Biomedical subjects

V Grill

Publications and source records attributed to V Grill.

At least 181 records · Page 10Linked to original sources

PubMed1986

Inhibitors of adriamycin-induced histamine release in vitro limit adriamycin cardiotoxicity in vivo.

The activity of theophylline and disodium cromoglycate was tested on adriamycin-induced histamine release in vitro and on adriamycin cardiotoxicity in vivo. Both substances significantly inhibited the release of histamine induced by 100 micrograms ml-1 of adriamycin on rat peritoneal cells and produced significant protection against adriamycin-mediated acute and chronic cardiotoxicity in mice. N-acetylcysteine, a free radical scavenger, successfully used in the prevention of the cardiomyopathy, was also found to be an inhibitor of histamine release induced by adriamycin and compound 48/80 on rat peritoneal cells. This study further supports the hypothesis that the release of histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.

Acetylcysteine↗

PubMed1986

Effects of insulin on fasting and meal-stimulated somatostatin-like immunoreactivity in noninsulin-dependent diabetes mellitus: evidence for more than one mechanism of action.

We assessed the effects of insulin and normalization of blood glucose on plasma levels of somatostatin-like immunoreactivity (SLI) in patients with noninsulin-dependent diabetes mellitus (NIDDM). In one series of experiments, normalization of blood glucose was achieved by Biostator-controlled feedback infusion of insulin. This procedure reduced plasma SLI levels by 34% [from 17.1 +/- 2.1 (+/- SEM) to 11.3 +/- 1.9 pg/ml; P less than 0.05], concomitant with a significant reduction in plasma glucagon and C-peptide and an evanescent decrease in plasma gastric inhibitory peptide (GIP) levels. An ensuing mixed meal elicited a rise in SLI that reached the same levels during infusion of insulin as during uncontrolled hyperglycemia; the incremental increase was, however, 45% higher (P less than 0.005) during insulin infusion. Furthermore feedback insulin infusion enhanced GIP and decreased C-peptide responses, but did not affect the glucagon response to the meal. To further evaluate the influence of insulin of SLI levels, we compared the effects of normo- and hyperglycemia during constant hyperinsulinemia by varying the rate of glucose infusion (glucose clamping). Basal SLI levels decreased significantly only during the normoglycemic clamp. The SLI response to a meal was more pronounced during the normoglycemic than the hyperglycemic clamp. The patterns of glucagon and GIP were similar during the two clamp conditions, while both basal and stimulated C-peptide levels were lower during the normoglycemic clamp. To investigate the temporal relationship between changes in blood glucose and SLI levels, patients were studied during a prolonged (270-min) period of normoglycemic clamp and fasting. After attaining normoglycemia, SLI levels continued to decline for 150 min, whereas glucagon and GIP levels did not change. We conclude that in patients with NIDDM, insulin significantly lowers basal SLI levels if normoglycemia is concomitantly attained; this action of insulin was partially dissociated from its hypoglycemic action; hyperglycemia per se inhibits a meal-induced SLI response, and insulin effects on SLI are not secondary to changes in glucagon or GIP levels.

Adult↗

PubMed1986

Abnormalities of insulin responses after ambient and previous exposure to glucose in streptozocin-diabetic and dexamethasone-treated rats. Role of hyperglycemia and increased B-cell demands.

