Hyperglycemia and blood-brain barrier glucose transport.
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Biomedical subjects
R M Bryan
Publications and source records attributed to R M Bryan.
Regional cerebral blood flow during hypoxia-ischemia in the immature rat: comparison of iodoantipyrine and iodoamphetamine as radioactive tracers.
The indicator fractionation method was used to measure regional cerebral blood flow (rCBF) in immature rats, using either iodo-[14C]antipyrine (IAP) or isopropyl-[14C]iodoamphetamine (IPIA) as the radioisotope. Seven-day postnatal rats received a subcutaneous injection of either IAP (5 microCi) of IPIA (10 microCi), two minutes following which the animals were sacrificed and their brains prepared for quantitative autoradiography. Blood flows to cerebral cortex, hippocampus, striatum, thalamus and hypothalamus were comparable using the two methods, whereas blood flows to white matter structures were substantially higher (+ 64-85%) with IAP. Spatial resolution, especially of the gray matter structures, was greater with IPIA than with IAP. During cerebral hypoxia-ischemia (unilateral common carotid artery ligation and hypoxia with 8% oxygen), blood flows to all regions of the ipsilateral cerebral hemisphere were not different from control at 10 and 20 min. At 1-3 h of hypoxia-ischemia, blood flows were decreased in all analyzed structures of the cerebral hemisphere ipsilateral to the carotid artery occlusion, ranging from 7% to 40% of control values. A columnar or patchy distribution of preferential perfusion was seen within the cerebral cortex, striatum and thalamus, with IPIA, which corresponds closely to the pathologic pattern of injury seen within these structures of the immature rat. Such a preferential perfusion was not seen in hippocampus, in which metabolic factors (intrinsic vulnerability) most likely predict the distribution of hypoxic-ischemic brain damage.
Amphetamines↗
Vascular responses of choroid plexus during hypercapnia in rats.
The response of blood flow to choroid plexus (CPBF) during hypercapnia is controversial. The goal of this study was to determine the effect of hypercapnia on CPBF in unanesthetized rats. Rats breathed air or a mixture of 5-8% CO2 in air, and CPBF was measured with [14C]isopropyliodoamphetamine and quantitative autoradiography. In hypercapnic rats [arterial PCO2 61.6 +/- 1.6 (SE) mmHg; n = 7] CPBF was similar to that of normocapnic control rats (525 +/- 39 ml.min-1.100 g-1; arterial PCO2 42.7 +/- 0.6 mmHg; n = 5). In contrast, blood flow to cerebral cortex increased 67% during hypercapnia. CPBF in normocapnic rats that were treated with phentolamine was similar to untreated normocapnic and hypercapnic rat CPBF. However, during hypercapnia, CPBF in phentolamine-treated rats increased 29%. Responses were similar in blood flow to choroid plexus of lateral, third, and fourth ventricles. Our findings indicate that hypercapnia has no effect on CPBF when alpha-adrenergic receptors are intact. In contrast, after blockade of alpha-adrenergic receptors, hypercapnia increases CPBF. These findings suggest that, during hypercapnia, levels of sympathetic activity or blood-borne catecholamines are increased that prevent increases in CPBF.
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Effect of neurotensin on regional cerebral glucose utilization in cold water-restrained rats.
Neurotensin (NT), given intracerebroventricularly (icv), attenuates cold water restraint (CWR)-induced gastric mucosal injury; however, it is not clear which brain nuclear group or groups are involved. These studies tested the hypothesis that neuronal function, as measured by regional cerebral metabolic rate for glucose (rCMRGlc), is altered by icv NT with or without CWR. CWR resulted in a reduced global glucose utilization of 72 and 65% in control and NT-treated rats, respectively. NT, given icv, protected against ulcer formation induced by CWR. In those rats given NT icv, rCMRGlc was elevated significantly in amygdala, nucleus accumbens, substantia nigra, tuberculum olfactrium, hypothalamus, and cerebellum compared with CWR rats without NT pretreatment. This rCMRGlc increase was observed in both unstressed and stressed rats given NT icv in the nucleus accumbens and amygdala. These observations suggest that the nucleus accumbens and amygdala, both components of the mesolimbic dopamine system, are involved in the central action of NT on the gastric mucosa.
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Cerebral blood flow and energy metabolism during stress.
