[Anesthetic management for removal of a giant ovarian tumor using FloTrac x Vigileo monitoring system].

We successfully managed anesthesia in a patient with a giant ovarian tumor weighting 22 kg, using FloTrac x Vigileo monitoring system. A 43-year-old woman (67.2 kg, 154.5 cm and abdominal girth 111.3 cm) was admitted for removal of a giant ovarian tumor. Arterial blood pressure (ABP), heart rate, percutaneous arterial oxygen saturation, cardiac index (CI) and stroke volume variation (SVV) were monitored. General anesthesia was induced, with the patient in the supine position, using 50 mg propofol, 0.25 microgram x kg(-1) x min(-1) remifentanil. 30 mg rocuronium bromide and inhalation of 100% oxygen, and maintained with sevoflurane 1.5% and remifentanil administration between 0.1-0.3 microgram x kg(-1) x min(-1). Following 6 l fluid drainage from the ovarian tumor, ABP and CI decreased, but SVV remained within normal ranges. Therefore, we only decreased the drainage speed without increasing fluid administration rate. When the tumor was lifted up, both CI and SVV increased, but the increase of SVV was 10%, still within normal ranges. Therefore, we did not increase fluid administration rate to avoid excessive hydration. After tracheal extubation, respiratory and hemodynamic states were stable, and the patient had no postoperative complication. We conclude that FloTrac x Vigileo System is useful for monitoring cardiac performance parameters, and helps anesthesiologists adjust drainage speed of the content and infusion rate to maintain the stability of circulatory state, in removal of a giant cyst.

Suppression of inflammatory cell recruitment by histamine receptor stimulation in ischemic rat brains.

Inflammation is a crucial factor in the development of ischemia-induced brain injury. Since facilitation of central histaminergic activity ameliorates reperfusion injury, effects of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with antibodies against myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12-24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by L-histidine injections. The L-histidine administration decreased the number of CD4+ T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of thioperamide prolonged the effect. Although administration of mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration, ranitidine tended to reverse the effect of L-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through histamine H2 receptors, which may be a mechanism underlying the protective effect of L-histidine.

Recovery of brain dopamine metabolism by branched-chain amino acids in rats with acute hepatic failure.

A decrease in the serum ratio of branched-chain amino acids (BCAAs) to aromatic amino acids (Fischer ratio) reflects the severity of hepatic encephalopathy, and clinical improvement by dietary augmentation with BCAAs has been demonstrated. As behavioral alteration results from changes in central neurotransmission, we investigated the role of BCAA administration on changes in the levels of central neurotransmitters in acute liver injury. Male Wistar rats were subjected to liver ischemia by occluding the left portal vein and hepatic artery for 90 minutes. A 4% BCAA solution containing valine, leucine, and isoleucine was intraperitoneally administered 3 times (8 mL/kg, each) at 1 hour, 6 hours, and 24 hours after vascular reperfusion, and changes in the extracellular concentrations of neurotransmitter amino acids, monoamines, and their metabolites were evaluated in the striatum by a microdialysis procedure. Although the extracellular concentration of dopamine was affected by neither liver ischemia nor BCAA injections, the level of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 34% in the ischemic group 24 hours after reperfusion. The 3,4-dihydroxyphenylacetic acid level was normalized by treatments with BCAAs. The improvement of deranged cerebral dopaminergic activity may be a contributing factor in the improvement of hepatic encephalopathy by BCAAs.

Histaminergic involvement in neuropathic pain produced by partial ligation of the sciatic nerve in rats.

