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G Sager

Publications and source records attributed to G Sager.

At least 37 records · Page 2Linked to original sources
PubMed1997

Binding characterization of a putative cGMP transporter in the cell membrane of human erythrocytes.

Cyclic GMP is an intracellular signal molecule whose biological and pharmacological role is not well understood. Recent studies with human erythrocytes and other cell types (normal and transformed) have shown that the extrusion of cGMP is an ATP-dependent and saturable process. In this paper, we present our studies on binding of [3H]-cGMP to human erythrocyte ghost and its solubilized extracts. At 4 degrees C, an apparent dissociation constant of 0.15 microM was found in the samples. Maximum specific binding values in ghost and solubilized extracts were 9.0 pmol/mg of protein and 1.0 pmol/mg of protein, respectively. The low dissociation constant was confirmed by kinetic studies with a value of 0.16 microM. Specific [3H]-cGMP binding was inhibited by cAMP, cGMP, and cIMP with KD values of 0.22 microM, 0.09 microM, and 0.17 microM, respectively. Unlabeled cGMP and cIMP inhibited [3H]-cGMP binding completely whereas cAMP inhibited only 70%. The membrane-localized cGMP-binding protein discriminates between cyclic and noncyclic nucleotides, since GMP, IMP, and AMP were unable to displace [3H]-cGMP. A zwitterionic detergent, CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfate), was able to solubilize a protein with identical binding affinity. The results of this study show that erythrocyte ghosts possess a cGMP-binding protein which is not a kinase (due to a similar affinity for cAMP, cGMP, and cIMP) or phosphodiesterase (due to the inability of IBMX, 3-isobutyl-1-methylxanthine, to inhibit specific [3H]-cGMP binding). We hypothesize that this protein is the cell membrane cGMP transporter.

Binding Sites↗
PubMed1997

[How hazardous is the use of female steroid hormones?].

The development of female steroid hormone-related neoplasms such as gynaecologic and mammary cancers is influenced by hormones administered exogenously. Hormonal contraceptives and hormone replacement therapy both affect the risk of developing cancers in the endometrium, cervix, ovarium, and mammary glands. The authors refer to the recent literature and discuss the findings for the different types of cancers individually. Oestrogens promote development of cancers of the uterine corpus, but women who take progestins combined with oestrogens run no greater risk than women who do not take hormones. Female steroid hormones appear to increase the risk of developing cancer of the uterine cervix slightly, but protect against the development of ovarian cancer. An higher risk of developing mammary cancer is seen after taking oral contraceptive pills.

Breast Neoplasms↗
PubMed1997

Counterregulatory hormone and symptom responses to hypoglycaemia in diabetic children.

The hormonal responses to, and symptoms of, hypoglycaemia were investigated in 19 diabetic children (mean age 14.2 (SD 1.4) years, mean HbA1c 9.8 (SD 1.2)%) and 16 non-diabetic children (14.4(1.0) years) during a gradual reduction in plasma glucose with the glucose clamp technique. Plasma glucose was reduced from approximately 5.7 to approximately 2.6 mmol l(-1) in the diabetic children and from approximately 5.7 to approximately 2.9 mmol l(-1) in the non-diabetic children over 200 min. The mean glycaemic thresholds for adrenaline, and for autonomic and total symptom score, were similar in the diabetic and non-diabetic groups, and were found at plasma glucose levels between 3.4 and 3.7 mmol l(-1). The mean glucose levels which elicited increase of cortisol, growth hormone, and glucagon were lower (p < 0.01), and the mean incremental responses of adrenaline, cortisol, and glucagon were smaller in the diabetic than in the non-diabetic children. In the diabetic children, a correlation was found between Body Mass Index (BMI) and the hypoglycaemic thresholds for autonomic and total symptom scores (r = 0.64, p < 0.01 and r = 0.72, p = 0.001, respectively). We conclude that counterregulatory hormone responses are attenuated in diabetic as compared to non-diabetic children, whereas recognition of autonomic symptoms is similar in the two groups. Diabetic children with a higher BMI seem to have increased awareness of a declining plasma glucose level.

Adolescent↗
PubMed1997

Return of beta-adrenergic sensitivity in a patient with insulinoma after removal of the tumour.