Many, but not all, stressful events are accompanied by increases in cerebral blood flow and/or energy metabolism. The stressful events include pharmacological paralysis, footshock, conditioned fear, hypotension, hypoglycemia, hypoxia, noise, and ethanol withdrawal. These increases are significant because 1) all brain regions are often affected, i.e., certain stressful events have global effects on cerebral blood flow and energy metabolism; and 2) various stressful events appear to have a common adrenergic mechanism for increasing cerebral blood flow and energy metabolism. The adrenergic mechanism involves beta-adrenergic receptor stimulation by either epinephrine secreted from the adrenal medulla or possibly norepinephrine endogenous to the brain. While adrenergic mechanisms are not the only mechanism controlling flow and metabolism for a given stressful condition, they do appear to be common to many situations. At least part of the increase in cerebral blood flow and energy metabolism during many conditions appears to be the result of the stress response and not directly a result of the condition itself.
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Role of catecholamines in regulating ovine median eminence blood flow.
Blood flow was measured in the ovine median eminence and neural lobe before and after the intravenous infusion of dopamine (n = 7), the D1 agonist SKF 38393 (n = 4), the D2 agonist bromocriptine (n = 4), and the dopamine antagonist haloperidol (n = 5). It was also measured before and after the intracarotid infusion of dopamine into eight naive sheep and seven sheep pretreated with phenoxybenzamine. Radiolabeled microspheres were used to determine regional cerebral and regional neurohypophysial blood flows (RNHBF) in these 35 adult female sheep anesthetized with pentobarbital sodium. Samples for serum prolactin measurement by radioimmunoassay were obtained before and after drug infusion. Intravenous dopamine infusion did not change median eminence or neural lobe blood flow (RNHBF) but increased renal and choroid plexus blood flow. Intravenous haloperidol caused a significant fall in RNHBF and blood flow in choroid plexus, caudate nucleus, and kidneys. Intracarotid dopamine infusion decreased RNHBF but increased choroid plexus blood flow. RNHBF was significantly greater in the seven sheep pretreated with phenoxybenzamine than in the eight naive sheep. These findings do not support a role for dopamine in the regulation of median eminence blood flow. The last observation does add support to the hypothesis that norepinephrine or epinephrine interaction with alpha-receptors plays a role in the control of ovine median eminence blood flow and hence in the regulation of delivery of humoral messages from the brain to the anterior pituitary gland.
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Cerebral blood flow during chronic hypoglycemia in the rat.
Regional cerebral blood flow (rCBF) was measured in normoglycemic and chronically hypoglycemic rats. Chronic hypoglycemia was produced by continuously infusing insulin for 6-7 days. During chronic hypoglycemia (plasma glucose = 1.97 mumol/ml), rCBF increased in all regions except the cerebellum and hypothalamus. Blood flow increases present during chronic hypoglycemia were not as great as those previously measured during acute hypoglycemia. Therefore, adjustments in the regulation of rCBF occurred during chronic hypoglycemia compared to acute hypoglycemia.
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Cerebral glucose utilization after aversive conditioning and during conditioned fear in the rat.
Regional cerebral glucose utilization (rCMRglu) was studied in rats with and without previous aversive conditioning. Four groups of rats were studied. Two groups of rats were aversely conditioned by placing them in a shock chamber (conditioned stimulus) where they received random footshocks. The two remaining groups were placed in the shock chamber but not conditioned. Regional CMRglu and systemic parameters (heart rate, mean arterial blood pressure (MABP), blood gases and pH, plasma catecholamines, and plasma glucose) were measured in unconditioned and conditioned rats in the presence and in the absence of the conditioned stimulus. The changes in rCMRglu described below appeared to be global and not limited to specific regions. Results are as follows: (1) transferring unconditioned rats to the shock chamber had no significant effect on rCMRglu even though the systemic parameters indicated a stress response. It appears that stress capable of inducing changes in heart rate, MABP, and plasma catecholamines is not necessarily accompanied by increases in cerebral glucose utilization. (2) Conditioned rats not exposed to the shock chamber at the time rCMRglu was measured had decreased rates of rCMRglu compared to rats that were not conditioned. Except for plasma epinephrine, which increased after conditioning, systemic parameters were not affected. (3) Conditioned fear, elicited by transferring conditioned rats to the shock chamber, increased rCMRglu when compared to a control group that was conditioned to footshock using the same paradigm but not exposed to the shock chamber at the time rCMRglu was measured. The systemic parameters indicated a stress response in conditioned rats transferred to the shock chamber.(ABSTRACT TRUNCATED AT 250 WORDS)
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Regional cerebral glucose utilization transiently increases during mild hypoxia.
