Biomedical subjects

G M Knudsen

Publications and source records attributed to G M Knudsen.

70 records · Page 4Linked to original sources

PubMed1991

Kinetic analysis of the human blood-brain barrier transport of lactate and its influence by hypercapnia.

Blood-brain barrier permeability to L-lactate was studied in 18 patients with the double indicator technique. Venous outflow curves were obtained during normo- and hypercapnia and were analyzed by means of a model that takes tracer backflux and capillary heterogeneity of transit times into account. The average unidirectional extraction of L-lactate was 15%; the transport from the blood to the brain (PS1) was 0.081 ml g-1 min-1 and the transport from the brain to the blood (PS2) was on the same order of magnitude. In hypercapnia, arterial pH decreased from 7.39 to 7.26 and PS1 to L-lactate increased significantly by 110%. PS2 also increased although a statistically significant difference compared to the resting state was not reached. It is concluded that L-lactate is easily taken up by the human brain, and that the mechanism by which it crosses the blood-brain barrier is equilibrative. Furthermore, the brain permeability to lactate is enhanced by hypercapnia and the mechanism is believed to act through the decrease in pH.

Adult↗

PubMed1991

Regional density of perfused capillaries and cerebral blood flow in untreated short-term and long-term streptozotocin diabetes.

The regional density of perfused cerebral capillaries (rDPC) and regional cerebral blood flow (rCBF) were measured in 12 selected brain regions in rats after 3 and 20 weeks of streptozotocin-induced diabetes and in control groups. After 3 weeks of diabetes, both rCBF and rDPC were unchanged in the diabetic group compared to the control group. A diabetes duration of 20 weeks causing bilateral cataracts induced a significant (p less than 0.05) reduction in rCBF in two structures in the visual system compared to the control group (visual cortex: 105 versus 129 ml 100 g-1 min-1; lateral geniculate body: 106 versus 128 ml 100 g-1 min-1) and in the pontine reticular nucleus (82 versus 128 ml 100 g min-1), whereas rDPC remained unchanged. A highly significant correlation between rCBF and rDPC was found in both control groups (r = 0.8, p less than 0.005) whereas the correlation was more scattered in the diabetic groups (r = 0.6, p less than 0.05). The present results show that during chronic diabetes, a reduction of rCBF does not affect the number of perfused capillaries.

Animals↗

PubMed1990

Kinetic analysis of blood-brain barrier transport of D-glucose in man: quantitative evaluation in the presence of tracer backflux and capillary heterogeneity.

The present study deals with the analysis of double-indicator curves for blood-brain barrier studies. Two mathematical models which provide for the estimation of backflux of tracer from brain to blood in conjunction with heterogeneity of the cerebral capillary and large-vessel transit times were used for the analysis of D-glucose transport on the basis of cerebral venous outflow curves. The two models, non-mixed and well mixed, arise from differing assumptions regarding the effective region surrounding the capillary lumen. An approximate solution for the well-mixed model was developed to increase computation speed. Fourteen D-glucose outflow curves and their reference curves were obtained from nine patients and subsequently analyzed by the two models. Further, in five patients data were obtained under different physiological conditions: normal, decreased, and increased cerebral blood flow rates. The results support the appropriateness of the well-mixed model and heterogeneity of the cerebral capillary transit times. The median value for the average extraction was 0.18 and the median distribution space was 0.14. The latter value is similar to the brain extracellular space that has been estimated by other methods. The extraction values calculated from the peak of the venous outflow curves were significantly smaller than the whole-brain average extraction values estimated with the well-mixed model (0.157 vs 0.178, P less than 0.0005). In summary: (a) capillary heterogeneity is present in the human brain and changes with cerebral blood flow; (b) after crossing the blood-brain barrier, D-glucose distributes in the brain extracellular fluid; and (c) the extraction curve is significantly influenced by backflux.

Biological Transport, Active↗

PubMed1990

No effect of pulsed magnetic stimulation on the blood-brain barrier in rats.

The impact of transcranial pulsed magnetic stimulation on blood-brain barrier permeability was studied in rats. An integral uptake technique was used to asses the blood-brain barrier permeability to the tracers [3H]sucrose, [14C]urea, and 36Cl-. From the arterial plasma concentration-time curve-integral the permeability surface-area products were calculated. A Dantec magnetic stimulator delivering a peak magnetic field of 1.9 T with a rise-time of 160 microseconds was used for transcranial stimulation of the rats. One group of rats had about 50-60 stimulations during the 15-min infusion of the tracers while another group was exposed to 50 magnetic stimulations a day for one week. A third group comprised the controls. No differences in permeability surface-area product were found for any of the three tracers in the rats exposed to magnetic stimulation as compared with the controls. It is concluded that with regard to blood-barrier integrity, pulsed magnetic stimulation of the brain can be regarded as safe.