BACKGROUND AND OBJECTIVES: Because the histaminergic system in the brain is involved in regulation of pain, the relationship between central histaminergic activity and neuropathic pain is of interest. METHODS: Neuropathic pain was induced in rats by partial ligation of the left sciatic nerve, and changes in the extracellular concentration of histamine in the right striatum were examined by a microdialysis procedure 2 weeks later. The nociceptive threshold was determined with von Frey tests, and effects of histaminergic ligands were examined. RESULTS: Although the extracellular concentration of histamine did not differ between the sham-operated and ligated groups, histaminergic activity assessed by metoprine-induced accumulation of histamine was facilitated in ligated animals. The metoprine treatment ameliorated neuropathic pain in ligated animals, although the agent did not affect the threshold in sham-operated rats. Either intracerebroventricular (ICV) administration of histamine (30 microg) or intraperitoneal (IP) administration of L-histidine (370 mg/kg) decreased the nociceptive threshold in ligated rats. However, a high dose of histamine (180 microg ICV) increased the nociceptive threshold. Ranitidine (100 microg ICV), an H2 antagonist, increased the threshold, whereas pyrilamine (15 microg ICV), an H1 antagonist, showed no remarkable change. Administration of thioperamide (30 microg ICV), an H3 antagonist, increased the threshold, although systemic administration of the agent (3.6 mg/kg IP) decreased it. CONCLUSIONS: Blockade of supraspinal histamine H2 receptors or stimulation of spinal H3 receptors may contribute to alleviation of neuropathic pain.

Suppression of ischemia/reperfusion liver injury by histamine H4 receptor stimulation in rats.

Inflammatory reactions play an important role in ischemia/reperfusion injury in various organs. Since histamine is closely related to inflammatory reactions and immune responses, effects of postischemic administration of histaminergic ligands on ischemia-induced liver injury were examined in rats. Animals were subjected to warm ischemia for 30 min by occlusion of the left portal vein and hepatic artery under halothane anesthesia, and liver damage was evaluated by assessing plasma concentrations of transaminases after 24 h. Warm ischemia for 30 min provoked severe liver damage after 24 h, and the plasma concentrations of alanine transaminase (ALT) and aspartate transaminase (AST) were 8600 I.U./l and 13100 I.U./l, respectively. Subcutaneous injections of histamine twice, immediately and 6 h after reperfusion (20 mg/kg, each), alleviated liver damage. The plasma concentrations of ALT and AST in the histamine group were 35% and 24% of those in the control group, respectively. Neither mepyramine (3 mg/kg x 2), an H1 antagonist, nor cimetidine (15 mg/kg x 2), an H2 antagonist, affected the outcome in histamine-treated rats. However, thioperamide (5 mg/kg x 2), an H3/H4 antagonist, completely abolished the alleviation caused by histamine. Administration of dimaprit (1-10 mg/kg x 2), an H2/H4 agonist, mimicked the protective effect of histamine, and the effect of dimaprit is reversed by thioperamide, whereas neither H1 nor H2 antagonists altered the outcome caused by dimaprit. Clozapine (15 mg/kg x 2), an H4 agonist, also mimicked the protective effect of histamine. These findings indicate that stimulation of histamine H4 receptors after ischemic events prevents development of reperfusion injury in the liver.

A comparison of protective effects between L-histidine and hypothermia against ischemia-induced neuronal damage in gerbil hippocampus.

An increase in the histamine concentration in the brain has been demonstrated to provide protective effects against ischemia/reperfusion brain injury. Since hypothermia and barbiturates are also regarded to protect ischemic brains, effects of postischemic treatments were compared in gerbils between mild hypothermia and intraperitoneal administration of L-histidine, a precursor of histamine. Furthermore, effects of thioperamide, a histamine H(3) receptor antagonist, were evaluated in histidine-treated gerbils after 60 days. Transient forebrain ischemia for 4 min at 37 degrees C provoked severe neuronal damage in the hippocampal CA1 pyramidal cells after 7 days. Postischemic hypothermia (33 degrees C) for 3 h under pentobarbital anesthesia alleviated neuronal death, and the number of preserved neurons was 77+/-56/mm (mean+/-S.D., n=14). The effect of L-histidine injected three times, immediately, 6 h, and 24 h after reperfusion (1,000 mg/kg, i.p., each), was more prominent than that of hypothermia, and the number of preserved neurons was 142+/-55/mm (n=14). When the histologic outcome was evaluated after 60 days, most neurons were damaged in both the hypothermic and histidine groups. The improvement of the histologic outcome was observed even after 60 days in animals injected with thioperamide, immediately and 6 h after reperfusion (5 mg/kg, s.c., each), with three injections of l-histidine. The number of preserved neurons was 133+/-88/mm (n=10), while that in the hypothermic group was 7+/-15 (n=10). Activation of the central histaminergic system provides beneficial effects against cerebral ischemia.

