Uraemia suppresses central dopaminergic metabolism and impairs motor activity in rats.

OBJECTIVE: Uraemia often provokes various neurological disorders, such as mental changes, malperception, confusion, seizures and coma. Since changes in neurotransmissions induce neurological symptoms, we investigated changes in the monoamine metabolism and motor activity in uraemic rats. DESIGN: Prospective, randomised, controlled animal study. SUBJECTS: Male Wistar rats. INTERVENTIONS: Acute renal failure was induced by occlusion of bilateral renal arteries for 60 min, and the motor activity and brain monoamine turnover were examined 48 h later. The brain monoamine turnover was evaluated by the depletion of norepinephrine (NE) and dopamine (DA) induced by alpha-methyl-p-tyrosine (alpha-MT), or the accumulation of 5-hydroxyindoleacetic acid (5-HIAA) induced by probenecid. MEASUREMENTS AND RESULTS: Marked damage in renal function was found in animals subjected to renal ischaemia 48 h after the operation. The motor activity of the uraemic rats was impaired. The turnover of DA in the striatum, mesencephalon and hypothalamus was decreased in these rats. The turnover of NE and 5-hydroxytryptamine (5-HT) was unchanged in all regions examined. CONCLUSIONS: Suppression of the central DA turnover appears to be involved in the impairment of motor activity in uraemic rats.

New pain following cordotomy: clinical features, mechanisms, and clinical importance.

OBJECT: The clinical features, possible causes, and contributing factors associated with novel spontaneous pain following unilateral cordotomy were investigated to clarify the mechanism and clinical importance of this pain. METHODS: Forty-five patients who underwent cordotomy for severe unilateral cancer pain were included in this study. New pain occurred in 33 (73.3%) of 45 patients. Pathological conditions of tissue demonstrated on imaging corresponded to new pain in eight patients, referred pain in five, and neither of these in 15 patients. New pain was centered opposite the site of the original pain in a mirror-image location in 28 patients and rostral to the original pain in five patients. It was temporary in seven patients, weaker than the original pain in 25, and as severe as the original pain in one patient. The incidence of moderate or severe pain was significantly higher in patients with confirmed tissue disease (six of eight patients) than in those without (six of 20 patients). An important contributing factor to the occurrence of new pain was the achievement of analgesia by performing the cordotomy. CONCLUSIONS: The present results indicate that new pain occurs frequently after unilateral cordotomy. Nonetheless, cordotomy may still be indicated for unilateral uncontrollable pain because new pain, when present, was weaker and more easily controlled than the original pain in nearly all cases. The authors speculate that new pain may represent a type of referred pain from the original painful area or may arise from sensitization of contralateral spinal nociceptive circuits due to metastasis or tumor infiltration, and that new pain is potentiated by the interruption of descending inhibitory pathways.

Dexamethasone reduces energy utilization in ischemic gerbil brain.

Glucocorticoids have been reported to aggravate ischemic neuronal damage. Because energy failure is a crucial factor in the development of ischemic neuronal injury, the effects of dexamethasone on histologic outcome and energy metabolism were investigated in gerbil brain. Dexamethasone (3 microg, i.c.v.) was administered 1 h prior to ischemia, and its effect on delayed neuronal death caused by 2 min of bilateral common carotid artery occlusion was observed in hippocampal CA1 pyramidal neurons. The brain concentration of ATP after various durations of decapitation ischemia was determined, and the effect of dexamethasone (3 microg, i.c.v.) was examined. Na+,K+-activated adenosine triphosphatase (Na+,K+-ATPase) activity was evaluated after the administration of the agent. Forebrain ischemia for 2 min produced neuronal damage in animals pretreated with dexamethasone, although neuronal damage was not observed in vehicle-injected animals. Decapitation ischemia for 0.5 and 1 min reduced the brain ATP concentration to 44% and 15% of the basal level, respectively. Dexamethasone attenuated the ischemia-induced reduction in ATP, and the values were 58% and 25% of the basal level, respectively. Na+,K+-ATPase activity at pH 6.7 was suppressed to 47% by dexamethasone treatment (3 microg, i.c.v.), whereas the activity at pH 7.4 was not influenced by the agent. The results show that a contributing factor to the aggravation of ischemic neuronal damage may be a disturbance in Na+,K+-ATPase despite adequate levels of ATP.

[Evaluation of efficiency of ACD-CPR and STD-CPR; a multi-institutional study].

