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Biomedical subjects

M Ingvar

Publications and source records attributed to M Ingvar.

107 records · Page 6Linked to original sources
PubMed1982

Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [14C]2-deoxy-D-glucose autoradiography.

Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudate-putamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudate-putamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplant-reinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral transplants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Effects of methamphetamine on blood flow in the caudate-putamen after lesions of the nigrostriatal dopaminergic bundle in the rat.

Methamphetamine was given to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic bundle. In these animals local cerebral blood flow, measured autoradiographically with [14C]iodoantipyrine as the diffusible tracer, was more than twice as high in the denervated caudate-putamen as compared to control. Measurements of local glucose consumption with the [14C]deoxyglucose technique showed no corresponding change in local metabolic rate. In fact, glucose consumption was lower in the caudate-putamen on the lesion side. The results show that the amphetamine-induced increase in cerebral blood flow does not require an inact nigrostriatal dopaminergic system. Furthermore, dopamine released by amphetamine seems to constrict the vessels and reduce the blood flow in the caudate-putamen.

Animals↗
PubMed1981

Influence of nitrous oxide on local cerebral blood flow in awake, minimally restrained rats.

In order to evaluate the effect of 70-80% N2O on local cerebral blood flow (1-CBF) in the rat brain, we developed a procedure for measuring CBF by an autoradiographic [14C]iodoantipyrine technique in awake, minimally restrained animals. Results on 1-CBF, as measured in 22 different structures, showed little variability between animals. In the majority of structures analyzed, 70-80% N2O failed to alter 1-CBF. These included all cerebral cortical and most subcortical structures. However, nitrous oxide reduced CBF in the inferior colliculus and the superior olive, in two of the limbic structures analyzed, and in the hypothalamus. In no structure, except the striatum (p less than 0.05), was a significant increase in 1-CBF obtained in N2O-breathing animals. However, the results suggest that CBF may have been increased in the auditory cortex. Immobilization was found to reduce 1-CBF in the cerebellum, inferior colliculus, superior olive, hippocampus, and septal nuclei. The results also suggest that the procedure somewhat increased CBF in frontal and parietal cortex. When the results obtained in awake, air-breathing animals were compared with those obtained in immobilized animals ventilated on N2O, there was no significant increase in any of the structures analyzed, although there were suggested increases in all cortical areas except the visual cortex. However, the data showed that ventilation with 70-80% N2O significantly decreased CBF in several structures (inferior colliculus, superior olive, hippocampus, amygdala, septal nuclei, and hypothalamus). In some of these, the effects of 70-80% N2O and of immobilization were obviously additive.

Animals↗
PubMed1981

Effect of indomethacin on local cerebral blood flow in awake, minimally restrained rats.

The effect of indomethacin (10 mg kg-1) on local CBF (1-CBF) was studied with autoradiographic techniques in awake, minimally restrained rats. When compared with uninjected awake control animals, those given indomethacin showed a reduction of 1-CBF by 25-45%. This reduction is somewhat less pronounced than that previously obtained in paralyzed animals maintained on 70% N2O (a reduction by 30-60%). An enhancement of the indomethacin response during nitrous oxide anesthesia was mainly observed in structures which show a maintained or increased CBF during anesthesia.

Anesthesia↗
PubMed1981

Effect of propranolol on local cerebral blood flow under normocapnic and hypercapnic conditions.

The effect of propranolol (2.5 mg kg-1, i.v.) on local cerebral blood flow (CBF) in normocapnia was studied in rats maintained artificially ventilated on 70% N2O and 30% O2. The method used was autoradiography with [14C]iodoantipyrine. Although a single dose of propranolol, given 30 min prior to CBF measurements, somewhat reduced mean CBF values in all of the 22 structures analysed, none of the changes were significant. The results confirm previous ones, in which overall CBF was measured, in showing that beta-adrenergic mechanisms have little effect on normal cerebrovascular tone. Following a single dose of propranolol, results obtained in hypercapnia were equally negative; neither did CBF fall significantly when propranolol was given by constant infusion during 15 min. Furthermore, local CBF did not differ between animals infused with dl-propranolol and d-propranolol. It is concluded that in the rat, propranolol has but small effects on the CBF response to hypercapnia, if any. The results reveal that local CO2 responsiveness, calculated as delta CBF/delta PCO2, varies with normocapnic flow rates.