Fluoroscopically guided epidural block in the thoracic and lumbar regions.

BACKGROUND AND OBJECTIVES: Epidural block in the midthoracic region is difficult, even with fluoroscopically guided methods, because of the inability to view the interlaminar space on radiographs. We have, therefore, proposed fluoroscopically guided epidural block for the midthoracic region, as well as other thoracic and lumbar regions, by use of the pedicle as a landmark to show the height of the interlaminar space. METHODS: Twenty patients scheduled to receive an indwelling epidural catheter at Th6-7, Th9-10, Th12-L1, or L3-4 were studied. The skin insertion site was at the junction of a line parallel to the vertebral column that passed through the middle of the pedicle and the lower border of vertebral body, immediately inferior to the target interlaminar space on an anteroposterior radiograph. The needle was walked up the lamina, and the interlaminar space was sought near the midline of the vertebra at the height of the pedicle. RESULTS: Epidural block was easily performed in all cases. No difference was observed in the angulation of the epidural needle among the groups; the mean inward and upward angulation were 38 degrees and 63 degrees , respectively, although the skin insertion site relative to the spinous process was different among the groups. CONCLUSIONS: This study showed the usefulness of our fluoroscopically guided method for the midthoracic region, and other thoracic and lumbar regions. We propose an alternative method for a blind epidural approach at Th6-7, Th9-10, Th12-L1, or L3-4.

Prevention of brain infarction by postischemic administration of histidine in rats.

Focal cerebral ischemia for 2 h by occlusion of the right middle cerebral artery provoked severe brain infarction in the rat brain after 24 h. Intraperitoneal administration of histidine, a precursor of histamine, immediately and 6 h after reperfusion, alleviated brain infarction. The infarct size in the histidine (200 mg/kg, 500 mg/kg, and 1000 mg/kg, each time) groups was 71%, 39%, and 7% of that in the control group, respectively. Although intracerebroventricular administration of mepyramine (3 nmol), an H1 antagonist, did not affect the morphologic outcome in histidine-treated rats, ranitidine (30 nmol), an H2 antagonist, completely abolished the alleviation caused by histidine. These findings indicate that postischemic administration of histidine prevents development of brain infarction by stimulating central histamine H2 receptors.

Reduction in brain infarction by augmentation of central histaminergic activity in rats.

Inflammation is a factor in the aggravation of reperfusion injury after cerebral ischemia. Since histamine H(2) receptor stimulation suppresses inflammatory reactions, effects of the central histaminergic activation on brain infarction were examined in rats. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery, and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride stain after 24 h. Effects of postischemic administration of thioperamide, an H(3) antagonist, and metoprine, an inhibitor of histamine-N-methyltransferase, were evaluated in rats treated with l-histidine, a precursor of histamine. Furthermore, effects of these agents on changes in the striatal histamine level were examined by a microdialysis procedure. Focal ischemia provoked marked damage in rats treated with l-histidine (1000 mg/kg) alone. Administration of l-histidine (1000 mg/kg) with either thioperamide (5 mg/kg) or metoprine (10 mg/kg) alleviated brain infarction. The size of brain infarction was 27% and 10% of that in animals treated solely with l-histidine, respectively. The combination treatment with thioperamide and metoprine decreased the size of brain infarction in rats given l-histidine (500 mg/kg), although protective effects were not clear without l-histidine. A marked increase in the histamine concentration was observed in the histidine plus metoprine group, the value being 363% of that in the saline-injected group after 2-3 h. The histamine concentrations in the histidine group and histidine plus thioperamide group were 188% and 248%, respectively. These findings indicate that facilitation of central histaminergic activity reduced the brain infarction.

