Biomedical subjects

G Sager

Publications and source records attributed to G Sager.

At least 55 records · Page 3Linked to original sources

PubMed1995

Intraosseous infusion of a small volume of hyperosmotic fluid increases mean arterial pressure and lessens the catecholamine response in pigs with haemorrhagic shock.

OBJECTIVE: To measure the plasma catecholamine concentrations during an episode of haemorrhagic shock treated by intraosseous infusion of a small volume of hyperosmotic fluid in a standardised porcine model. DESIGN: Randomised open study. SETTING: University hospital, Norway. MATERIAL: 14 piglets. INTERVENTION: Two groups of piglets (n=7 each) were anaesthetised with ketamine and bled to a mean arterial pressure of 40 mm Hg. After 30 minutes the animals were randomised to receive 100 ml of either hyperosmotic (2.4 mo/l) or iso-osmotic (0.29 mo/l) fluid (equal volumes of glucose and sodium chloride) into the tibial bone marrow. MAIN OUTCOME MEASURES: Short term (70 minutes) observation of changes in haemodynamic, biochemical and hormonal variables. RESULTS: The hyperosmotic infusion significantly improved the circulation (mean arterial pressure and cardiac index) compared with the iso-osmotic infusion (p < 0.05). The increased plasma catecholamine concentrations returned to the reference ranges 20 minutes after the hyperosmotic infusion, and were significantly different (p < 0.05) from the catecholamine concentrations observed in the iso-osmotic treatment group. CONCLUSION: Intraosseous hyperosmotic resuscitation increases the circulatory performance and reduces the plasma catecholamine concentrations during haemorrhagic shock in pigs.

Animals↗

PubMed1994

Cell density dependence of cAMP and cGMP levels in four human cell lines derived from carcinomas of the uterine cervix.

Several studies have shown altered biokinetics of cyclic nucleotides in human cancer. In order to mimic the growing tumor bulk in carcinomas of the uterine cervix, four human cell lines (C4-I, C33A, ME-180, and SiHa) were expanded in serum-supplemented cell cultures. The extra- and intracellular levels of cAMP and cGMP were determined at increasing cell densities. In all of the cell lines, a cell density-dependent increase in the extracellular cGMP/cAMP ratio was observed. cAMP was distributed to the extracellular compartment against a concentration gradient at low cell densities but was retained in the intracellular compartment at high cell densities. In contrast, cGMP was distributed to the extracellular compartment against a concentration gradient for the whole range of cell densities. This study suggests that the cell density-dependent increase in the extracellular cGMP/cAMP ratio in cell lines derived from carcinomas of the uterine cervix is a result of changes occurring in both intracellular levels and cellular excretion of cyclic nucleotides.

Cell Count↗

PubMed1994

Effect of bretylium tosylate on ventricular fibrillation threshold during hypothermia in dogs.

How bretylium tosylate affected the ventricular fibrillation threshold, electrophysiological parameters, and plasma catecholamine levels during hypothermia in dogs was studied. Threshold for ventricular fibrillation was determined by programmed electrical stimulation using a stimulation protocol that involved applying a maximum of five extrastimuli at body temperatures 37, 34, 31, 28, and 25 degrees C, and at the same temperatures during rewarming. Electrocardiogram, epicardial monophasic action potentials (MAP), and electrograms were recorded, and ventricular effective refractory period (VERP) was determined at each of the above temperatures. In one group (n = 7), a bolus dosage of bretylium tosylate (BT), 6 mg/kg body wt, was administered at 25 degrees C before rewarming. Another group (n = 4) was exposed to cooling and rewarming without addition of BT. Cooling to 25 degrees C reduced ventricular fibrillation threshold linearly, reduced heart rate, increased VERP and MAP, and slowed myocardial conduction velocity in both groups. There was no overall increase in plasma catecholamine levels during cooling. Addition of BT at 25 degrees C increased ventricular fibrillation threshold during rewarming compared with cooling. Addition of BT at 25 degrees C increased VERP by +/- 32 milliseconds and the corrected JT time by 0.06 +/- 0.02 seconds. VERP and JTc increased during rewarming with BT compared with cooling with no drug. BT had no effect on conduction velocity, and plasma catecholamine levels were not reduced. The antiarrhythmic effect of BT during hypothermia was attributed to an increased wavelength of refractoriness by its increase in the refractory period. This increased wavelength of refractoriness may prevent excitable gaps or increase circuit pathway in the setting of reentry arrhythmias.