In NIDDM, B-cells are insensitive to glucose. We studied the specificity and evolution of this abnormality in 6-10-wk-old neonatally streptozocin-diabetic (STZ) and in dexamethasone-treated (DMT) rats. Not only the effect of ambient but also that of previous glucose (priming effect) was characterized in the perfused pancreas. In fed STZ, blood glucose was elevated to 9.2 +/- 0.8 versus 5.3 +/- 0.2 mM in control (C) rats. Ambient glucose (27 mM) in the perfusate induced a significant but reduced total response (11% of C) that was predominantly monophasic. Secretion was promptly induced (in less than 20 s) both in STZ and C. Other nutrients, i.e., glyceraldehyde (10 mM) and alpha-ketoisocaproic acid (KIC) (5 mM) also induced reduced and monophasic responses, whereas, in contrast, 3-isobutyl-1-methylxanthine (IBMX) induced an enhanced response that was 3.8-fold larger than in C. In DMT, blood glucose was normal (5.4 +/- 0.3 mM). Ambient glucose (27 mM) in the perfusate induced a normal first phase and a moderately reduced second phase (52% of untreated rats). DMT rats were hyperresponsive to IBMX, this agent inducing 2.5-fold higher release than in untreated rats. Previous perfusion with 27 mM glucose enhanced twofold the effect of a second stimulation period with glucose in C. This induction of priming by glucose could not be demonstrated in fed STZ or in DMT. However, when STZ were fasted or insulin treated for 36 h, induction of priming reappeared, i.e., the second pulse of glucose evoked 2-3-fold more insulin release than the first pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1986

Potentiation by previous nutrients of glibenclamide-induced insulin release in man. An effect which is counteracted by meal-induced retardation of drug absorption.

We have studied the impact of a previous meal on insulin and glucose responses to the subsequent administration of glibenclamide. Healthy volunteers and NIDDM patients ingested a standard low-carbohydrate breakfast, and glibenclamide was administered 110-120 min later either as an intravenous bolus (12.5 micrograms/kg body wt), or as a tablet (5 mg HB 419). When glibenclamide was administered i.v. the drug raised insulin and lowered blood glucose levels, and previous breakfast potentiated these effects both in healthy volunteers and in NIDDM patients. Conversely when glibenclamide was given as a tablet the drug per se raised C-peptide and lowered blood glucose levels under fasting conditions, whereas the drug had no effect when ingested after breakfast. Measurements of glibenclamide in plasma revealed that previous breakfast delayed the systemic appearance of ingested glibenclamide. We conclude that nutrients sensitize insulin-releasing cells to subsequent stimulation by glibenclamide, thereby aggravate a blood-glucose-lowering effect of the drug. However this effect, which could potentially induce undesirable hypoglycaemia in sulphonylurea-treated diabetics, is counteracted when glibenclamide is taken orally because of a meal-induced decrease in drug absorption.

Adult↗

PubMed1985

Impairment of motor coordination induced by doxorubicin in mice.

The neurotoxic effects of a single intraperitoneal or intravenous injection of doxorubicin were evaluated in CD1 mice by means of the rotarod test. The test was performed daily for nine weeks after treatment. For both routes of administration, animals were treated with various doxorubicin dosages ranging from 18 to 5.9 mg/kg. The three higher i.v. doses (18, 14.4 and 12.5 mg/kg) of doxorubicin induced a severe motor coordination impairment. The histopathological analysis of these animals showed severe damage of sensory nerves. On the contrary, all the i.p. treated animals did not show any sign of motor impairment and of appreciable neurohistological lesion.

Animals↗

PubMed1985

Effects of previous intake of glucose on postprandial hyperglycemia in type 2 diabetics.

Previous glucose improves subsequent glucose tolerance (the Staub-Traugott effect) in normal man. We have investigated whether a small amount of glucose (5 g) given perorally 30 min before breakfast would improve postprandial hyperglycemia in type 2 diabetics (19 patients). Blood glucose was increased 30 min after glucose ingestion (from 7.6 +/- 0.4 to 8.7 +/- 0.4 mmol/l, p less than 0.001). Total glucose areas measured between the time of glucose ingestion and 180 min after breakfast were similar during test and control conditions (breakfast alone). Apparent differences between individuals with regard to the effects of previous glucose on hyperglycemia were further analyzed. Differences could not be explained by interexperimental variation since they persisted on repeated testing (3 patients). Differences were not correlated with age, sex, duration of diabetes, obesity, fasting blood glucose or the insulin responses evoked in the experiments. We conclude that a small amount of glucose before breakfast fails to ameliorate postprandial hyperglycemia in overt type 2 diabetics except in individual patients in whom, in turn, the effect is not directly related to insulin secretion.

Adult↗

PubMed1985

Glucose exerts opposite effects on muscarinic receptor binding to A and B cells of the endocrine pancreas.