We compared the efficacy of ACD-CPR and STD-CPR based on 64 multi-institutional reports. No significant differences were observed in the rate of restoration of spontaneous circulation (ROSC) and in cardiopulmonary parameters during CPR using the two methods. There were 5 cases in which cardiopulmonary parameters improved after switching from STD-CPR to ACD-CPR and, eventually, in two of them spontaneous circulation was restored. In the ROSC cases of both groups, ETCO2 and values of SpO2, PaO2, and systolic BP at 30 minutes were higher than those of non-ROSC cases. ETCO2 never exceeded 20 mmHg in the non-ROSC cases, but it was higher in the ROSC cases. ACD-CPR is a good choice when trained persons are present or when extra hands are available to continue the CPR.

Prostaglandin E1 improves hepatic encephalopathy produced by ischaemia-reperfusion liver injury in rats.

OBJECTIVE: To investigate the action of prostaglandin E1 on hepatic encephalopathy. DESIGN: Prospective, randomised, controlled animal study. SETTING: University animal laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: After passive avoidance learning, acute liver failure was induced by occlusion of the left portal vein and the hepatic artery for 90 min. Then memory retention was evaluated 48 h later. The effects of prostaglandin E1 on memory retention were examined in animals treated with the agent systemically (intravenous injections with prostaglandin E1 twice before and after surgery, 20 microg/kg each time) and animals treated with the agent topically (intracerebroventricular injection with prostaglandin E1, 0.1 microg/h for 48 h beginning at liver ischaemia). MEASUREMENTS AND RESULTS: Marked damage was found on plasma analysis in animals subjected to liver ischaemia, and the memory retention was also impaired. Intravenous administration of prostaglandin E1 improved both the liver injury and memory retention. However, intracerebroventricular administration of prostaglandin E1 alleviated neither. CONCLUSION: These findings show that prostaglandin E1 contributes to the amelioration of hepatic encephalopathy by improving liver function.

[Effects of intravenous nicardipine, prostaglandin E1, nitroglycerin, sodium nitroprusside, and epidural lidocaine on hepatic and renal blood flow during hypotensive anesthesia].

We studied the effects of intravenous nicardipine (NIC), prostaglandin E1 (PGE1), nitroglycerin (TNG), sodium nitroprusside (SNP) and epidural lidocaine (LID) on hepatic and renal blood flow during general anesthesia (nitrous oxide-oxygen-sevoflurane) in 46 female patients undergoing unilateral total hip arthroplasty. During operations, hepatic blood flow, glomerular filtration rate, renal plasma flow, and renal tubular injury were measured by R 15 ICG (15 minutes retention rate of indocyanine green), CCR (creatinine clearance), CPAH (para-aminohippuric acid clearance), and urinary excretion of NAG and beta 2-microglobulin. Significant elevation of R 15 ICG was observed in the hypotensive state in the TNG group and the elevation of R 15 ICG indicates that blood flow to the liver has decreased during hypotensive anesthesia. Urine volume in the PGE1 group was larger than that in the TNG, SNP or LID group. CCR in the PGE1 group was larger than that in the NIC, TNG or SNP groups. CPAH in the PGE1 group was larger than that in the SNP or LID group. The value of urine NAG in the TNG group was larger than that in the NIC or PGE1 group. The value of urine beta 2-microglobulin in the NIC group was larger than that in the PGE1 or SNP group. The results of urine volume, CCR, CPAH, urine NAG, and urine beta 2-microglobulin indicate that blood flow to the kidneys was greater in the PGE1 group as compared to other groups. This study indicates that prostaglandin E1 is the best hypotensive drug for hepatic and renal blood flow during hypotensive anesthesia.

Measurement of total nitric oxide metabolite (NO(x)(-)) levels in vivo.

The measurement of the total level of nitric oxide (NO) metabolite (NO(x)(-)) by microdialysis has recently been used to assess the production of NO in the in vivo brain [D. Luo, S. Knezevich, S.R. Vincent, N-Methyl-D-aspartate-induced nitric oxide release: an in vivo microdialysis study, Neuroscience, 57 (1993), 897-900; K. Ohta, N. Arai, M. Shibata, J. Hamada, S. Komatsumoto, K. Shimazu, Y. Fukuuchi, A novel in vivo system for consecutive measurement of brain nitric oxide production combined with the microdialysis technique, Neurosci. Lett., 176 (1994), 165-168; K. Shintani, S. Kanba, T. Nakai, K. Sato, G. Yagi, R. Kato, M. Arai, Measurement by in vivo microdialysis of nitric oxide release in the rat cerebellum, J. Psychiatr. Neurosci., 3 (1994), 217-221; H. Togashi, K. Mori, K. Ueno, M. Matsumoto, N. Suda, H. Saito, M. Yoshika, Consecutive evaluation of nitric oxide production after transient cerebral ischemia in the rat hippocampus using in vivo brain microdialysis, Neurosci. Lett., 240 (1998), 53-57]. Although several methods are available for detecting NO(x)(-) levels in dialysates, these methods are either not sensitive enough or require expensive experimental equipment. The method described herein provides a convenient and sensitive procedure for determining NO(x)(-) levels in dialysates. This method is useful for the in vivo study of NO production from various brain regions in various pathological conditions, and can be applied to other tissues.