Animals↗

PubMed1990

Asymmetrical transport of amino acids across the blood-brain barrier in humans.

Blood-brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood-brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10-20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood-brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood-brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17-40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.

Adult↗

PubMed1990

Hypothalamic-pituitary and thyroid function in chronic alcoholics with neurological complications.

Endocrinological tests were performed in 14 chronic alcoholic men with signs of intellectual impairment and/or peripheral neuropathy. All had been abstinent from alcohol for at least 1 month. Basal serum growth hormone (GH) was consistently increased in only one patient whereas the GH responses to insulin hypoglycemia stimulation was normal in all patients. Thyroid function values (T4, T3, rT3, TSH) were normal in all patients whereas baseline serum prolactin values were significantly increased in alcoholics as compared with a control group. In a combined TRH- and GnRH-stimulation tests, GH-responses were also normal whereas TSH and prolactin responses were blunted or absent in about half of the patients, the responses correlating significantly (p less than 0.01). It is concluded that disturbances in the hypothalamic-pituitary axis may occur in chronic alcoholics with nervous impairment independently of the physical deterioration, which often is associated with chronic alcoholism.

Adult↗

PubMed1989

Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes.

The effect of a dietary supplement of an aldose reductase inhibitor (ponalrestat) or of myo-inositol on sodium transport into the rat brain and on concentrations of saccharide and polyols in cortical brain tissue and sciatic nerve was investigated in control rats and in streptozotocin-diabetic rats after a diabetes duration of 2 weeks. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 28% (3.4 +/- 0.4 vs 4.7 +/- 1.6 x 10(-5) ml/s g, mean +/- SD) as compared to controls. Levels of glucose, sorbitol and fructose increased in brain as well as in nerve tissues, whereas myo-inositol depletion was not demonstrable. Ponalrestat treatment of diabetic animals had no effect upon the decreased neocortical blood-brain barrier permeability to sodium (3.5 +/- 0.9 vs 4.7 +/- 1.1 x 10(-5) ml/s g) despite normalization of brain and nerve content of sorbitol and fructose. Myo-inositol supplementation of diabetic rats normalized sodium passage into the brain (4.2 +/- 1.1 vs 4.4 +/- 0.5 x 10(-5) ml/s g). Brain concentrations of monosaccharides and polyols were normalized as compared to the myo-inositol treated control group and nerve concentrations of glucose, sorbitol, and fructose were significantly increased. Myo-inositol treatment leads to a normalization of blood-brain barrier permeability; it is suggested that myo-inositol exerts a restituting effect upon Na+/K+-ATPase activity of the cerebral endothelial cells.

Animals↗

PubMed1989

Blood-brain barrier permeability to sodium. Modification by glucose or insulin?

In order to explore the pathogenetic mechanism underlying the changes in blood-brain barrier sodium transport in experimental diabetes, the effects of hyperglycemia and of hypoinsulinemia were studied in nondiabetic rats. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 20% (5.6 +/- 0.7 versus 7.0 +/- 0.8 X 10(5) ml/g/s) as compared to controls. Intravenous infusion of 50% glucose for 2 h was associated with a decrease in the blood-brain barrier permeability to sodium (5.4 +/- 1.2 X 10(5) ml/g/s), whereas rats treated with an inhibitor of insulin-secretion (SMS 201-995, a somatostatin-analogue) had normal sodium permeability (7.3 +/- 2.0 X 10(5) ml/g/s). Acute insulin treatment of diabetic rats normalized the sodium permeability within a few hours as compared to a separate control group (7.7 +/- 1.1 versus 6.9 +/- 1.4 X 10(5) ml/g/s). To elucidate whether the abnormal blood-brain barrier passage is caused by a metabolic effect of glucose or by the concomitant hyperosmolality, rats were made hyperosmolar by intravenous injection of 50% mannitol. Although not statistically significant, blood-brain barrier sodium permeability increased in hyperosmolar rats as compared to the control rats (8.3 +/- 1.0 and 7.0 +/- 1.9 X 10(5) ml/g/s, respectively). It is concluded that either hyperglycemia per se or a glucose metabolite is responsible for the blood-brain barrier abnormality which occurs in diabetes. Further, we suggest that the specific decrease of sodium permeability could be the result of glucose-mediated inhibition of the Na+K+-ATPase localized at the blood-brain barrier.