Action Potentials↗

PubMed1994

Relationship between unbound plasma concentrations and various psychomotor and subjective effects after intakes of diazepam and flunitrazepam.

Unbound plasma concentrations of diazepam and flunitrazepam were related to psychomotor and subjective effects of the two drugs. The interindividual variability in plasma protein binding of both diazepam (98.5 +/- 0.14%) and flunitrazepam (84.5 +/- 1.2%) was relatively small, and high correlations were therefore observed between the individual unbound and total drug plasma concentrations after a particular dose. However, poor correlations were seen between individual unbound drug plasma concentrations and psychomotor or subjective effects. This observation indicates that factors other than individual variability in drug plasma concentration, account for the pronounced individual differences in, for example, psychomotor impairment frequently observed after intake of benzodiazepines. Furthermore, based on a linear relationship between unbound drug plasma concentrations and increase in either complex choice or simple reaction time, the potency of flunitrazepam was calculated to be about seven times higher than the potency of diazepam. This is approximately two times higher than expected from the reported in vitro affinity of the two drugs for the benzodiazepine receptor. This finding may indicate that flunitrazepam may have a higher apparent in vivo intrinsic efficacy than diazepam when assessed by psychomotor impairment.

Adult↗

PubMed1994

Reduced sensitivity to beta-adrenoceptor stimulation and blockade in insulin dependent diabetic patients with hypoglycaemia unawareness.

Nine IDDM-patients with hypoglycaemia unawareness, seven IDDM-patients with hypoglycemia awareness and a control group of nine healthy persons were included in this study. The patients were recruited from the medical out-patients' department of the University Hospital of Tromsø. The pathophysiological changes which cause hypoglycaemia unawareness are today not clear. Reduced peripheral tissue sensitivity to catecholamines is suggested as one of several mechanisms which may contribute. For further investigation of beta-adrenergic sensitivity an isoprenaline/metoprolol sensitivity test was performed. Isoprenaline and metoprolol were administered intravenously, and the effects on heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and plasma levels of adrenaline (ADR) and noradrenaline (NA) were measured. All subjects were given the same doses of isoprenaline (0.25-8 micrograms) and metoprolol (0.5-8 mg). Metoprolol was given together with the dose of isoprenaline which increased heart rate by 25 beats min-1. The dose/response curves of both isoprenaline/HR and metoprolol/HR were significantly shifted to the right in IDDM-patients with hypoglycaemia unawareness compared with controls and IDDM-patients with hypoglycaemia awareness (P < 0.05). Reduced sensitivity of isoprenaline stimulation has also been shown before, whereas reduced sensitivity of a blocking agent has not earlier been shown. These findings support the hypothesis of reduced beta-adrenergic sensitivity as one pathophysiological component in hypoglycaemia unawareness.

Adult↗

PubMed1994

Glycemic thresholds for hypoglycemic responses in obese subjects.

The objective of this study was to compare glycemic thresholds for hypoglycemic responses in obese and control subjects. A modified glucose-clamp technique was used to produce a standardized fall in plasma glucose (0.5 mmol/l per 40 min) in nine morbidly obese and ten control subjects. The release of the counter-regulatory hormones was measured and a symptom questionnaire was filled out every 10 min. The hypoglycemic thresholds (taken as the plasma glucose level where the response exceeded the basal level +2 s.d.) were practically identical in the two groups both for the hormones and the symptoms (including hunger). Our results argue against the hypothesis that an increased sensitivity to a falling plasma glucose is of importance in the pathogenesis of obesity.

Adult↗

PubMed1993

Effect of serum and cell density on transmembrane distribution of cAMP and cGMP in transformed (C4-I) and non-transformed (WI-38) human cells.

The ratio between cGMP and cAMP in plasma/urine is elevated in several types of malignancies. The present in vitro study showed that the ratio between extracellular cGMP and cAMP increased during the proliferation of C4-I cells (derived from a carcinoma of the uterine cervix), whereas this ratio decreased in WI-38 cells (normal lung fibroblasts). These results can be explained by differences between the transformed and non-transformed cells in the cell-density-dependent transmembrane distribution and intracellular levels of cyclic nucleotides. In the serum-deprived cultures, no profound effects were seen on the cell-density-dependent biokinetics of cAMP and cGMP. In the absence of serum, growth of C4-I cells was markedly retarded, whereas WI-38 cells were unable to expand at all.

Cell Count↗

PubMed1993

Epinephrine induces beta-adrenergic desensitization and differentiation of HL-60 cells.