Ambient glucose stimulates insulin but inhibits glucagon secretion. We investigated whether mirror-image regulation pertains also to glucose effects on muscarinic receptor binding to B and A cells. We compared binding of [3H]methylscopolamine to islets from normal guinea pigs and to A-cell rich islets from streptozotocin-treated animals. Binding was assessed in intact islets at 37 C after previous culture for 72 h in 3.3, 5.5, or 11 mM glucose. For both types of islets, specific binding was observed after 1 min and reached a plateau after 10 min of incubation. Half-maximal displacement of 2.8 X 10(-9) M [3H] methylscopolamine occurred with 10(-9) - 10(-8) M unlabeled methylscopolamine. In normal islets, specific binding was significantly higher after culture in 11 mM than after 3.3 or 5.5 mM glucose. Conversely, in A-cell rich islets, binding was significantly higher at 3.3 or 5.5 than at 11 mM glucose. Glucagon release induced by acetylcholine (10(-5) M) was half-maximally suppressed by methylscopolamine at a concentration of 10(-9) - 10(-8) M. Acetylcholine-stimulated glucagon release was higher from A-cell rich islets when cultured at 3.3 mM than when cultured at 11 mM glucose. It is concluded: 1) that both A and B cells appear to contain muscarinic receptors, 2) that long term glucose environment exerts opposite effects on binding of methylscopolamine to A and B cells, and 3) that inhibition of binding to A cells is correlated with reduction of acetylcholine-induced glucagon release.

Animals↗

PubMed1985

Influence of thiol groups, calcium, and glucose metabolism on cholinergic-induced insulin release and on methylscopolamine binding to muscarinic receptors in pancreatic islets of the rat.

Short-term regulation of [3H]methylscopolamine binding to muscarinic receptors and acetylcholine-induced stimulation of insulin release was investigated in pancreatic islets of the rat. Binding of methylscopolamine was reversible; 47% of label was displaced 10 min and 70% 30 min after addition of unlabelled substance. 0.1 mM chloromercuribenzoic acid, when present during binding incubations, inhibited binding by 54%, whereas acetylcholine-induced insulin release was unaffected by the presence of the thiol reactant. Pre-incubation for 60 min in a calcium-deprived medium or in the presence of 50 microM trifluoroperazine likewise inhibited binding. Pre-incubation with 1.0 mM 3-isobutyl-l-methylxanthine or 16.7 M glucose failed to influence subsequent binding although acetylcholine-induced insulin release was 4-fold enhanced by priming with glucose. We conclude that 1) binding to muscarinic receptors is influenced by thiol interaction, 2) short-term alterations in calcium fluxes influence binding, whereas short-term changes in cyclic AMP (cAMP) or glucose metabolism do not, 3) a priming effect of glucose on insulin secretion is not mediated by changes in receptor binding.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Evidence that a "memory' for glucose metabolism desensitizes A-cell responsiveness in the perfused pancreas of the rat.

UNLABELLED: The effects of prior exposure to glucose or an inhibitor of glycolysis (iodoacetate) on A-cell sensitivity to glucose in the perfused pancreas of the rat was investigated. Inhibition of glucagon secretion by a high glucose concentration (22 mM) was attenuated and delayed when tested 20 min after a previous infusion with the same glucose concentration. Previously elevated glucose also delayed for 2 min a glucagon response to glucose omission whereas the total response was not significantly affected. During a 20 min perfusion with 1 mM iodoacetate, glucagon secretion increased and rates of secretion were further augmented after withdrawal of iodoacetate. When introduced 10 min after cessation of the iodoacetate pulse, 22 mM glucose failed to affect insulin or somatostatin release but, conversely, induced a profound decrease in glucagon secretion which was more marked than during control conditions. CONCLUSIONS: A-cell sensitivity to glucose is diminished and enhanced by prior fuel abundance and deprivation, respectively. Such effects could be due to persisting changes in A-cell energy availability rather than to pertubations in insulin or somatostatin secretion.