Animals↗
PubMed1981

Selective metabolic activation of the hippocampus during lidocaine-induced pre-seizure activity.

Neurophysiologic studies indicate that local anesthetic-induced seizures are generated in subcortical brain structures. The authors utilized a quantitative autoradiographic technique to measure cerebral metabolism during lidocaine-induced seizure activity in rats anesthetized with nitrous oxide. Local cerebral metabolic rate for glucose (l-CMRg) was determined when lidocaine infusion resulted in sustained electroencephalographic patterns consisting of approximately 100--125-mu volt discharges with a frequency of about 9 Hz, lasting 1-2 sec, and superimposed upon almost isoelectric periods lasting 1-3 sec. Significant reductions in 1-CMRg (30-70 per cent decreases) occurred in 19 of 26 regions surveyed. All areas of cerebral cortex had decreased glucose uptake following lidocaine administration. The hippocampus developed a striking increase in 1-CMRg of 237 per cent, while the amygdala and other related nuclei sustained metabolic rates similar to those present before lidocaine was given. This study demonstrates a coupling of metabolic activity with functional activity in subcortical structures recognized to be involved in the generation of local anesthetic seizure activity. Additionally, it reveals a heterogeneous response of cerebral metabolism to lidocaine infusion in the presence of subcortically localized seizures.

Animals↗
PubMed1981

Metabolic changes in cerebral cortex, hippocampus, and cerebellum during sustained bicuculline-induced seizures.

The objective of the present experiments was to study metabolic correlates to the localization of neuronal lesions during sustained seizures. To that end, status epilepticus was induced by i.v. administration of bicuculline in immobilized and artificially ventilated rats, since this model is known to cause neuronal cell damage in cerebral cortex and hippocampus but not in the cerebellum. After 20 or 120 min of continuous seizure activity, brain tissue was frozen in situ through the skull bone, and samples of cerebral cortex, hippocampus, and cerebellum were collected for analysis of glycolytic metabolites, phosphocreatine (PCr), ATP, ADP, AMP, and cyclic nucleotides. After 20 min of seizure activity, the two "vulnerable" structures (cerebral cortex and hippocampus) and the "resistant" one (cerebellum) showed similar changes in cerebral metabolic state, characterized by decreased tissue concentrations of PCr, ATP, and glycogen, and increased lactate concentrations and lactate/pyruvate ratios. In all structures, though, the adenylate energy charge remained close to control. At the end of a 2-h period of status epilepticus, a clear deterioration of the energy state was observed in the cerebral cortex and the hippocampus, but not in the cerebellum. The reduction in adenylate energy charge in the cortex and hippocampus was associated with a seemingly paradoxical decrease in tissue lactate levels and with failure of glycogen resynthesis (cerebral cortex). Experiments with infusion of glucose during the second hour of a 2-h period of status epilepticus verified that the deterioration of tissue energy state was partly due to reduced substrate supply; however, even in animals with adequate tissue glucose concentrations, the energy charge of the two structures was significantly lowered. The cyclic nucleotides (cAMP and cGMP) behaved differently. Thus, whereas cAMP concentrations were either close to control (hippocampus and cerebellum) or moderately increased (cerebral cortex), the cGMP concentrations remained markedly elevated throughout the seizure period, the largest change being observed in the cerebellum. It is concluded that although the localization of neuronal damage and perturbation of cerebral energy state seem to correlate, the results cannot be taken as evidence that cellular energy failure is the cause of the damage. Thus, it appears equally probable that the pathologically enhanced neuronal activity (and metabolic rate) underlies both the cell damage and the perturbed metabolic state. The observed changes in cyclic nucleotides do not appear to bear a causal relationship to the mechanisms of damage.

Animals↗
PubMed1981

Local cerebral blood flow in the brain during bicuculline-induced seizures and the modulating influence of inhibition of prostaglandin synthesis.