Regional cerebral glucose utilization (rCMRglu) was studied during mild hypoxic hypoxia in awake free-ranging rats. Rats were prepared with chronic arterial and venous catheters and placed in individual chambers for 4 days to recover from surgery before the experiments. The catheters were accessible by passing them through the top of the chambers. Hypoxia was induced by filling the chambers with a gas mixture consisting of 11% O2 in a balance of N2. Regional CMRglu and physiological parameters were measured in normoxic controls and in rats that had been hypoxic for 2 and 17 min before beginning the measurements. Regional CMRglu was measured in 17 brain regions using [6-14C]glucose. PaO2 decreased from 88 mm Hg in the controls to approximately 40 mm Hg during hypoxia. In the early stages of hypoxia (2-12 min), rCMRglu increased approximately 10-25% above the control rates. In later stages of hypoxia (17-27 min), rCMRglu was not different from that in the normoxic controls. The increase in rCMRglu in the early hypoxia was not blocked by propranolol (1.4 mg/kg), indicating that beta-adrenergic receptors were not involved with the increase in rCMRglu. It was concluded that mild hypoxia is associated with an increased rate of cerebral glucose utilization; however, the increase is transitory, with glucose utilization returning to control rates before 17 min.
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Regional neurohypophysial and hypothalamic blood flow in rats during hypercapnia.
Regional cerebral blood flow (rCBF) was measured in the neurohypophysis and hypothalamus in normocapnic and hypercapnic rats using [14C]isopropyliodoamphetamine. Rats were surgically prepared using nitrous oxide and halothane and placed in plaster restraining casts. Hypercapnia was produced by increasing the fractional concentration of inspired CO2 (FICO2). rCBF in normocapnic rats was higher in the paraventricular nucleus, supraoptic nucleus, median eminence, and neural lobe than rates previously measured by use of diffusible tracers. During hypercapnia blood flow increased linearly with arterial PCO2 (PACO2) in all regions except the median eminence and neural lobe, which were not affected by hypercapnia. When rats were pretreated with phentolamine (1 mg/kg) to block the alpha-adrenergic receptors, blood flow in the median eminence and neural lobe increased significantly during hypercapnia. We conclude that blood flow in the cell bodies of the paraventricular nucleus and supraoptic nucleus is regulated differently during hypercapnia than blood flow in the nerve terminals in the median eminence and neural lobe. Furthermore, vasodilation produced by increased CO2 is offset by alpha-receptor stimulation in the median eminence and neural lobe.
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Regional cerebral glucose utilization during vasopressin-induced barrel rotations or bicuculline-induced seizures in rats.
Regional cerebral metabolic rates of glucose (rCMRglu) were measured in conscious rats grouped according to three treatments: control, bicuculline (5.5 mg/kg s.c.), and intracerebroventricular arginine vasopressin (0.5 micrograms/5 microliter). Rats in the latter group were pre-exposed to the peptide 48 h earlier to render them 100% susceptible to a motor output termed barrel rotation (BR). Marked increases in rCMRglu occurred in all brain areas investigated after bicuculline. Increases after intracerebroventricular arginine vasopressin were smaller and occurred in fewer brain areas. Opposite to bicuculline, arginine vasopressin reduced rCMRglu in hippocampus and auditory cortex. The data confirm marked stimulation of rCMRglu during bicuculline-induced seizures and provide initial data for an endogenous peptide that causes BR. Generalized seizures and BR may share some neural substrates, but they produce distinct changes in rCMRglu. The rCMRglu changes are compatible with the interpretation that BR is initiated by brainstem/cerebellar areas that process visual-vestibular information, with subsequent involvement of higher brain structures.
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Regional cerebral and neural lobe blood flow during insulin-induced hypoglycemia in unanesthetized rats.