The HL-60 cell line was cultured in a serum-free medium and exposed to various concentrations of EPI. The effects on cell growth, differentiation and beta-adrenergic response were followed during the culture period of 72 h. Short-term exposure (3 min) to EPI (1 nM-1 mM) in the presence of theophylline (4 mM) caused a dose-dependent increase of cAMP levels with a maximum of 1500% above basal levels. When the cells were exposed to EPI (1 nM-10 microM) for 72 h, a dose-dependent increase of cAMP levels with a maximum of 60% above basal levels. Sustained exposure to EPI generated a dose-dependent desensitization of the beta-adrenergic signal system. After EPI treatment for 72 h, IPR (10 microM for 3 min) in the presence of theophylline (4 mM) increased cAMP-levels by only 80% above baseline level (cAMP levels after maintained exposure to EPI), compared to 1080% above unstimulated level in control cells. The alpha-adrenergic receptor blocker PHENT (10 microM) did not affect baseline cAMP level or IPR-dependent cAMP response, but a mixture of EPI and PHENT increased the response to IPR. The HL-60 cell growth was not influenced by EPI. However, after repeated exposure to EPI for 72 h a concentration-dependent increase of HL-60 differentiation was demonstrated. Differentiation was not influenced by PHENT. These results suggest a differentiation induction due to a beta-adrenergic-induced cAMP elevation.

Adenylyl Cyclases↗

PubMed1992

Fluorescence studies of beta-adrenergic ligand binding to alpha 1-acid glycoprotein with 1-anilino-8-naphthalene sulfonate, isoprenaline, adrenaline and propranolol.

The present study shows that ANS (1-anilino-8-naphthalene sulfonate), propranolol, isoprenaline, adrenaline and dopamine have common binding sites on AAG (alpha 1-acid glycoprotein). A fluorescence technique was employed to characterize the interaction between the ligands and AAG at 20-22 degrees. The binding of ANS to AAG caused increased fluorescence intensity at emission and excitation wavelengths of 400 and 470 nm. In this situation, propranolol displaced ANS in a concentration-dependent mode with an apparent dissociation constant of 6.2 +/- 0.01 microM, whereas isoprenaline did not reduce the ANS-AAG fluorescence. However, in the presence of AAG, catecholamines caused a marked increase of fluorescence at excitation and emission wavelengths of 250 and 325 nm, respectively. These wavelengths were employed to characterize the binding of isoprenaline, adrenaline and propranolol to AAG. Two subsets of binding sites were demonstrated. The Kd values were 0.87 +/- 0.03 and 25.1 +/- 10.7 microM for ANS, 0.76 +/- 0.09 and 133 +/- 30.4 microM for propranolol, 140 +/- 14 and 2.18 +/- 0.58 mM for isoprenaline, 137 +/- 24 and 14.8 +/- 0.1 mM for adrenaline, respectively. AAG had identical high affinity binding capacity for these ligands (n approximately 1). However, the second class of binding sites showed ligand-dependent binding capacity: n = 1 for ANS, n approximately 10 for propranolol, n approximately 15 for adrenaline, n approximately 20 for isoprenaline, respectively. ANS, propranolol, dopamine and adrenaline caused concentration-dependent inhibition of isoprenaline binding to AAG with apparent dissociation constants of 5.1 +/- 1.8 microM, 6.4 +/- 1.1 microM, 0.57 +/- 0.13 mM and 1.5 +/- 0.46 mM, respectively.

Anilino Naphthalenesulfonates↗

PubMed1992

Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects.

Nine healthy subjects were studied on two separate occasions, at least two weeks apart, using the glucose clamp technique to produce a gradual hypoglycaemia. Glucose thresholds for neuroendocrine and symptom responses varied up to 1.5 mmol/l between subjects. There was a significant correlation between individual glucose thresholds on day 1 and 2 for adrenaline (p = 0.0008), growth hormone (p = 0.007) and pancreatic polypeptide (p = 0.02), and for autonomic (p = 0.018) and neuroglycopoenic (p = 0.023) symptoms, whereas no significant correlations were found for glucagon and cortisol. The mean intra-individual differences in glucose thresholds between day 1 and 2 were 0.22 mmol/l for the hormones and 0.25 mmol/l for the symptoms. We conclude that healthy subjects differ in hypoglycaemic thresholds, and that the difference reflects individual variation.

Adult↗

PubMed1992

Therapeutic lidocaine concentrations have no effect on blood platelet function and plasma catecholamine levels.