The purpose of this study was to measure changes in local cerebral blood flow (1-CBF) during generalized seizures, and to study whether or not formation of prostaglandins or related substances contributes to the increased flow rates. Seizures were induced in ventilated rats maintained on 70% N2O and 30% O2 by the i.v. injection of the GABA receptor blocker bicuculline (1.2 mg . kg-1). Formation of prostaglandins was inhibited by the administration of the fatty acid cyclo-oxygenase inhibitor indomethacin (10 mg . kg-1). Local CBF in 21 defined brain structures was measured autoradiographically with 14C-iodoantipyrine as the diffusible tracer. After 20 min of continuous seizure activity 1-CBF increased 1.5--5-fold, the smallest increases (less than 200% of control) being observed in frontal and auditory cortex and in the caudoputamen, and the largest (greater than 400% of control) in substantia nigra, thalamus, visual cortex, lateral geniculate and hypothalamus. In general, the largest increases in 1-CBF occurred in sensory and limbic systems (and hypothalamus) while motor systems showed a pronounced variability. In the majority of structures examined indomethacin failed to modify the CBF response during seizures. Although this result suggests that seizures, in contrast to hypercapnia, lead to an increased CBF by other mechanisms than those related to prostaglandin formation, some structures (nucleus ruber, cerebellum, and superior colliculus) showed a clearly reduced 1-CBF in indomethacin-treated animals.

Animals↗
PubMed1981

Cerebrovascular response during and following severe insulin-induced hypoglycemia: CO2-sensitivity, autoregulation, and influence of prostaglandin synthesis inhibition.

The objective of the present experiments was to study mechanisms governing cerebrovascular responses during severe hypoglycemia, and in the posthypoglycemic recovery period. To that end, lightly anesthetized (70% N2O) and artificially ventilated rats were injected with insulin so as to abolish spontaneous EEG activity for 15 or 30 min ("coma"). In separate animals, recovery was induced by glucose administration. Previous experiments have shown that in normo- or moderately hypertensive animals hypoglycemic coma is accompanied by a relatively marked increase in cerebral blood flow (CBF), and that a delayed hypoperfusion develops in the recovery period. The present results demonstrate that oxygen supply is in excess of the demands during coma, and falls below control during recovery. During hypoglycemic coma, the CO2 response of the circulation was retained but autoregulation was lost. In the recovery period, both CO2 response and autoregulation were lost. Pretreatment with indomethacin was introduced in order to evaluate the possible influence of fatty acid cyclo-oxygenase products on the pattern of CBF changes. Measurements of local cerebral blood flow (1-CBF) showed that, in the majority of structures analysed, indomethacin failed to modulate the changes in CBF. It is concluded that alterations in cerebrovascular tone and loss of autoregulation induce flow changes that may influence substrate and oxygen availability during hypoglycemia. The pronounced decrease in CBF and the loss of autoregulation and CO2-response in the post-hypoglycemic period may influence functional, metabolic and morphological recovery. The 1-CBF findings indicate that neither the increase in CBF during hypoglycemia nor the reduction in flow in the posthypoglycemic period are mediated by mechanisms related to prostaglandin metabolism.

Animals↗
PubMed1980

Cerebral circulatory and metabolic responses to intravenously administered lorazepam.

Cerebral vascular and metabolic effects of lorazepam were evaluated in ten awake monkeys by use of a modification of the Kety-Schmidt technique. Five received ketamine, 10 mg/kg, im, five to eight hours prior to the study, but all animals were otherwise treated identically. Monkeys receiving ketamine had significantly greater (P < 0.05) cerebral blood flow (CBF) values before lorazepam was given (46 +/- 1 ml/100 g/min) than did monkeys not receiving ketamine (41 +/- 1 ml/100 g/min), but in all other respects, premedicated and unpremedicated animals did not differ. Lorazepam administration did not significantly alter systemic arterial blood pressure or blood-gas values. However, it did decrease CBF by 26 per cent and increase cerebral vascular resistance (CVR) by approximately 25 per cent (P < 0.01). The cerebral metabolic rate for glucose (CMRg) decreased 42 per cent (P < 0.05). Following lorazepam administration, the cerebral metabolic rate for oxygen (CMRO2) decreased by 21-30 per cent. When combined CMRO2 data for the two anesthetic groups are pooled, this decrease is significant (P < 0.05). This study indicates that sedative doses of lorazepam decrease cerebral blood flow and metabolism with minimal effects on blood pressure and blood-gas values. Lorazepam administration did not produce any change in cerebral metabolism indicative of brain hypoxia or ischemia.

Anesthesia, Intravenous↗
PubMed1980

Local cerebral glucose consumption in the artificially ventilated rat: influence of nitrous oxide analgesia and of phenobarbital anesthesia.