Beta-adrenergic sensitivity and counterregulatory hormone and symptomatic responses to hypoglycaemia were studied in a 22-year-old man before and 3 and 34 weeks after removal of an insulinoma. The beta-adrenergic sensitivity was measured by the effect of an isoprenaline infusion on the heart rate, and the dose needed to increase the heart rate by 25 beats min(-1) (I25) calculated from regression lines. The glucose thresholds for the hormonal responses and symptoms were studied during a gradual fall in plasma glucose using a hypoglycaemic clamp technique. As compared with preoperative values, beta-adrenergic sensitivity was unchanged 3 weeks after surgery, but showed a marked improvement after 34 weeks, the I25 (in microg isoprenaline) being 0.96, 0.86, and 0.56, respectively. The hormone responses to hypoglycaemia were earlier, but with no improvement in symptom generation at 3 weeks. After 34 weeks, the thresholds for both hormone release and symptom generation occurred at a plasma glucose approximately 1 mmol l(-1) higher than before surgery. Thus, in our patient, there was a marked improvement in beta-adrenergic sensitivity, an earlier release of counterregulatory hormones, and an earlier recognition of hypoglycaemic symptoms after surgery. However, the restoration of these responses took more than 3 weeks.

Adrenergic beta-Agonists↗
PubMed1997

Cardiovascular effects of MnDPDP and MnCl2 in dogs with acute ischaemic heart failure.

PURPOSE: To examine the cardiovascular effects of MnDPDP in a model of acute heart failure in the dog, and to compare these effects with those of MnCl2. MATERIAL AND METHODS: The study involved slow i.v. infusion of either 10, 60 and 300 mumol/kg of MnDPDP, or 1, 6 and 30 mumol/kg MnCl2, in increasing doses to groups of 5 dogs. Acute ischaemic heart failure was first induced by injection of polystyrene microspheres (50 +/- 10 microns) into the left coronary artery until a stable left ventricular end-diastolic pressure of approximately 20 mm Hg was achieved. The following test parameters were measured: left ventricular end-diastolic pressure; the first derivatives of maximum rate of left ventricular contraction and relaxation; mean aortic pressure; pulmonary artery pressure; right atrial pressure; cardiac output; heart rate; QT-time; PQ-time; QRS-width; and plasma catecholamines. RESULTS: Slow infusion of MnDPDP at doses up to and including 12 times the clinical dose was well tolerated in dogs without further depression of cardiovascular function during acute ischaemic heart failure. At 300 mumol/kg, i.e. 60 times the human dose, only minor haemodynamic and electrophysiological effects were seen, and these were similar to those seen after administration of 30 mumol/kg MnCl2. CONCLUSION: The present study suggests that slow infusion of MnDPDP should not cause further deterioration of cardiac function in patients with heart failure.

Acute Disease↗
PubMed1997

Intrapleurally instilled mitoxantrone in metastatic pleural effusions: a phase II study.

Thirty cases (breast cancer-20 cases, malignant lymphoma-4 cases, different malignancies-6 cases) of histologically/cytologically verified malignant pleural effusion (MPE) in 29 patients were treated with intrapleurally instilled mitoxantrone (30 mg). The therapy was well tolerated. At evaluation, 25 patients had died of progressive disease. The median survival was 3 months (range 0.3-21.3 months). There were 26 responders (12 complete responses (CR), 14 partial responses (PR)), whereas 4 patients relapsed and 3 of these had an early relapse (within 3 months). Patients achieving PR or CR had a low risk (15%) of treatment failure. Five patients were subjected to a pharmacokinetic evaluation. This demonstrated rapidly declining plasma and pleural exudate levels of mitoxantrone within the first 6 hours. At 24 hours after instillation, mitoxantrone was only detected in circulating mononuclear cells. This study shows that mitoxantrone is efficacious in the treatment of MPE, and may represent a cost-effective alternative.

Adolescent↗
PubMed1997

Urinary excretion of adrenaline and noradrenaline during hypoglycaemic clamp in diabetic and non-diabetic adolescents.