The effects of therapeutic plasma concentrations of lidocaine on blood platelet function and plasma catecholamine levels were assessed in 9 healthy subjects. There were no significant effects on plasma levels of beta-thromboglobulin, collagen and adenosine diphosphate-stimulated platelet aggregation, thromboxane-B2-concentration in plasma after collagen and ADP stimulated platelet aggregation, or on plasma nor-adrenaline and adrenaline. No significant correlation could be demonstrated between any of the variables tested. Thus, it appeared that lidocaine had no effect on platelets that could be of benefit in acute myocardial infarction. It should be possible to use lidocaine, in combination with thrombolytic therapies without increasing the risk of bleeding complications.

Adult↗

PubMed1992

Plasma protein binding of catecholamines, prazosin and propranolol in diabetes mellitus.

In the present study equilibrium dialysis has been used to determine the degree of protein binding of the catecholamines adrenaline and noradrenaline and the adrenergic receptor blockers, prazosin and propranolol in diabetics. The binding of the catecholamines in plasma from Type I and II diabetic patients was not significantly different from that of healthy subjects. The ratio of the bound and free catecholamine concentrations was correlated with the level of albumin (HSA). Significantly reduced protein binding of prazosin was observed in Type I and II diabetic subjects compared to healthy volunteers. The binding of propranolol was significantly reduced in Type I patients. The ratios between the bound and unbound concentrations of prazosin and propranolol were significantly correlated with the levels of alpha 1-acid glycoprotein (AAG). The results suggest that non-enzymatic glycosylation of plasma proteins may increase the unbound fraction of the adrenergic blockers prazosin and propranolol.

Adult↗

PubMed1992

Pre- and postoperative glucose levels for eliciting hypoglycaemic responses in a patient with insulinoma.

Counterregulatory hormones and hypoglycaemic symptoms were studied during a gradual decline in plasma glucose in a 66-year-old man before and 9 weeks after removal of an insulin-producing tumour. Before surgery the adrenaline started to respond first at plasma glucose 2.8 mmol l-1. He reported no autonomic symptoms although plasma glucose fell to 2.3 mmol l-1 with a corresponding adrenaline rise to 4.64 nmol l-1. After surgery adrenaline responded at a plasma glucose of 3.7 mmol l-1 and he started to sweat and tremble at a plasma glucose of 3.1 mmol l-1 (corresponding adrenaline 2.63 nmol l-1). The lack of autonomic symptoms preoperatively may indicate adrenaline insensitivity, possibly as a result of repeated hypoglycaemia.

Aged↗

PubMed1992

The effect of selective beta 1-blockade on glucose thresholds for release of counterregulatory hormones and symptoms in insulin-dependent diabetes mellitus.

To evaluate the effect of beta 1-blockade (metoprolol) on the plasma glucose thresholds initiating counterregulatory hormone responses and symptoms of hypoglycemia, we used a modified glucose clamp technique to produce a standardized gradual glucose decline from 5.0 to 2.0 mmol/l in nine patients with insulin-dependent diabetes mellitus (IDDM) (HbAlc range 6.7-10.3%, duration of diabetes 5-18 years, autonomous neuropathy present in three of the patients). The responses were studied once with metoprolol and once with placebo, in random order. With the beta 1-selective blockade, epinephrine release was triggered at a significantly higher (p less than 0.02) plasma glucose level (3.5 mmol/l) than it was with placebo (3.0 mmol/l). Metoprolol did not change thresholds for growth hormone (3.7/3.5 mmol/l), cortisol (2.9/2.9 mmol/l), glucagon (2.8/2.8 mmol/l) or for pancreatic polypeptide (2.8/2.7 mmol/l). The peak responses of epinephrine and growth hormone were significantly higher (p less than 0.01) with the beta 1-blockade. Metoprolol did not change the thresholds for neuroglycopenic and autonomic symptoms. Six out of the seven patients who answered yes to having hypoglycemia did so at a higher blood glucose with metoprolol than without. In our study, the beta 1-selective blockade altered the responses of counterregulatory hormones, but it did not change the thresholds for hypoglycemic symptoms.

Adrenergic beta-Antagonists↗

PubMed1991

Delayed spontaneous pubertal growth spurt in girls with the Ullrich-Turner syndrome.

By means of an appropriate mathematical model (Sager's 2-components-concept) a delayed spontaneous pubertal growth spurt can be demonstrated in girls with 45,X Ullrich-Turner syndrome (UTS) (n1 = 45) as well as in those with 45,X/46,XX mosaicism (n2 = 14) never treated with any growth stimulating drug. On the average, this growth spurt begins later and its extent is smaller (mean growth rate = 3.10 and 2.79 cm, respectively, in the 15th year of chronological age) than in normal girls. The delay in acute growth spurt corresponds very well to the delay of skeletal maturation in the UTS (on the average 2 to 3 years of chronological age).