The objectives of the present study, which concerns local glucose consumption (1-CMRgl) in the rat brain as measured with the 14C-deoxyglucose technique of Sokoloff et al. (1977), were (1) to provide data for 10CMRgl in nitroux oxide analgesia and in phenobarbital anesthesia, allowing a comparison with previous results on oxygen consumption, and (2) to test a recent proposal that 70% N2O markedly reduces 1-CMRgl in (mainly) cortical structures. Under 70% N2O, 1-CMRgl in frontal and parietal cortex was close to 0.7 mumol x g-1 x min-1. This value is in excellent agreement with previous values for "cortical" oxygen consumption. In phenobarbital anesthesia, 1-CMRgl was lower than that expected from oxygen consumption, probably reflecting the fact that barbiturate anesthesia is accompanied by consumption of endogenous substrates. Experiments on adrenalectomized animals that were given local anesthesia and protected from external stimuli failed to demonstrate that 70% N2O depresses 1-CMRgl. In fact, N2O was found to increase 1-CMRgl in many structures. It is concluded that if 1-CMRgl is lower in ventilated animals than in spontaneously breathing, conscious controls, the depression is more likely to be due to the neuromuscular blockade.

Anesthesia, General↗
PubMed1979

Local versus regional cerebral blood flow in the rat at high (hypoxia) and low (phenobarbital anesthesia) flow rates.

Local cerebral blood flow (CBF) was measured in rats, using an autoradiographic technique with 14C-iodoantipyrine as diffusible tracer, in situations with low, normal and high flow rates (phenobarbital anesthesia, analgesia with 75% N2O, and hypoxia, respectively). A comparison of the results with previous data obtained in conscious rats (Sakurada et al. 1978) demonstrates that 75% N2O moderately reduces local CBF in some, but not all, cortical and subcortical areas, that phenobarbital anesthesia reduces local CBF to between 30 and 65% of (conscious) control, and that pronounced hypoxia (arterial P02 about 25 mmHg) increases local CBF 3- to 4-fold. A comparison of the values obtained for cortical structures with those previously measured with a technique based on the Fick principle shows that the autoradiographic technique gives similar values at low and normal flow rates but that it moderately underestimates CBF at high flow rates, probably due to diffusion limitation.

Anesthesia, General↗
PubMed1976

Brain-blood partition coefficients of 85Krypton at 37 C and 29.5 C.

To permit utilization of the Kety-Schmidt technique for measuring cerebral blood flow during hypothermia, the brain-blood partition coefficients for 85krypton at 37 C and 29.5 C were determined in a series of cats. At 37 C the partition coefficient for 85krypton was 1.092 +/- 0.009; it was 0.931 +/- 0.007 (SE) at 29.5 C. These values were significantly different from each other (P less than .001).

Animals↗
PubMedDate not supplied

Hypotension as a complication of hypoglycemia leads to enhanced energy failure but no increase in neuronal necrosis.

The hypothesis that arterial hypotension aggravates hypoglycemic brain damage was tested. Thirty minutes of insulin induced hypoglycemia with a flat EEG ("isoelectricity") was compared in seven series of rats. In three series of animals, the energy state of the cerebral cortex was determined at blood pressures of 140, 100 and 80 mm Hg respectively. Hypotension during hypoglycemia exacerbated cortical energy failure. In the fourth to sixth series, blood pressure was adjusted during isoelectricity to 160, 100 and 60 mm Hg, respectively. A seventh series had induced hypotension to 60 mm Hg only in the recovery period. Quantitation of neuronal death was performed in the fourth to seventh series of rats by direct visual counting of acidophilic neurons in sub-serially sectioned brains after one week survival. Although the first three series demonstrated enhanced deterioration of the cerebral energy state with lower blood pressures during hypoglycemia, the fourth to seventh series showed no augmentation of quantitated hypoglycemic neuronal necrosis. The distinct distribution of hypoglycemic brain damage, suggesting a fluid-borne toxin, was present at normal and reduced blood pressures, with no tendency toward an ischemic pattern of pathology. In spite of previously demonstrated reductions of cerebral blood flow to ischemic levels in regions with pronounced loss of autoregulation, no regional exacerbation of neuronal necrosis was seen in these brain areas. It is concluded that hypoglycemic brain damage is distinct from ischemic brain damage, and that the two insults are not additive. Furthermore, moderate hypotension to 60 mm Hg does not aggravate the damage in spite of an enhanced energy failure.

Animals↗