The effects of hypoglycemia on regional cerebral blood flow (rCBF) were studied in awake restrained rats. The rats were divided into three groups consisting of a normoglycemic control group that received only saline, a hypoglycemic group A, which was given insulin 30 min before flow was measured, and a hypoglycemic group B, which was given insulin 90 and 30 min before flow was measured. Regional CBF was measured using 14C-iodoantipyrine. Mean plasma glucose was 8.76 mumol/ml in the control group, 2.63 mumol/ml in hypoglycemic group A, and 1.51 mumol/ml in hypoglycemic group B. Plasma epinephrine and norepinephrine concentrations increased to approximately 375% and 160%, respectively, of control values in hypoglycemic groups A and B. In the hypoglycemic group A, rCBF significantly increased in three brain regions. In the hypoglycemic group B, rCBF increased significantly in all brain regions measured, with the exception of the neural lobe, in which it decreased. The increase in rCBF ranged from 38% in the hypothalamus to 138% in the thalamus. Neural lobe blood flow significantly decreased by 31%. The neural lobe was the only brain region studied that is not protected by a blood-brain barrier. It may be sensitive to changes in the concentration of vasoactive agents in blood, such as epinephrine and norepinephrine.
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Regional cerebral glucose utilization during hyperglycemia.
Previous data indicate that regional cerebral blood flow (rCBF) decreases during acute and chronic hyperglycemia. To test the hypothesis that the decrease in rCBF is secondary to a decrease in cerebral metabolic rate, the rate of regional cerebral glucose utilization (rCMRgl) was measured in awake-restrained rats during acute and chronic hyperglycemia. Acute hyperglycemia was produced by intraperitoneal injection of glucose, and chronic hyperglycemia was produced by treatment with streptozotocin. The rCMRgl was measured over a 10-min period using [6-14C]glucose. Glucose utilization was normal during acute hyperglycemia but decreased by 13% following 3 weeks of chronic hyperglycemia. The absence of a decrease in rCMRgl measured during acute hyperglycemia indicates that decreased rCBF cannot be explained by a change in the metabolic rate of the brain. The decrease in rCMRgl measured during chronic hyperglycemia does not necessarily indicate the presence of a drop in the metabolic rate of the brain because ketone bodies are available as an alternate fuel for oxidative metabolism. Therefore, it is unlikely that the decrease in rCMRgl measured during chronic hyperglycemia accounts for decreased rCBF.
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Beta-receptor-mediated increase in cerebral blood flow during hypoglycemia.
We tested the hypothesis that beta-adrenergic receptor stimulation is involved with the increase in regional cerebral blood flow (rCBF) during hypoglycemia. Rats were surgically prepared with the use of halothane-nitrous oxide anesthesia. A plaster restraining cast was placed around the hindquarters, and anesthesia was discontinued. Hypoglycemia was produced by an intravenous injection of insulin (15 U/kg); normoglycemic control rats were given saline. Propranolol (1.5 mg/kg) was administered to some control and some hypoglycemic rats to block the beta-adrenergic receptors. Regional CBF was measured using 4-[N-methyl-14C]iodoantipyrine. Plasma glucose in the normoglycemic and hypoglycemic groups was approximately 6 and 1.4 mumol/ml, respectively. Regional CBF increased during hypoglycemia in rats that were not treated with propranolol. The increase varied from approximately 60 to 200% depending on the brain region. During hypoglycemia, propranolol abolished the increase in rCBF in the hypothalamus, cerebellum, and pyramidal tract. In other regions the increase in rCBF was only 33-65% of the increase in hypoglycemic rats that were not treated with propranolol. We conclude that beta-receptor stimulation plays a major role in the increase in rCBF during hypoglycemia.
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Prognostic factors in breast cancer and the development of a prognostic index.
A number of different factors are known to be correlated with survival of patients with breast cancer. Among these are lymph node status, tumour size, oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) status. The purpose of this study was to investigate the relative significance of these factors and use this information to construct a prognostic index capable of predicting survival. These factors together with age and menopausal status were studied and correlated with prognosis in 796 women with primary breast cancer. The data were analysed in a stepwise manner by the Cox proportional hazards regression technique. Statistically, greater than 3 nodes involved gave the worst prognosis (P less than 0.001). This was followed by ER if less than 10 fmol/mg cytosol protein (P less than 0.001), PR if less than 10 fmol (P less than 0.01), greater than 0 lymph nodes involved (P less than 0.01) and the number of years over age 65 (P less than 0.01). When these factors were accounted for, tumour size, menopausal status and AR did not significantly improve prediction of survival. The significant factors were incorporated into a prognostic index: I = N + E + P + A, where N = 0 if no nodes involved, 13 (if 1-3 nodes involved and 31 if greater than 3 nodes involved, E = 15 if ER less than 10 fmol, P = 12.5 if PR less than 10 fmol and A = number of years over 65. Using this index five year survival curves were constructed corresponding to groups of patients with widely differing prognoses. Predicted five year survival ranged from 96 to 12 per cent.