Adolescent↗

PubMed1991

Regulation of lipolysis in normoxic and hypoxic rat myocytes.

The mechanism involved in ischemia-induced myocardial lipolysis is still a matter of controversy. To elucidate the regulation of lipolysis at the cellular level, we incubated isolated rat myocytes in normoxic or hypoxic medium containing 11.1 mM glucose. Rates of lipolysis (glycerol output) were significantly (P less than 0.05, n = 12) higher in hypoxic than in normoxic myocytes (34.9 +/- 3.9 vs. 17.7 +/- 3.4 nmol/10(6) cells.30 min). However, there was no change in the content of cellular triacylglycerol (TG) in normoxic myocytes whereas it fell slightly (8 +/- 2 nmol/10(6) cells.30 min, P less than 0.05, n = 12) in hypoxic myocytes. On a molar basis glycerol output was significantly higher than the corresponding fall in TG (P less than 0.05, n = 12, both normoxic and hypoxic myocytes). This difference (glycerol output--TG reduction) amounted to 17.1 +/- 3.4 nmol/10(6) cells.30 min in normoxic myocytes and 27.6 +/- 5.1 nmol/10(6) cells.30 min in hypoxic myocytes (P less than 0.05, n = 12, normoxic vs. hypoxic). The hypoxia-induced rise in glycerol output was paralleled by an increased intracellular level of glycerol-3-phosphate. Both these responses were, however, dose-dependently inhibited by addition of pyruvate to the incubation medium, giving rise to a close correlation between cellular glycerol-3-phosphate and glycerol output (r = 0.75, P less than 0.05). This indicates mass action of glycerol-3-phosphate on fatty acid-TG cycling under these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1991

Beta-adrenoceptor regulation in insulin-dependent diabetes mellitus.

The study was performed to determine whether the regulation of mononuclear leukocyte beta-adrenergic receptors and responses was changed in insulin-dependent diabetes mellitus (IDDM). The concentrations of noradrenaline, the beta-adrenoceptor densities, basal cAMP levels and maximal isoprenaline-induced cAMP responses were the same in the diabetic and healthy subjects. After isoprenaline-promoted receptor internalization and uncoupling, the receptor densities and the responsiveness did not differ. In the control group, a highly significant correlation existed between the number of beta-adrenoceptors and maximal isoprenaline responses, before (r = 0.99, p less than 0.01) and after (r = 0.96, p less than 0.01) receptor internalization and uncoupling. This correlation between receptor densities and responses was not present in the IDDM group, which also showed elevated levels of plasma adrenaline. This study demonstrates that IDDM subjects have an unaltered mechanism of agonist-promoted beta-adrenoceptor internalization, but indicates a partial dysfunction of the beta-adrenoceptor-coupling to adenylate cyclase.

Adult↗

PubMed1990

Effects of insulin on mononuclear leukocyte beta-adrenoceptor density and adenylate cyclase coupling.

The effects of insulin on human beta-adrenoceptor density and isoproterenol-induced cyclic AMP (cAMP) accumulation were characterized in mononuclear leukocytes from healthy subjects. In cells equilibrated with theophylline (4 mM) at 37 degrees C, insulin (4 microU/ml) was present in periods from 1 to 35 min prior to stimulation. The basal cAMP levels were not influenced. After 1 min pretreatment with insulin, the (-)-isoproterenol concentration necessary to cause half-maximal stimulation (EC50) decreased from 260 to 170 nM (P less than 0.025) and the maximal (-)-isoproterenol response above basal increased from 44 to 63 pmol/10(6) cells (P less than 0.01). The short exposure to insulin caused an increase in the number of functional beta-adrenoceptors from 1420 to 2160 receptors/cell (P less than 0.01). The increased (-)-isoproterenol responsiveness showed a time-dependent decline. When insulin had been present for 35 min before stimulation, the EC50 value had increased to 600 nM (P less than 0.01 vs. control) and the maximal (-)-isoproterenol response above basal was reduced to 29 pmol/10(6) cells (P less than 0.01 vs. control). The receptor density decreased to the pretreatment value (1480 receptors/cell) after 35 min exposure to insulin. The present study shows that insulin modifies the beta-adrenoceptor density as well as the beta-adrenoceptor coupling to adenylate cyclase, dependent on the duration of exposure.

Adenylyl Cyclases↗