The urinary excretion of non-conjugated adrenaline and noradrenaline during hypoglycaemic clamp was investigated in 16 diabetic and 15 non-diabetic adolescents. In the diabetic adolescents, the mean excretion of adrenaline was approximately nine times higher in clamp urine than in morning urine (p < 0.0001). In the non-diabetic adolescents, the mean excretion of adrenaline was 20-30 times higher in clamp urine than in morning urine (p < 0.0001). Plasma catecholamines were measured, and the area under the plasma concentration-time curve (AUC) and renal clearance of catecholamines were calculated. There was a linear correlation between the AUC and the urinary excretion of adrenaline (r = 0.57, p = 0.001) and noradrenaline (r = 0.49, p = 0.006) during the hypoglycaemic clamp. The renal clearance of adrenaline and noradrenaline did not differ between the diabetic and non-diabetic subjects. In the diabetic group, there was a positive correlation between HbA1c and the adrenaline excretion in clamp urine (r = 0.60, p = 0.015). The eight diabetic subjects with HbA1c < 10% had lower adrenaline excretion in clamp urine than the subjects with HbA1c > 10% and the non-diabetic subjects (all p values < 0.05). We conclude that there is a marked increase in urinary adrenaline excretion during hypoglycaemia in diabetic and non-diabetic adolescents. The increase in adrenaline excretion during hypoglycaemia was attenuated in the better-controlled diabetic adolescents in our study.

Adolescent↗
PubMed1997

Growth hormone increases and IGF-1 reduces the response to Escherichia coli infusion in injured pigs.

OBJECTIVE: To investigate if growth hormone (GH) or its main mediator insulin-like growth factor-1 (IGF-1) alters the response to infusion of live Escherichia coli in injured pigs. DESIGN: Controlled experiment. SETTING: University laboratory, Norway. SUBJECTS: 30 piglets. INTERVENTIONS: The response to infusion of Escherichia coli was compared after a bolus of GH 16 IU (n = 8) or a continuous infusion of IGF-1 1.3 mg/hour (n = 8) in injured piglets. A group with trauma (surgery) and Escherichia coli infusion (n = 8) and a group with trauma only (n = 6) served as controls. MAIN OUTCOME MEASURES: Systemic and regional haemodynamics, oxygen consumption, and acid-base regulation; and circulating concentrations of catecholamines, free fatty acids (FFA), glucose, and lactate Results: After infusion of Escherichia coli, cardiac output was lower and heart rate was higher in the GH than in the IGF-1-treated group. Aortic pH was lower in the GH group compared with the septic controls, whereas aortic pH was higher in the IGF-1 group compared with the septic controls. Portal vein pH was lower in the GH group than in the other three groups. Free fatty acids and lactate concentrations were higher in the GH group than in the other three groups. Glucose concentrations were lower in the IGF-1 group than in the other three groups. Renal artery flow was higher in the IGF-1 than in the GH group and the septic controls. Circulating concentrations of dopamine was higher in the IGF-1 group than in the other three groups, whereas that of noradrenaline was higher in the GH group than in the IGF-1 group. (For all differences stated, p < 0.05). CONCLUSIONS: Acute treatment with GH increased the circulatory and metabolic response to Escherichia coli infusion, in contrast to treatment with IGF-1, which reduced the response

Analysis of Variance↗
PubMed1996

Export of guanosine 3',5'-cyclic monophosphate (cGMP) from human erythrocytes characterized by inside-out membrane vesicles.

The present study was undertaken to characterize the export of cGMP from human erythrocytes at 37 degrees C. Inside-out membrane vesicles were exposed to cGMP and [3H]-cGMP in the presence and absence of 2 mmol l-1 ATP. In the absence of ATP, an equilibrium was reached within 15 min for the lowest tested concentration (0.65 mumol l-1), and the amount of cGMP in the vesicles was linearly correlated to the cGMP concentrations in the incubate. These observations suggest that the ATP-independent process represents passive diffusion or non-saturated binding to membrane components. In the presence of ATP, cGMP accumulated linearly during the test period (up to 120 min) and the transport into the inside-out vesicles was dependent on both low- and high-Km transport. The kinetic parameters for the low-Km process were determined after 5 and 120 min, the Km values being 4.6 (SD 1.9) and 4.7 (SD 1.1) mumol l-1 (n = 3), respectively. The corresponding Vmax values were 400 (SD 50) and 440 (SD 70) fmol mg-1 min-1. The high-Km process was characterized by Km = 170 (SD 50) mumol-1 and Vmax = 1610 (SD 280) fmol mg-1 min-1 (n = 5). The present data demonstrate an ATP-requiring saturable transport system for cGMP in human erythrocytes.