Animals↗

PubMed1984

Infiltration of liver and brain by tumor cells in leukemic mice: prevention by dimethyltriazenes and cyclophosphamide.

The dimethyltriazenes p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) increase, unlike cyclophosphamide (Cy), the survival time of mice bearing L1210 lymphoid leukemia, P388 lymphocytic leukemia and TLX5 lymphoma with a mechanism unrelated to cytotoxicity for tumor cells. The in vivo bioassays of brains, and the histologic examinations of the livers of leukemic mice show that DM-COOK and DTIC prevent leukemic infiltration in these organs at dosages devoid of cytotoxic effects for peritoneal tumor cells. At a dosage equitoxic with that of dimethyltriazenes, cyclophosphamide causes the absence of tumor cells in the peritoneal cavity and in the brains and livers of mice bearing P388 and L1210 leukemias. DM-COOK and DTIC thus possess a mild or insignificant cytotoxic action together with antimetastatic properties also on mouse transplantable leukemias. The use of DM-COOK appears advantageous over that of cyclophosphamide and DTIC because of a reduced host toxicity, which is particularly evident for cyclophosphamide and DTIC on liver parenchyma and bone marrow.

Animals↗

PubMed1984

Stimulation by calcium and barium of somatostatin release. Evidence for lower sensitivity of D- vis-à-vis B- and A-cells.

To address the question whether a "second messenger" function of calcium differs between D-cells and other cells of the endocrine pancreas, we compared effects of calcium and barium (a calcium substitute) on somatostatin secretion to effects on insulin and glucagon secretion from the perfused pancreas of the rat. 6.5 mmol/l of calcium, when administered early during perfusion, failed to stimulate somatostatin release. 0.05 mmol/l of barium, when added to calcium-deprived media failed to affect somatostatin secretion while 0.5 induced a slight and 2.0 mmol/l a marked and sustained response. Barium-induced insulin release was left-shifted in relation to the somatostatin response, since 0.05 mmol/l of barium stimulated and 0.5 mmol/l evoked a near-maximal insulin response. All concentrations of barium evoked diphasic glucagon responses, i.e. a small (1 min) stimulation followed by sustained inhibition. Addition of 0.5 mmol/l of EGTA to calcium-deprived media abolished D- as well as B- and A-cell secretion. Reintroduction of 0.5-6.5 mmol/l of calcium stimulated somatostatin release; the secretory response was proportionate to the calcium concentration. In contrast, addition of calcium stimulated insulin and glucagon secretion maximally already at 0.5 mmol/l of calcium. We conclude that the D-cell is less sensitive than B- and A-cells to a regulatory effect on secretion exerted by extracellular calcium or barium.

Animals↗

PubMed1984

Abnormal D cell secretion in alloxan-diabetes: influence by drug and aberrant metabolism.

Abnormalities of somatostatin secretion in diabetes may be secondary to B cell damage with resulting insulinopenia or other effects of diabetogenic agents, including toxicity toward the somatostatin-producing D cells. These possibilities were evaluated in isolated perfused pancreas from normal and alloxan-diabetic rats. In normal rats 3-isobutyl-1-methylxanthine (IBMX, 1 mM), alpha-ketoisocaproic acid (KIC, 5 mM), D-glucose (27 mM), and D-glyceraldehyde (5 mM) stimulated somatostatin release. In diabetic rats 3 days after alloxan, IBMX and KIC elicited somatostatin release, whereas glucose or glyceraldehyde were without effect. In diabetic rats 14 days after alloxan, an otherwise (in normal and 3-day diabetic rats) nonstimulatory concentration of IBMX (0.05 mM) markedly stimulated somatostatin release, whereas as in 3-day diabetic rats glucose was ineffective. Insulin treatment for 2 days did not affect the somatostatin response to glucose in normal rats, did not restore a somatostatin response to glucose 3 days after alloxan, but partially restored (P less than 0.01) a response to glucose (28% of normal) 14 days after alloxan. Insulin in vitro (1 mU/ml, 20 min) failed to restore a glucose effect. Administration of alloxan (1.0 mM) for 5 min to pancreases from normal rats inhibited glucose-induced somatostatin response from 1,562 +/- 401 to 206 +/- 83 pg/15 min (P less than 0.01), whereas the response to IBMX (1 mM) was not significantly decreased. Following different time courses, both an effect of alloxan and of metabolic derangement inhibit somatostatin responses to glucose in alloxan diabetes.