Metyrapone alleviates ischemic neuronal damage in the gerbil hippocampus.

Transient forebrain ischemia was induced in gerbils, and the effect of a pre-ischemic treatment with metyrapone (100 mg/kg) on delayed neuronal death in hippocampal CA1 neurons was evaluated. The effect of metyrapone on the ischemic release of amino acids in the CA1 region was also examined by microdialysis. Hippocampal slices were used for the evaluation of the hypoxia-induced intracellular Ca2+ increase by microfluorometry. The metyrapone treatment morphologically improved the damage provoked by 3 min of ischemia, although it did not alleviate the damage by 5 min. Ischemia for 3 min produced a 306% increase in the glutamate concentration in perfusates, and metyrapone suppressed the peak value to 42% of that in the control group. The extent of the increase in fluorescence intensity by intracellular Ca2+ was lower by 16% in slices from metyrapone-treated animals than in controls 600 s after induction of hypoxia. The removal of Ca2+ from the perfusion medium suppressed the hypoxic Ca2+ increase, and the increase was further reduced in slices pretreated with metyrapone. The increase in the level of endogenous glucocorticoids, which occurs in cerebral ischemia, may aggravate ischemic neuronal damage.

Sepsis facilitates brain serotonin activity and impairs learning ability in rats.

Sepsis often provokes various neurological disorders. Because many neurologic symptoms are caused by changes in neurotransmissions, we investigated the relationship between behavioral alterations and changes in activities of the monoaminergic systems in rats. Sepsis was induced by cecal ligation and puncture. A step-through passive avoidance test was used for the behavioral evaluation. Passive avoidance retention in animals subjected to learning immediately before the septic or sham operation was examined after 24 or 48 h. Retention performance in animals subjected to learning 24 h after the operation was also examined after a further 24 h. Plasma concentrations of amino acids were determined 24 h after the operation. The activities of the brain monoaminergic systems were evaluated by ratios of metabolites to monoamines. Marked damage was found in the septic rats in the blood analysis 24 h after the operation. The plasma concentrations of tyrosine and arginine in the septic rats were decreased to 69% and 70% of those in the sham-operated animals, respectively. Retention performance was impaired in the septic rats when they were subjected to learning 24 h after the operation, but it was not impaired when animals were subjected to learning before the septic operation. The brain concentration of serotonin was increased in the cerebral cortex, striatum, and hippocampus 48 h after the septic operation, but not after 24 h. The concentration of 5-hydroxyindoleacetic acid, a metabolite of serotonin, was increased in the above three regions both 24 and 48 h after the operation, but not in the hypothalamus. Facilitation of the serotonergic activity in the telencephalon and hippocampus is suggested to be involved in the impairment of learning ability in sepsis.

Nitric oxide production in the CA1 field of the gerbil hippocampus after transient forebrain ischemia : effects of 7-nitroindazole and NG-nitro-L-arginine methyl ester.

BACKGROUND AND PURPOSE: The present study was designed to examine the time course of nitric oxide (NO) production and the source of NO in the CA1 field of the gerbil hippocampus after transient forebrain ischemia. METHODS: The production of NO in the CA1 field of the hippocampus after transient ischemia was monitored consecutively by measuring total NO metabolites (NOx-, NO2- plus NO3-) with the use of brain microdialysis. 7-Nitroindazole (7-NI) and NG-nitro-L-arginine methyl ester were used to dissect the relative contributions of neuronal NO synthase and endothelial NO synthase to the NO production. The histological outcomes of 7-NI in 5- and 10-minute global ischemia were also evaluated. RESULTS: The production of NO in the CA1 field of the hippocampus after ischemia was dependent on the severity of ischemia. Ischemia for 2 or 5 minutes did not induce a significant increase in NOx- levels in the CA1 field of the hippocampus after reperfusion, whereas the 10- and 15-minute ischemias produced significant and persistent increases in NOx- levels. 7-NI did not inhibit the basal NOx- levels and showed no effects on NOx- levels after 5 minutes of ischemia. However, it completely inhibited the increased NOx- levels after 10 or 15 minutes of ischemia. 7-NI provided minor neuroprotection in 5 minutes but not in 10 minutes of global ischemia. CONCLUSIONS: The increased NO level in the CA1 field of the hippocampus after ischemia is produced mostly by neuronal NO synthase, whereas the basal NO level mainly originates from endothelial NO synthase. The observed neuroprotective effect of 7-NI in 5-minute global ischemia in gerbils may not be due to neuronal NO synthase inhibition by this drug.