Adenosine Triphosphate↗
PubMed1996

Impaired glucose tolerance in patients with chronic hypoxic pulmonary disease.

This study investigated glucose metabolism and glucose-mediated hormone responses in patients with chronic respiratory hypoxaemia. Glucose as well as insulin, glucagon, adrenaline, cortisol and growth hormone (GH) were measured before and at 30, 60 and 120 min during an oral glucose-tolerance test. The following chronic obstructive pulmonary disease (COPD) patients were studied: 10 normoxaemic (mean paO2 10.9 +/- 0.4 kPa), 10 hypoxaemic (mean paO2 7.6 +/- 0.2 kPa before, and 10.6 +/- 0.4 after 24-h oxygentherapy, and 6 hypoxaemic patients on long-term oxygen therapy (LTOT) (mean paO2 10.9 +/- 0.7 kPa before, and 7.1 +/- 0.3 after 4 h with less than 0.5 litre oxygen per minute). The hypoxaemic patients were tested both with and without (or reduced) oxygen therapy. Twenty healthy sex- and age-matched subjects served as controls. Plasma glucose at 120 min was significantly higher in LTOT patients than in controls (p < 0.01), normoxaemic patients (p < 0.01) or hypoxaemic patients (p < 0.01). The areas under the curve for plasma glucose and insulin were significantly higher in both the LTOT and hypoxaemic groups compared to controls (p < 0.01 and 0.05, respectively). Glucose values for normoxaemic COPD patients were similar to those for controls. Glucagon, adrenaline, cortisol and GH levels did not differ significantly between the groups. A 4-h low-dose or oxygen-free interval in the LTOT group or 24 h of oxygen supplementation in the hypoxaemic group did not affect glucose and hormone levels significantly. It is concluded that severely hypoxaemic COPD patients have altered glucose metabolism which cannot be readily explained by changes in gluco-regulatory hormones or short-term alterations in oxygenation.

Aged↗
PubMed1995

Pineal and thyroid functions in newborn seals.

Daily variations of pineal and plasma melatonin and plasma thyroid hormones were measured in harp seals (Phoca groenlandica), grey seals (Halichoerus grypus), and hooded seals (Cystophora cristata), ranging in age from newborn to 14 days. In newborn harp seals the mean mass of the pineal gland was 273 mg (+/- 45 SEM, n = 11), containing 49 ng (median) melatonin. In newborn, 4- and 10-day-old grey seals, the pineal mass was similar, weighing on average 337 mg (+/- 74, n = 6) and containing 90 ng melatonin. Two newborn hooded seal pups had pineals weighing 520 and 1289 mg, with 254 and 7600 ng melatonin, respectively. There were no day-night differences in the pineal contents of melatonin or in the number of pineal beta-adrenergic receptors measured in newborn harp seals, and, in newborn, 4- and 10-day-old grey seals, there were no day-night or age differences in pineal melatonin content. Plasma melatonin levels were 10 times higher in newborn seals than in two 10-day-old grey seals and one 14-day-old harp seal pup. In all seal pups, the levels exhibited a 24-hr rhythmicity, with increasing night- and decreasing daytime concentrations. Plasma levels of thyroxine (T4) and triiodothyronine (T3) were generally higher in newborn seals than in 10- and 14-day-old seals or in adult females. There was no apparent 24-hr rhythmicity, but the thyroid hormone levels generally declined throughout each sampling sequence. High pineal and thyroid activities may play a thermoregulatory role in newborn seals, but the results do not indicate a stimulatory action of melatonin in the peripheral conversion of T4 to T3. It is speculated that the large and active pineal gland, particularly in newborn seals, may be related to aspects of their diving habit.

Aging↗
PubMed1995

Dysfunction in the beta 2-adrenergic signal pathway in patients with insulin dependent diabetes mellitus (IDDM) and unawareness of hypoglycaemia.