Flumazenil-induced improvement of the central dopaminergic system in rats with acute hepatic failure.

Several reports have demonstrated the alleviation of hepatic encephalopathy by flumazenil, an antagonist of benzodiazepine receptors. As changes in central monoaminergic activity are involved in the mechanisms for hepatic encephalopathy, the effects of flumazenil on central monoaminergic activity were evaluated in acute hepatic failure produced by ischemia-reperfusion injury in rats. Eighteen male Wistar rats were evenly assigned to three groups: sham-operated group given saline, liver-ischemic group given saline, and liver-ischemic group given flumazenil. Flumazenil (1 mg/kg) or saline (10 mL/kg) was intraperitoneally administered three times, at 1, 6, and 24 hours after 90 minutes of liver ischemia produced by occlusion of the left portal vein. The extracellular concentrations of neurotransmitter amino acids, monoamines, and their metabolites were determined in the striatum using a microdialysis procedure. Another set of 12 rats was subjected to liver ischemia, and the effect of flumazenil on spontaneous motor activity was examined after 24 hours. The extracellular concentration of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 39% of that in sham-operated animals 24 hours after surgery (P < 0.05), although the dopamine level did not change. The treatment with flumazenil completely abolished the decrease in the metabolite (P < 0.05). Although the glutamate level in the injured animals decreased to 42% of that in sham-operated animals (P < 0.05), no remarkable increase in the glutamate level was observed in animals treated with flumazenil. Spontaneous motor activity decreased 24 hours after surgery in animals subjected to liver ischemia. Flumazenil led to improvement of spontaneous motor activity 5 minutes after administration, but this effect was not observed after 30 minutes. The restoration of the central dopaminergic function may be a contributing factor in the improvement of hepatic encephalopathy.

Suppression of energy requirement by lidocaine in the ischemic mouse brain.

Effects of lidocaine on parameters of membrane functional integrity were investigated in the mouse brain. Changes in the direct-current potential shift in the cerebral cortex provoked by decapitation ischemia were compared in animals given lidocaine (0.05, 0.25, or 1.0 micromol, intracerebroventricular) or saline 15 minutes before ischemia. The brain content of adenosine 5'-triphosphate (ATP) was measured in animals subjected to 0, 0.5, 1, and 2 minutes of decapitation ischemia, and the effect of preischemic administration of lidocaine (0.25 micromol, intracerebroventricular) was evaluated. Na+, K+-ATPase, and Ca2+-ATPase activity was evaluated in brains pretreated with lidocaine (0.25 micromol, intracerebroventricular) or saline 15 minutes before decapitation. Changes in the intracellular Ca concentration ([Ca2+]i) were evaluated in hippocampal slices and the effects of lidocaine (50, 100, or 400 microM) were assessed in the hippocampal CA1 field and dentate gyrus at pH 7.4 and pH 6.8 every 60s for a duration of 50 min. The preischemic administration of lidocaine (1.0 and 0.25 micromol) delayed the onset of anoxic depolarization to 49 seconds and 44 seconds, respectively, as compared with that in the saline group at 27 seconds. Lidocaine maintained ATP levels higher than those in corresponding saline groups, values being 165% after 1 minute of ischemia and 212% after 2 minutes, respectively. Lidocaine did not affect Na+, K+-ATPase, and Ca2+-ATPase activity. Lidocaine did not affect changes in the [Ca2+]i in either area at either pH. The findings may suggest that lidocaine maintains the energy level by delaying depolarization in neurons, which may contribute to removal of cytosolic Ca2+ in ischemic states.

Acute effects of 17beta-estradiol on oxidative stress in ischemic rat striatum.