[A case of Guillain-Barrè syndrome with severe sciatica preceding motor paralysis in the lower extremities].

A 62-year-old man was referred to our clinic for a three-day history of intractable sciatic pain. The pain was so severe that he could not sleep for days. Initially there was no neuronal sign except for the pain, nor any abnormality in lumbar CT and MRI. Cerebrospinal fluid sampled on the third hospital day revealed elevated protein (192 mg.dl-1) with minimal cells. On the 4th hospital day motor weakness of lower extremities appeared and he developed complete flaccid paraplegia in a week without loss of sensation. He was diagnosed as Guillain-Barrè syndrome. For the relief of this pain, intermittent injection of 4 ml 0.25% bupivacaine from lumbar epidural catheter was started on the admission day. By using patient controlled analgesia system, we could treat his repetitive demand timely and well control the pain. The leg weakness started to recover slowly from the 13th hospital day and at the same time the pain started to diminish rapidly in a few days. From the 20th hospital day he started to have rehabilitation in walking and recovered completely in two months without complication. We should remember that sudden onset of severe pain is one of early symptoms of Guillain-Barrè syndrome.

Dexamethasone changes brain monoamine metabolism and aggravates ischemic neuronal damage in rats.

BACKGROUND: Glucocorticoids have been reported to aggravate ischemic brain damage. Because changes in the activities of various neuronal systems are closely related to the outcome of ischemic damage, the authors evaluated the effects of dexamethasone on the monoaminergic systems and ischemic neuronal damage. METHODS: The right middle cerebral artery was occluded for 2 h, and the tissue concentrations of monoamines and their metabolites were determined in the cerebral cortex and the striatum of rats. The turnover of 5-hydroxytryptamine was compared in animals injected with saline and those injected with dexamethasone twice (2 mg/kg in each injection) by evaluating the probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The turnovers of norepinephrine and dopamine were estimated from the alpha-methyl-p-tyrosine-induced depletion of norepinephrine and dopamine, respectively. The effect of dexamethasone on the infarct volume was evaluated by triphenyltetrazolium chloride stain in rats subjected to 2 h of occlusion. RESULTS: Dexamethasone did not affect the cortical 5-hydroxytryptamine or 5-hydroxyindoleacetic acid contents. However, it suppressed the turnover of the cortical 5-hydroxytryptamine on both sides. Dexamethasone reduced the turnover of the striatal 5-hydroxytryptamine and facilitated the dopamine turnover. In rats subjected to 2 h of occlusion and 2 h of reperfusion, the infarct volume was 10.5 times greater in the group that received dexamethasone than in the animals that received saline. CONCLUSIONS: Dexamethasone suppresses the inhibitory serotonergic system and facilitates the excitatory dopaminergic system in the rat telencephalon. This may be a mechanism by which dexamethasone aggravates ischemic neuronal injury.

Dexamethasone augments ischemia-induced extracellular accumulation of glutamate in gerbil hippocampus.

Glucocorticoids exacerbate neuronal damage due to hypoxia, ischemia, seizure and hypoglycemia. Because the release of glutamate is closely involved in neuronal damage, the effects of dexamethasone on the ischemia-induced accumulation of extracellular amino acids (aspartate, glutamate, and glycine) were investigated in the gerbil hippocampal CA1 region by a microdialysis-high-performance liquid chromatography procedure in vivo. There were no differences in the extracellular concentrations of amino acids before ischemia between the control group and the dexamethasone (3m microg, i.c.v.)-injected group. The concentration of glutamate reached 246% of that before ischemia within 2.5 min of transient forebrain ischemia. Dexamethasone augmented the increase in glutamate to 508% of that before ischemia. This finding suggests that glucocorticoids aggravate ischemic neuronal damage by causing glutamate to accumulate in the extracellular space.