The majority of the impaired symptoms in hypoglycaemia unawareness, such as palpitations, tachycardia and tremor, are caused by increased release of adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of beta-adrenergic receptors. Binding of ADR or NA to the beta-adrenergic receptor generates a signal, transmitted via a guanine nucleotide binding protein complex (G-protein), which in turn activates adenylate cyclase with increased production of cAMP. The aim of this study was to show whether IDDM-patients with hypoglycaemia unawareness had deficient coupling between beta2-adrenergic receptors and G-proteins compared to IDDM-patients with hypoglycaemia unawareness and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or unaware based on questionnaire answers, clinical information and the results of isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from venous blood. By saturation binding experiments, using [125I]-(-)-iodopindolol ((-)-IPIN), total receptor number (Bmax) and affinity (Kd) were determined. By displacement experiments the relative number of low- and high-affinity receptors for the beta-adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We found no difference in Bmax- or Kd-values. for (-)-IPIN between the subgroups. However, there was a reduced capability to form high-affinity binding complexes with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction of the proximal beta2-adrenergic signal pathway.

Adrenergic beta-Agonists↗
PubMed1995

Influence of intra-osseous infusion of a small volume of hyperosmotic fluid on beta-adrenergic function in circulating lymphocytes from bled pigs.

The regulation of beta-adrenergic function in circulating mononuclear leukocytes was evaluated during an episode of haemorrhagic shock treated by intra-osseous infusion of a small volume of hyperosmotic fluid. Two groups of piglets (n = 14) were anaesthetized with ketamine and bled to a mean arterial pressure of 40 mmHg. After 45 min the animals were randomized to receive 100 ml of either hyperosmotic (2.4 mol l-1) or iso-osmotic (0.29 mol l-1) fluid (equal volumes of glucose/sodium chloride) into the tibial bone marrow. Observations of haemodynamic variables and levels of plasma catecholamines and cAMP of circulating mononuclear leukocytes were carried out for 70 min. Infusion of hyperosmotic fluid enhanced the circulatory performance and attenuated the plasma catecholamine release significantly (p < 0.05) compared to the corresponding values in the animals that had iso-osmotic fluid infusion. Measurements of unstimulated and isoprenaline-stimulated cAMP levels in mononuclear lymphocytes indicated that the high plasma catecholamine levels in the iso-osmotic treatment group induced a desensitization of the beta-adrenoceptors 70 min after initiation of the shock. This effect was not seen in animals that had undergone hyperosmotic infusion.

Animals↗
PubMed1995

Reduced beta-adrenergic sensitivity in healthy volunteers induced by hypoglycemia.

A single causative mechanism for development of hypoglycemia unawareness in insulin-dependent diabetes mellitus (IDDM) is not yet apparent. Reduced adrenergic sensitivity may be part of the explanation. This study was carried out to investigate the effect of hypoglycemia on beta-adrenergic sensitivity. Ten healthy male subjects (age 19-23 years) gave informed consent to take part in the study. They were hospitalized overnight at the University Hospital of Tromsø, Department of Clinical Research, on two occasions. Isoprenaline and metoprolol sensitivity tests were performed the morning after hospitalization: once after an intravenous (iv) injection of placebo (0.9% NaCl), and once after an iv injection of insulin (0.15 IU insulin/kg body weight) to induce hypoglycemia. The dose of isoprenaline needed to increase heart rate (HR) by 25 beats per minute (bpm) (I25), and the dose of metoprolol (M-12.5) needed to inhibit I25 with 50% or 12.5 bpm, when injected simultaneously, were used as determinants of isoprenaline and metoprolol sensitivity. In this study, there was a significant (p < 0.05) increase both in I25 and M-12.5 after hypoglycemia. The dose-response curve of isoprenaline/HR was significantly shifted to the right after hypoglycemia. This study shows that acute hypoglycemia induces a reduction in beta-adrenergic sensitivity, and it supports the hypothesis of reduced beta-adrenergic sensitivity as an important pathophysiological mechanism in hypoglycemia unawareness in IDDM.

Adult↗
PubMed1995

Altered cAMP response after isoprenaline stimulation of mononuclear leucocytes from insulin-dependent diabetic patients with hypoglycaemia unawareness.