Changes in the extracellular concentrations of monoamines, their metabolites, and hydrogen peroxide in the rat striatum during middle cerebral artery (MCA) occlusion and reperfusion were investigated by a microdialysis procedure, and the effects of 17beta-estradiol and tamoxifen (an antagonist of estrogen receptors) on them were evaluated. Male Wistar rats were randomly divided into four groups: saline-treated animals, 17beta-estradiol-treated animals, saline-plus-tamoxifen-treated animals, and 17beta-estradiol-plus-tamoxifen-treated animals. Sixty minutes after an intracerebroventricular injection of saline (20 microL) or 17beta-estradiol (150 microg/20 microL), all animals were subjected to 15-minute MCA occlusion under anesthesia. Tamoxifen (1.5 mg) or vehicle was intravenously administered 30 minutes before the saline or 17beta-estradiol treatment. Microdialysis samples in the striatum were collected every 15 minutes, and concentrations of monoamines, their metabolites, and hydrogen peroxide were determined. Delayed neuronal death in the striatal neurons was observed after 7 days by light microscopy. Administration of 17beta-estradiol reduced neuronal damage caused by focal ischemia. Tamoxifen did not affect the improvement by 17beta-estradiol. Although transient ischemia produced a marked increase in the dopamine level, there were no differences in the peak level among the groups. The level of hydrogen peroxide was increased after reperfusion in the saline group. The level in the 17beta-estradiol group was suppressed before induction of ischemia, and no increase was observed by ischemia. Tamoxifen did not affect the suppression of the increase by 17beta-estradiol. Acute treatment with 17beta-estradiol showed a protective effect against ischemia-reperfusion injury. Antioxidant effects of the agent may be a predominant mechanism underlying the protection.

A mechanism of new pain following cordotomy; reference of sensation.

An antero-lateral cordotomy was performed on a 62-year-old man who had been suffering from intractable right chest pain caused by lung cancer. Six hours after the cordotomy a new pain occurred in an analogous part of the body on the opposite side; the intensity increased gradually and it became as severe as the original within 1 week. Reference of sensation from analgesic area of cordotomy to the opposite side of the body was induced by noxious stimuli. Intrathecal phenol block to the nerves conveying the cancer pain abolished the new pain and the reference of sensation from this blocked area, though it remained unchanged in other analgesic areas of cordotomy. This substantiates that the new pain was a reference of the original cancer pain.

Reference of pain following percutaneous cervical cordotomy.

In order to clarify the mechanism of reference of pain following cordotomy (ROPC), the authors investigated ROPC in 66 patients undergoing percutaneous cervical cordotomy (PCC) and examined the features of ROPC and the correlation between the occurrence of ROPC and the pre-operative pain states, as well as the results of PCC. ROPC was observed in 7 patients. It occurred immediately after PCC in 6 of 7 patients and 6 h after PCC in 1 patient. The pain was referred horizontally and cranially from the region rendered totally or largely analgesic by PCC to the normally innervated region. The region to which the pain was referred was not fixed. The referred pain disappeared by rendering the region where referred pain was felt analgesic with additional PCC. There was no correlation between the occurrence of ROPC and pre-operative pain states, or the results of PCC. From these results we postulate that: (1) ROPC occurs via a subsidiary pathway consisting of ascending chains of short neurons connecting dorsal horn neurons longitudinally and latitudinally; (2) the subsidiary pathway is inhibited under normal conditions by feedback inhibition from second-order neurons and/or higher central neurons of the nociceptive pathway; and (3) ROPC results from the release of the feedback inhibition by cordotomy.

Ipsilateral referral of pain following cordotomy.

We report a patient who developed ipsilateral referred pain following unilateral percutaneous cervical cordotomy (PCC). A right-sided PCC was performed on a 44-year-old woman who had been suffering from left groin and thigh pain caused by a fibrosarcoma. PCC produced analgesia below T7 on the left side, and the pain disappeared. A novel spontaneous pain with prominent allodynia occurred postoperatively in the right infraclavicular region (C3-C4). Strong pressure on the left groin where severe spontaneous pain and tenderness had been before PCC increased the new pain, and an epidural block which produced analgesia below T10 relieved the new pain. These facts indicate that the new pain was induced by afferent inputs from the originally painful region.

Percutaneous cervical cordotomy and subarachnoid phenol block using fluoroscopy in pain control of costopleural syndrome.