1-Methyl-3-isobutylxanthine↗

PubMed1984

A stimulating effect of glucose on somatostatin release is impaired in noninsulin-dependent diabetes mellitus.

The effect of oral glucose (1 g/kg BW) on levels of immunoreactive somatostatin (SLI) in peripheral venous plasma was investigated in young and older nondiabetic subjects (mean ages, 25.8 and 56.7 yr, respectively) as well as in subjects with decreased iv glucose tolerance (K value less than 1.0) and in diet-treated diabetic patients with fasting hyperglycemia (blood glucose, greater than 7.0 mmol/liter). SLI was assayed after extraction of plasma on silica glass beads. In control experiments (glucose omitted), SLI levels tended to decline. Ingestion of glucose was followed by a moderate (52% or less) increase in SLI levels in subjects with normal or decreased iv glucose tolerance. The stimulating effect was sustained for 90 or 120 min after glucose ingestion and the increase in plasma SLI was significant (P less than 0.05-0.02) whether in relation to prestimulatory values or control experiments. In contrast, in overtly diabetic patients, glucose ingestion was not followed by increased SLI levels. It is concluded that oral glucose stimulates SLI secretion in individuals of different ages and with varying degrees of glucose tolerance, but the response is impaired in type 2 diabetic patients with fasting hyperglycemia.

Adult↗

PubMed1984

Glibenclamide stimulates and glucose inhibits glucagon release induced by calcium deprivation.

The effects of low extracellular calcium levels on glibenclamide- and glucose-induced A-, B-, and D-cell secretion were investigated using the perfused pancreas preparation of the rat. At normal (2.6 mM) calcium, glucagon secretion was unaffected by glibenclamide (1 microgram/ml) and transiently suppressed by glucose (6.7 and 16.7 mM). Reduction of extracellular calcium to 0.24 mM promptly and persistently enhanced glucagon secretion in the presence of 3.3 mM glucose; this effect of low calcium was, however, diminished (P less than 0.001) by 54% and 61% when the glucose concentration was increased to 6.7 and 16.7 mM, respectively. In contrast, glibenclamide enhanced the glucagon response to calcium reduction, a twofold stimulation by the drug being observed at all glucose concentrations. Reduction of calcium to 0.24 mM failed to inhibit first-phase glibenclamide or glucose-induced insulin release; second phase was, however, inhibited whether induced by glibenclamide (in the presence of 6.7 mM glucose) or by glucose 16.7 mM per se. Reduction of calcium uniformly and completely abolished glibenclamide and glucose-induced somatostatin responses. It is concluded that: (1) the glucagon response induced by calcium deprivation is inhibited by glucose but potentiated by glibenclamide, and (2) reversal of a D-cell paracrine effect could underlie the glibenclamide effect.

Animals↗

PubMed1983

Muscarinic receptors in pancreatic islets of the rat. Demonstration and dependence on long-term glucose environment.

The presence of muscarinic receptors in islets of Langerhans was assessed by measurement of specific binding of [3H]methylscopolamine. Specific binding was defined as total binding minus binding obtained in the presence of 1000-fold or higher excess of unlabeled methylscopolamine. At 37 degrees C specific binding was significant after 1 min and plateaued after 10 min of incubation. Displacement of label by increasing concentrations of unlabeled methylscopolamine indicated a dissociation constant of 1.5 x 10(-12) M. Effects of methylscopolamine on insulin release were evaluated from the inhibitions of cholinergic-induced insulin release. 4 x 10(-10) M methylscopolamine inhibited acetylcholine (20 microM)-induced insulin release more than 60%. Binding was not influenced by the following variations during binding incubations: changing the glucose concentration from 0 to 8.3 mM, adding rotenon (1 microM) or omitting calcium from the incubation medium. Islets kept in tissue culture exhibited higher binding when cultured at 11.1 than at 3.3 mM glucose for 96 h. It is concluded that islets contain muscarinic receptors, the binding to which can be subject to alteration by the long-term glucose environment.

