-containing cells and also in non-endocrine cells. Among endocrine cells, the majority of BrdU labeling occurred in beta cells. Beta-cell replication potential was assessed using different concentrations of glucose. The incorporation of BrdU into beta cells was affected in a dose-dependent manner by glucose; over a 10-fold increase of beta-cell BrdU labeling was observed when glucose concentration was raised from 5.5 to 16.7 mM. The system proved advantageous for studying the replication potential of adult beta cells.

Animals↗
PubMed1993

Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells.

Hyperglycemia has been implicated in the pathogenesis of both micro- and macrovascular complications in diabetes. Little is known, however, about glucose transporters and their regulation in the vascular system. In this study, the regulation of glucose transporters by glucose was examined in cultured BAECs and BSMCs, and in human arterial smooth muscle cells. Both BAECs and BSMCs transported glucose via the facilitated diffusion transport system. Glucose-transport activity in vascular smooth muscle cells was inversely and reversibly regulated by glucose. Exposure of BSMCs and HSMCs to high glucose decreased Vmax for 2DG and 3-O-MG uptake, whereas Km remained unchanged. The hexose-transport system of BAECs exhibited lower 2DG and 3-O-MG uptake compared with BSMCs and showed little or no adaptation to changes in ambient glucose. Northern blot analysis demonstrated that GLUT1 mRNA levels in BAECs and BSMCs were unaffected by the concentration of glucose in the medium. GLUT2-5 mRNA could not be detected by Northern blot analysis. GLUT1 protein, quantified by Western blot analysis, was more abundant in BSMCs than in BAECs and was decreased by approximately 50% when medium glucose was elevated from 1.2 to 22 mM for 24 h. The alterations in the level of GLUT1 protein correlated with the changes observed in transport activity. These observations suggest differential regulation of glucose transporter in response to glucose between smooth muscle and endothelial cells. The sites of autoregulation may involve translational control and/or the stability of the protein in the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗
PubMed1992

In-vivo and in-vitro studies on the effect of amphotericin B on endothelin release.

Since amphotericin B nephrotoxicity is mediated, in part by hypoxic tubular injury, the role of endothelin in the renal vasoconstriction, characteristic of amphotericin toxicity has been studied. Intact and salt depleted rats were infused with amphotericin B (20 micrograms/kg per min) or 5% dextrose over 20 min. Plasma endothelin levels determined at the conclusion of the infusion period, did not differ between the experimental groups, despite a marked reduction in renal blood flow noted in rats infused with amphotericin B. Amphotericin B (10(-5)-10(-7) M) did not stimulate endothelin release from cultured bovine aortic endothelial cells. However, in a model of chronic amphotericin nephrotoxicity produced by repeated daily intraperitoneal injections of amphotericin B (5 mg/kg) to salt depleted rats, renal failure was associated with elevated plasma endothelin levels (29.3 +/- 4.4 fmol/mL, vs 10.8 +/- 1.2 fmol/mL in salt depleted controls, P less than 0.01). We conclude that while plasma endothelin may be increased in chronic amphotericin B nephropathy, this peptide does not mediate the acute renal vasoconstriction associated with the infusion of this drug.

Amphotericin B↗
PubMed1992

Radiocontrast agents induce endothelin release in vivo and in vitro.

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.

Animals↗
PubMed1991

Monolayer culture of adult rat pancreatic islets on extracellular matrix: modulation of B-cell function by chronic exposure to high glucose.

Studies in vivo indicate that chronic hyperglycemia is deleterious for insulin secretion. We have used an improved islet monolayer culture system to study chronic modulations of B-cell function. Adult rat islets maintained over several weeks on extracellular matrix in the presence of 11.1 mM glucose responded to an acute stimulation with 16.7 mM glucose by a 5- to 8-fold increase in insulin secretion. When cultured in the presence of higher glucose concentrations, the response to an acute glucose stimulus diminished time and dose dependently. In islets desensitized by exposure to 33.3 mM glucose for 1 week, reduction of the glucose level to 11.1 mM reversed the desensitization within 2 weeks. This desensitization was not limited to the glucose stimulus; responses to other nutrient secretagogues, such as glyceraldehyde and alpha-ketoisocaproic acid, were also reduced. In contrast, responses of insulin secretion to nonnutrient stimulators (tolbutamide and quinine) and amplifiers (isobutylmethylxanthine and carbachol) showed no desensitization in islets exposed to 33.3 mM glucose. Desensitization similar to that caused by 33.3 mM glucose could be induced by 11.1 mM glucose together with 0.1 mM isobutylmethylxanthine. High glucose also caused a time-dependent loss in compact monolayer organization with disruption of cell contacts. Our studies suggest that 1) generation of the reduced insulin response may be related to the prolonged high insulin secretion rate; 2) expression of the functional change is specific to the nutrient stimulus-secretion coupling; and 3) modifications in intercellular contacts may be involved in B-cell desensitization.

1-Methyl-3-isobutylxanthine↗