Animals↗

PubMed1989

Impaired beta-adrenergic mediated cerebral blood flow response in streptozotocin diabetic rats.

The influence of intracarotic infusion of isoproterenol on cerebral blood flow, on cerebrovascular CO2-reactivity, and on cerebral glucose metabolism were investigated in streptozotocin diabetic rats. Resting cerebral blood flow in diabetic rats decreased by 26% from a control value of 90 ml/100 g.min. to 66 ml/100 g.min. Intracarotid isoproterenol infusion leads to a significant increase in cerebral blood flow in both groups. The increase in cerebral blood flow in control rats (70%), significantly exceeded that in the streptozotocin diabetic rats (33%). Cerebrovascular reactivity to carbon dioxide was preserved after isoproterenol infusion in both groups and there was no significant difference in the relative cerebral blood flow increase in the two groups. Cerebral glucose metabolism was also unaffected by the isoproterenol infusion. The results indicate that impaired beta-adrenergic mechanisms may play a role for alterations in cerebral blood flow that is seen in diabetes mellitus.

Animals↗

PubMed1989

Angiotensin converting enzyme inhibition and the upper limit of cerebral blood flow autoregulation: effect of sympathetic stimulation.

The effect of stimulation of the cervical sympathetic ganglia on the upper limit of cerebral blood flow (CBF) autoregulation was studied in normotensive Wistar-Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR) following intravenous administration of the angiotensin converting enzyme inhibitor captopril (10 mg/kg). CBF was measured using the intracarotid 133Xe injection method in halothane/nitrous oxide anaesthetized WKY and SHR. Arterial blood pressure was raised stepwise by the intravenous infusion of noradrenaline. Toward the end of the study, Evans blue was injected and the brains examined for gross blood-brain barrier breakdown. In SHR, sympathetic stimulation reextended the upper limit of CBF autoregulation, which was at a mean arterial blood pressure level of 120-139 mm Hg in the control group of eight SHR and above 170 mm Hg in the stimulated group of nine SHR. In the group of nine WKY subjected to sympathetic stimulation, the upper limit of CBF autoregulation was reached at a mean arterial blood pressure level of 110-129 mm Hg as opposed to 90-109 mm Hg in a previous unstimulated group of WKY. In the two groups subjected to sympathetic stimulation, there was no extravasation of Evans blue in any of the brains. In the control group of SHR, in which there had been marked increases in CBF, three out of eight brains had foci with extravasation of the dye. It is concluded that in normotensive and in hypertensive rats sympathetic stimulation attenuates the downward shift of the upper limit of CBF autoregulation, which is known to accompany intravenous administration of captopril.

Animals↗

PubMed1988

Blood-brain barrier permeability in galactosamine-induced hepatic encephalopathy. No evidence for increased GABA-transport.

Blood-brain barrier permeability to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), to sucrose and to sodium was studied in rats with galactosamine-induced liver damage and hepatic encephalopathy by means of an arterial integral uptake technique. Permeability to GABA was unaltered in all examined brain regions (2.47 +/- 0.25.10(-5) cm3.s-1.g-1, mean +/- S.D.) as compared to control rats (2.49 +/- 0.19.10(-5) cm3.s-1.g-1). The permeability to sucrose (galactosamine 0.25 +/- 0.02 vs. controls 0.24 +/- 0.02.10(-5) cm3.s-1.g-1) and to sodium (galactosamine 5.33 +/- 0.04 vs. controls 5.40 +/- 0.05.10(-5) cm3.s-1.g-1) was also unchanged in hepatic encephalopathy. At the time of investigation mean liver function measured by antipyrine clearance was reduced from 0.39 in control rats to 0.23 ml/min/100 g body wt. in galactosamine-treated animals. The present study does not support the suggestion that peripheral GABA penetrates the blood-brain barrier to any higher extent in hepatic encephalopathy. This provides evidence against at least part of the GABA-hypothesis. Furthermore, an unspecific increased blood-brain barrier permeability in hepatic encephalopathy, as measured by sucrose and sodium uptake, was not found. It is concluded that the GABA-theory requires further careful reevaluation.

Animals↗

PubMed1987

Cation permeability of the blood-brain barrier in streptozotocin-diabetic rats.