Loss of adrenergic hypoglycaemic symptoms is the most distinctive feature in insulin-dependent diabetes mellitus (IDDM) patients with hypoglycaemia unawareness. Previous reports from in vivo studies show reduced heart rate responsiveness both to adrenergic agonists and antagonists in these patients. This study was carried out to investigate whether the reduced adrenergic sensitivity in IDDM patients with hypoglycaemia unawareness (IDDM-unaware) also could be demonstrated as reduced increase in cAMP production in mononuclear leucocytes induced by isoprenaline stimulation, or reduced inhibition by ICI-118551 (a selective beta 2-adrenergic receptor blocker) of isoprenaline induced cAMP production. We found that the slope of the concentration-response curves of isoprenaline/cAMP and the maximal cAMP concentrations obtained after isoprenaline stimulation were reduced in IDDM-unaware compared to control and IDDM patients with normal hypoglycaemia awareness (IDDM-aware). We did not find any significant differences in the response to ICI-118551 between control, IDDM-aware and IDDM-unaware. This study supports the reports of reduced sensitivity of adrenergic agonists as a part of the pathophysiological changes in hypoglycaemia unawareness, but we have not been able to confirm the reports of an association between hypoglycaemia unawareness and reduced effect of adrenergic antagonists.

Adrenergic beta-Agonists↗
PubMed1995

Effect of probenecid, verapamil and progesterone on the concentration-dependent and temperature-sensitive human erythrocyte uptake and export of guanosine 3',5' cyclic monophosphate (cGMP).

Elevated extracellular cGMP levels have been observed in various clinical conditions, and the analyte has been proposed as a diagnostic marker of cardiovascular as well as malignant diseases. However, the use of extracellular cGMP as a pathophysiological marker requires detailed knowledge about the cellular biokinetics of cGMP (synthesis, metabolic conversion and export). In the present study the transport of cGMP in human erythrocytes has been further characterized. The uptake of cGMP was dependent on a concentration gradient and was temperature-sensitive, compatible with passive diffusion. The cGMP export was temperature-sensitive, saturable (Km = 3.4 +/- 1.0 mu mol l-1), inhibited by probenecid and verapamil and stimulated by progesterone. The results show that human erythrocytes possess a cGMP transport system similar to that found in other cells and that extracellular levels of cGMP are dependent on intracellular levels, membrane transport and influenced by physiological factors and pharmacological agents.

Biological Transport↗
PubMed1995

Effect of haemorrhagic shock and intraosseous resuscitation on plasma and urine catecholamine concentrations and urinary clearance in pigs.

OBJECTIVE: To evaluate the plasma and urinary catecholamine concentrations after episodes of haemorrhagic shock treated by intraosseous infusion of a small volume of hyperosmotic fluid, followed by whole blood, in a standard porcine model. DESIGN: Randomised open study. SETTING: University hospital, Norway. MATERIAL: 18 piglets. INTERVENTIONS: All animals were bled to an arterial systolic pressure of 60 mm Hg. After 30 minutes 100 ml hyperosmotic (2.4 mol/l) fluid (glucose/sodium chloride) was given either intraosseously (n = 6) or intravenously (n = 6). Ninety minutes later the animals were again bled to a systolic pressure of 60 mm Hg, and after 30 minutes an autologous whole blood transfusion was given by either intraosseous or intravenous infusion. Six animals acted as untreated controls. MAIN OUTCOME MEASURES: Changes in haemodynamic variables and plasma and urinary catecholamine concentrations. RESULTS: Two pigs in the control group died. The hyperosmotic infusion improved the circulatory performance significantly (p < 0.05). Thirty minutes after both bleeds the plasma catecholamine concentrations were increased by 10-15 times, but returned to the reference range in all groups 90 minutes after the hyperosmotic infusion. Two hours after the whole blood infusion the catecholamine concentrations of the treated animals were at baseline values, significantly lower than those of the controls. The corresponding urinary catecholamine concentrations of the controls were significantly increased. There were no differences between the two treatment groups. CONCLUSION: The catecholamine measurements indicate that there may possibly be protective renal excretion of excess shock-induced plasma catecholamines after acute haemorrhage.

Animals↗