We examined the efficacy of percutaneous cervical cordotomy (PCC) and subarachnoid phenol block using fluoroscopy (SAPB-F) for control of chest and/or back pain from costopleural syndrome. The efficacy of each block was evaluated by changes in pain score (PS), analgesic dose and performance status 1 week after the block, as well as by the complications. Between 1980 and 1986, PCC was performed in 10 patients. SAPB-F was performed in 13 patients between 1987 and 1991. Pain was not well controlled by analgesics in any of these patients. For PCC the follow-up period was 94.7 +/- 71.1 days. PS (VAS, 0-10) reduced from 8.5 +/- 0.9 to 3.0 +/- 2.7. No analgesics were needed in 4 patients. Pain recurred in 1 patient. Hemiparesis occurred in 2 patients. General fatigue occurred in 6 patients. In 4 patients with these complications performance status deteriorated and did not recover during the follow-up period. For SAPB-F the follow-up period was 71.8 +/- 44.0 days. SAPB-F was designed to achieve selective phenol deposit at the targeted nerve root. PS decreased from 7.5 +/- 1.9 to 2.7 +/- 2.6. No analgesics were needed in 5 patients. Pain recurred in 3 patients. There were no complications and no changes in performance status. From this study we concluded that PCC is an effective method of pain control for costopleural syndrome, but a risk of serious complications is involved. SAPB-F is an effective and safe method and should be the first choice of nociceptive pathway block.

Alleviation of ischemic neuronal damage by postischemic loading with histidine in the rat striatum.

Inflammatory reactions play an important role in ischemia-reperfusion injury in the brain. Since histamine H(2) action suppresses inflammatory reactions, effects of postischemic loading with histidine, a precursor of histamine, were examined. Focal cerebral ischemia for 15 min was provoked by transient occlusion of the right middle cerebral artery in rats, and delayed neuronal death were evaluated in striatal neurons after 7 days. Histidine was administered four times, immediately, 6, 24, and 48 h after reperfusion of blood flow (1000 mg/kg, i.p., each time). To examine the role of histaminergic action on changes in histologic outcome, effects of mepyramine (3 nmol, i.c.v.), an H(1) antagonist, and ranitidine (30 nmol, i.c.v.), an H(2) antagonist, were evaluated in histidine-treated rats. Transient ischemia for 15 min provoked severe neuronal damage in the saline-injected control group, and the number of striatal neurons decreased to 21% of that on the contralateral side. Administration of histidine alleviated ischemic neuronal damage, and the number of preserved neurons was 76% of that on the contralateral side. Simultaneous administration of mepyramine with histidine did not affect the histologic outcome. However, administration of ranitidine abolished the alleviation by histidine. These findings indicate that the elevation of histamine H(2) receptor stimulation by massive administration of histidine suppresses reperfusion injury in the brain.

Suppression of sodium pump activity and an increase in the intracellular Ca2+ concentration by dexamethasone in acidotic mouse brain.

The effects of dexamethasone on adenosine 5'-triphosphatase (ATPase) activity and the intracellular Ca(2+) concentration ([Ca(2+)](i)) were investigated in acidotic mouse brain. Dexamethasone (3 mg/kg, i.p.) or vehicle was administered 3 h before decapitation ischemia, and the brain concentration of adenosine 5'-triphosphate (ATP) was determined 0.5-2 min after ischemia. The effects of dexamethasone (0.3-3 mg/kg, i.p.) on Na(+),K(+)-activated ATPase (Na(+),K(+)-ATPase) and Ca(2+)-ATPase activities were evaluated at pH 7.4 and 6.8. Changes in [Ca(2+)](i) in an acidic medium were determined in hippocampal slices by microfluorometry using rhod-2 acetoxymethyl ester as a Ca(2+) marker, and the effects of dexamethasone (240 microg/l) was evaluated. Decapitation ischemia for 0.5 and 1 min reduced the brain ATP contents to 32% and 16% of the basal level, respectively. Dexamethasone slightly suppressed the extent of the decrease in the ATP level. Although dexamethasone did not affect Na(+),K(+)-ATPase activity at pH 7.4, the activity was suppressed by dexamethasone (3 mg/kg) to 68% at pH 6.8. The activity of Ca(2+)-ATPase was not affected by dexamethasone at either pH 7.4 or pH 6.8. When the pH of the medium of the brain slices was changed from 7.4 to 6.8, almost no increase in [Ca(2+)](i) was observed in the control group. The dexamethasone treatment increased [Ca(2+)](i) in the CA1 field and dentate gyrus immediately after induction of the acidic medium, the effect being significant after 150 s. Because anaerobic glucose metabolism in the early stage of ischemia enhances intracellular lactic acidosis, the findings may suggest a mechanism for the aggravation of ischemic neuronal damage by glucocorticoids.