Decreased sodium permeability across the blood-brain barrier occurs in streptozotocin-treated rats after 2 weeks of diabetes. To establish whether this is a phenomenon specific for cations, the blood-brain barrier permeability for sodium, potassium and calcium was studied with an arterial integral uptake technique. Experiments were performed in control rats and, after two weeks after diabetes induction, in untreated streptozotocin-diabetic rats and in insulin-treated streptozotocin rats. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 35% (5.2 +/- 1.7 vs 3.4 +/- 1.1 10(-5).cm3.s-1.g-1) and potassium permeability by 39% (19.8 +/- 5.7 vs 12.1 +/- 3.9 10(-5).cm3.s-1.g-1), whereas no differences in calcium permeability occurred. Insulin treatment was associated with an increase in the blood-brain barrier permeability to sodium (4.8 +/- 1.0 10(-5).cm3.s-1.g-1) as compared to untreated diabetes (3.4 +/- 1.1 10(-5).cm3.s-1.g-1). It is concluded that the observed changes in sodium and potassium permeability cannot be caused by electrostatic membrane changes. More specific abnormalities of the transport of sodium and potassium across the blood-brain barrier are likely to occur; disturbances in the sodium-potassium-pump activity could account for such alterations.

Animals↗

PubMed1987

Discordance between the cortisol response to insulin-hypoglycemia and 30-minute ACTH stimulation test in chronic alcoholic men.

An insulin hypoglycemia test and a 30-min ACTH stimulation test was performed in 10 chronic alcoholic men, who had been abstinent from alcohol for at least one month. Attenuated serum cortisol responses were found in six of the patients despite a normal ACTH test. Four patients showed normal responses to both the insulin hypoglycemia test and the short ACTH test. No correlation was demonstrated between the cortisol response and the severity of alcoholism, cerebral atrophy, and peripheral neuropathy. It is concluded that in chronic alcoholism the short ACTH test may fail in disclosing hypofunction of the integrated hypothalamic-pituitary-adrenocortical (HPA) axis as assessed with the insulin hypoglycemia test.

Adrenocorticotropic Hormone↗

PubMed1986

Decreased blood-brain barrier permeability to sodium in early experimental diabetes.

Blood-brain barrier (BBB) permeability to 24Na+, 36Cl-, and [3H]sucrose was studied in rats after 2 wk of streptozocin-induced diabetes. The PS (permeability-surface area product) for Na+ in the cortex of the frontal lobes was 5.4 +/- 0.6 (10(-5) cm3 X g-1 X s-1; +/- SD) in diabetic rats compared with 7.1 +/- 1.7 in control rats. In the occipital cortex, the values were 7.6 +/- 1.5 and 9.9 +/- 1.6, respectively. In contrast, BBB permeability to Cl- and sucrose remained unchanged. We conclude that a selective alteration in BBB permeability to Na+ unrelated to changes in brain capillary surface area is present in experimental diabetes.

Animals↗

PubMedDate not supplied

Circulating levels of neuropeptides (CGRP, VIP, NPY) in patients with fulminant hepatic failure.

The present study investigated the circulating levels and cerebral fluxes of calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) and their relation to cerebral blood flow (CBF) during normoventilation and hyperventilation in patients with fulminant hepatic failure (FHF). Sixteen patients with FHF were studied and compared to six patients with cirrhosis of the liver. CBF was measured by the (133)Xe wash-out technique. Blood samples were obtained simultaneously from the artery and internal jugular bulb. Concentrations of CGRP and VIP were higher in FHF than in cirrhosis, 87 (55-218) vs. 29 (21-42) pmol/L, and 11 (6-29) vs. 5 (3-9)pmol/L, respectively. NPY was normal, none of the measures were related to CBF, and there was no detectable net brain fluxes. Hyperventilation did not alter any of the measures. CGRP and VIP in FHF seem to reflect hemodynamic changes in the systemic rather than in the cerebral circulation.

Adult↗

PubMedDate not supplied

Cerebral blood flow response to propranolol in streptozotocin diabetic rats.

The influence of propranolol on cerebral blood flow (CBF) was tested in streptozotocin diabetic rats and in control animals. Resting CBF values were 40% lower in the diabetic rats compared with controls. Intravenous injection of propranolol (2 mg kg-1) decreased CBF significantly in the control group; the CBF decreased for 15 min after propranolol injection and returned to baseline values after 90 min. In the diabetic rats, the CBF declined steadily but this decrease did not reach significance, even after 90 min. Impaired beta-adrenergic mechanisms may be an important factor in the CBF alterations which occur in diabetes mellitus. Further, it is suggested that an impaired CBF response may play a role in CNS lesions in diabetic patients treated with beta antagonists.

Animals↗