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A method for measuring regional cerebral blood flow in freely moving, unstressed rats.
Regional cerebral blood flow (rCBF) was measured in awake, freely moving, unstressed rats using the diffusible indicator, [14C]iodoantipyrine (IAP). Rats were prepared with catheters in the abdominal aorta and the right jugular vein and allowed to recover for 5-7 days in a special chamber. The catheters were accessible from the outside of the chamber and permitted cerebral blood flow to be measured without disturbing the rat. The length of the arterial catheter created a time delay and a dispersion of the tracer in blood as it was sampled over time. A correction was made for the catheter length using a numeric solution of the convolution integral. Blood flow in regions composed predominantly of grey matter ranged from 68 to 240 ml/100 g/min with the highest flow in the inferior colliculus. Flows in cortical regions ranged from 103 to 200 ml/100 g/min. Flow in the neural lobe of the pituitary was 454 ml/100 g/min. These studies demonstrate that the errors in measuring arterial tracer concentration when blood is sampled from a long catheter can be corrected. The correction permits rCBF to be measured in freely moving rats.
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Insufficient supply of reducing equivalents to the respiratory chain in cerebral cortex during severe insulin-induced hypoglycemia in cats.
The ability of endogenous substrates in brain to substitute for glucose as sources for energy metabolism during insulin-induced hypoglycemia was studied. The ratio of the arteriovenous difference of glucose to the arteriovenous difference of oxygen in the cerebral cortex was measured during progressive hypoglycemia in paralyzed, artificially ventilated cats that were anesthetized with pentobarbital sodium and nitrous oxide. The ratio did not change when blood glucose fell from a mean of 7.68 to approximately 2 mumol/ml. Below 2 mumol/ml the ratio decreased, indicating that substrates other than the glucose supplied by the blood were being utilized. In another series of experiments, changes in the redox state of respiratory chain NAD were monitored from the cerebral cortex using microfluorometry during the onset of hypoglycemia and the recovery. Hypoglycemia severe enough to produce isoelectric EEG was accompanied by an oxidation of NADH, demonstrating that the supply of reducing equivalents to the respiratory chain was decreased. Recovery from hypoglycemia, produced by intravenous glucose injections, was accompanied by an increase in blood glucose concentrations, the return of EEG activity, and a decrease in the NAD/NADH ratio. When blood glucose concentration reached 2.23 during the recovery, further increases in blood glucose had no effect on the redox state of NAD. Although alternative substrates appear to be utilized for energy metabolism during severe hypoglycemia, they cannot fully replace glucose as the source of reducing equivalent to the respiratory chain.
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Regional cerebral glucose utilization during insulin-induced hypoglycemia in unanesthetized rats.
Regional cerebral glucose utilization (rCMRgl) was studied during insulin-induced hypoglycemia in unanesthetized rats. Rats were surgically prepared using halothane and nitrous oxide anesthesia and allowed 5 h to recover from the anesthesia before rCMRgl was measured. The rCMRgl was measured using [6-14C]glucose in a normoglycemic control group and two hypoglycemic groups, A (30 min after insulin injection) and B (2 h after insulin injection). The mean plasma glucose level was 7.03 mumol/ml in the normoglycemic group, 1.96 mumol/ml in hypoglycemic group A, and 1.40 mumol/ml in hypoglycemic group B. The rCMRgl in hypoglycemic group A decreased 8-18% in 17 brain regions measured; five changes were statistically significant. The rCMRgl in hypoglycemic group B decreased significantly in all but one of the brain regions measured; the decrease ranged from 15% in the pyramidal tract to 36% in the motor and auditory cortices. The rCMRgl in every brain region decreased when the plasma glucose level fell below 1.5-2.5 mumol/ml. No brain region could maintain rCMRgl at plasma glucose concentrations lower than predicted by regional glucose influx described in previous studies. Glucose utilization in all brain regions appears to be limited by the influx of glucose.
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