Histaminergic H(2) blockade facilitates ischemic release of dopamine in gerbil striatum.

The blockade of central histaminergic H(2) receptors has been reported to aggravate ischemic neuronal damage. Since excess release of excitatory neurotransmitters is closely related to ischemic neuronal damage, the effects of ranitidine on ischemic release of dopamine were investigated in gerbil striatum. Changes in the extracellular concentration of dopamine produced by transient forebrain ischemia for 4 min were investigated by a microdialysis procedure, and the effect of intracerebroventricular administration of ranitidine (10 nmol) was evaluated. The histologic outcome was examined 7 days after ischemia by light microscopy. Forebrain ischemia produced a marked increase in the dopamine concentration in dialysates, and the level returned to the basal level after reperfusion. The preischemic administration of ranitidine enhanced the increase in the dopamine level during ischemia, and the peak value in the ranitidine group was 203% of that in the saline group. The histologic outcome was aggravated by the ranitidine treatment in the striatum, although aggravation was not observed in the cerebral cortex. The facilitation of the ischemic release of dopamine may be a contributing factor in the aggravation of ischemic damage by H(2) blockade.

Blockade of central histaminergic H2 receptors facilitates catecholaminergic metabolism and aggravates ischemic brain damage in the rat telencephalon.

Blockade of central H(2) receptors aggravates ischemic neuronal damage. Since changes in the activity of the monoaminergic system are contributing factors in the development of ischemic neuronal damage, the authors evaluated the effects of ranitidine on the monoaminergic system and ischemic neuronal damage in the middle cerebral artery (MCA) occlusion model of rats. Wistar rats pretreated with saline or ranitidine (3 and 30 nmol, i.c.v.) were subjected to reversible occlusion of MCA for 2 h. The total infarct volume was determined 24 h after reperfusion. The relationship between dopaminergic activity and the histologic outcome was estimated by lesioning the substantia nigra 2 days before MCA occlusion. In a second experiment, the animals were subjected to 15 min of MCA occlusion, and the effects of ranitidine on the histologic outcome was evaluated 7 days after ischemia. In a third experiment, the tissue concentrations of monoamines and their metabolites were determined in the cerebral cortex and striatum 2 h after reperfusion following MCA occlusion for 2 h. The turnover of norepinephrine and dopamine was compared between animals treated with saline and those treated with ranitidine by estimating the alpha-methyl-p-tyrosine-induced depletion of norepinephrine and dopamine, respectively. The turnover of 5-hydroxytryptamine was evaluated by the probenecid-induced accumulation of 5-hydroxyindoleacetic acid. Treatments with ranitidine markedly increased the infarct volume 24 h after reperfusion. Ranitidine also aggravated delayed neuronal death 7 days after ischemia. The aggravation was abolished by the lesion of the substantia nigra before MCA occlusion. The MCA occlusion increased the turnover of cortical norepinephrine and striatal dopamine. The turnover was further facilitated by ranitidine. Although ranitidine suppressed the 5-hydroxytryptamine turnover in the cerebral cortex, the extent of this effect was similar in both the ischemic and non-ischemic sides. These results suggest that facilitation of the catecholaminergic systems is involved in the aggravation of ischemic neuronal damage by H(2) blockade.