Animals↗

PubMed1983

Loss of a priming effect of glucose on A and D cell secretion in perfused pancreases from alloxan-diabetic rats: role of insulin and alloxan.

Under normal conditions, glucose acutely influences pancreatic islet B, A and D cell secretion. In addition, prior exposure to glucose modulates the secretory responsiveness of these cells (priming effect). We have tested whether alloxan diabetes influences priming effects of glucose on A and D cell secretion. Rat pancreases were perfused 72 h after alloxan treatment. A 20 min infusion of 27.7 mmol/l of glucose failed to induce priming effects, i.e. it did not inhibit the glucagon nor amplify the somatostatin response to a subsequent (15 min later) infusion of 8 mmol/l of arginine. Insulin treatment in vivo for 48 h restored a priming effect of glucose on glucagon secretion in the perfused pancreas, i.e. exposure to 27.7 mmol/l of glucose now inhibited subsequent arginine-induced glucagon secretion by 48% relative to a stimulation period with arginine preceding the glucose pulse (from 5.0 +/- 0.7 to 2.6 +/- 0.5 ng/min, p less than 0.01). Conversely, insulin treatment in vivo did not restore a priming effect of glucose on somatostatin secretion. Other effects noted were failure of 27.7 mmol/l glucose to stimulate, during its presence, the release of somatostatin from pancreases of the diabetic rats whether untreated or insulin-treated. Furthermore, insulin treatment abolished the arginine-induced somatostatin secretion observed in pancreases from untreated rats. It is concluded that short-term alloxan diabetes leads to loss of a priming effect of glucose on glucagon secretion and that this abnormality is secondary to direct or indirect effects of insulinopenia. Concomittant abnormalities of glucose regulation of somatostatin secretion may, in part, be secondary to a cytotoxic effect of alloxan on the D cell.

Alloxan↗

PubMed1983

Effects of ICRF 159 on adriamycin-induced cardiomyopathy in rats.

The effect of ICRF 159 on adriamycin (ADR) cardiotoxicity and on total myocardial calcium content was examined in rats. ICRF 159 did not increase the survival time of ADR-treated animals; however the histological findings showed a significant prevention of ADR-induced cardiomyopathy (CMP) by ICRF. The total myocardial calcium content of animals treated with ADR was significantly higher, while no significant difference was seen in animals pretreated with ICRF 159 as compared with controls. As these findings suggested a role of calcium in ADR CMP and in the pharmacological action of ICRF in this disease, we also tested a closely related chelating agent, EDTA. This molecule decreased myocardial calcium levels in ADR-treated animals almost to normal values; however the histological cardiac alterations were not prevented.

Animals↗

PubMed1983

Glucose- and arginine-induced insulin and glucagon responses from the isolated perfused pancreas of the BB-Wistar diabetic rat. Evidence for selective impairment of glucose regulation.

To investigate whether preferential responsiveness of residual B-cells is a feature of a diabetic state we compared insulin-releasing effects of glucose and arginine in perfused pancreases from moderately diabetic BB-Wistar rats. BB-rats were hyperglycaemic and insulin-dependent but possessed some insulin reserves (6 per cent of pancreatic content of control Wistar rats). Glucose (27.7 mM) failed to release insulin from diabetic pancreases while, conversely, arginine (8 mM) evoked a several-fold increase in insulin secretion. Ratios between responses from diabetic and normal pancreases were 0.01 and 0.29, respectively, when glucose or arginine were used as stimuli. This difference was significant (P less than 0.05, Wilcoxon test). Glucose furthermore failed to exert a time-dependent (= priming) effect on arginine-induced insulin secretion in the diabetic animals. Also A-cell responsiveness to glucose (acute and priming effects) were lost in BB-rats. It is concluded that selective loss of glucose effects on B- and A-cell secretion are associated with the diabetic state of the BB-Wistar rats.

Animals↗