Improvement of ischemic damage in gerbil hippocampal neurons by procaine.

Acute cerebral ischemia induces membrane depolarization in the neuron, thereby incurring the simultaneous influx of various ions such as Na+ and Ca2+. Since procaine possesses the ability to inhibit the release of Ca2+ from intracellular Ca2+ stores to the cytosol as well as the ability to block Na+ channels, the effects of procaine on ischemia were investigated in the present study in gerbils both in vivo and in vitro. The histologic outcome was evaluated 7 days after 3 min of transient forebrain ischemia by assessing delayed neuronal death in hippocampal CA1 pyramidal cells in animals administered procaine (0.2, 0.4, or 2 micromol) intracerebroventricularly 10 min before ischemia and in animals given saline. The changes in the direct-current potential shift in the hippocampal CA1 area were measured using an identical animal model. A hypoxia-induced intracellular Ca2+ increase was evaluated by in vitro microfluorometry in gerbil hippocampal slices, and the effects of procaine (10, 50, and 100 micromol/l) on the Ca2+ accumulation were examined. Additionally, the effect of procaine (100 micromol/l) in a Ca2+-free condition was investigated. The histologic outcome was improved and the onset of the ischemia-induced membrane depolarization was prolonged by the preischemic administration of procaine. The increase in the intracellular concentration of Ca2+ induced by the in vitro hypoxia was suppressed by the perfusion of procaine-containing mediums (50 and 100 micromol/l), regarding both the initiation and the extent of the increase. A hypoxia-induced intracellular Ca2+ elevation in the Ca2+-free condition was observed, and the perfusion with procaine (100 micromol/l) inhibited this elevation. Procaine helps protect neurons from ischemia by suppressing the direct-current potential shift and by inhibiting the release of Ca2+ from the intracellular Ca2+ stores, as well as by inhibiting the influx of Ca2+ from the extracellular space.

The effect of dopamine depletion on the H2O2 production in the rat striatum following transient middle cerebral artery occlusion.

The changes in the extracellular concentrations of rat striatal H2O2, dopamine (DA) and its metabolites during middle cerebral artery (MCA) occlusion and reperfusion were simultaneously examined by microdialysis, and the relationship between the ischemia-induced release of DA and the generation of H2O2 was estimated by assessing the effect of the lesion of the substantia nigra (SN). In the rats without SN lesions, a significant increase in the striatal H2O2 level was observed during the ischemia and reperfusion phases. In the rats with SN lesions, the ischemia-induced H2O2 production was not attenuated. These results suggest that DA is not an important source of H2O2 in cerebral ischemia and reperfusion.

Histaminergic H2 action protects hippocampal CA1 neurons by prolonging the onset of the anoxic depolarization in gerbils.

The central histaminergic action on ischemia-induced neuronal damage was examined by evaluating the histological outcome and the direct current (DC) potential shift in the hippocampal CA1 region in gerbils. An intracerebroventricular administration of histamine (10-100 nmol) improved the delayed ischemic damage in hippocampal CA1 pyramidal cells produced by 3 min of transient forebrain ischemia. A high dose (75 nmol) of mepyramine, an H1 antagonist, aggravated ischemia-induced neuronal damage, but not a low dose (0.75 nmol). Administration of cimetidine (4 nmol) and ranitidine (3 nmol), H2 antagonists, aggravated the neuronal damage. An injection of histamine (100 nmol) prolonged the onset time of the ischemia-induced sudden shift in the extracellular DC potential (anoxic depolarization; AD) to 133% of that in control animals. Administration of mepyramine (75 nmol) did not markedly change the AD, whereas injections of cimetidine (40 nmol) and ranitidine (3 nmol) reduced the onset latency to 47 and 45%, respectively. These findings suggest that the central H2 action serves to protect neurons by delaying the onset of AD in gerbils.

[Massive swelling of the tongue in two patients following the repair of cleft palate].

Massive swelling of the tongue occurred following the repair of cleft palate in a one-year-old girl and a one-year-old boy. The duration of operation was 285 min and 225 min respectively. Massive swelling of the tongue became prominent within 30 min after the operation in both infants. The trachea was intubated immediately. Swelling of the tongue recovered slowly, and the trachea was extubated 6 and 7 days after the operation, respectively. The compression of the tongue by the retractor for a long time during the operation probably caused the reperfusion edema of the tongue. Early recognition of the swelling and prompt maintenance of the airway are essential to prevent the serious outcomes resulting from the swelling of the tongue.