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Increased glutamate concentration in the cerebrospinal fluid has been reported in severely head-injured patients, suggesting that an excessive release of glutamate may be involved in the process of neuronal damage. Ischaemic damage after subdural haematoma has been reported to be reduced by glutamate (N-methyl-D-aspartate: NMDA) receptor antagonists such as dizocilpine and CGS 19755; even though these drugs were given 20-30 min after insult. Excessive release of excitatory amino acids may produce the neural damage after subdural haematoma and NMDA receptor antagonists may become valuable therapeutic drugs. This study compared the effects of ketamine and dizocilpine, on intracranial pressure and histopathological changes after acute subdural haematoma produced by an injection of autologous blood (150 microL) in rats.The control (n = 9), ketamine (n = 9) and dizocilpine (n = 9) groups, respectively, received saline, ketamine (total dose: 210 mg kg-1) or dizocilpine (total dose: 1.0 mg kg-1) from 0.5 to 8 h after acute subdural haematoma. A silicone group (n = 9) had the same volume of silicone injected subdurally.The volume of ischaemic damage in the silicone group (1.3 +/- 1.2 mm3) was significantly smaller than in the control group (11.9 +/- 3.8 mm3). Ketamine and dizocilpine did not increase intracranial pressure. Dizocilpine significantly decreased the volume of ischaemic damage (6.1 +/- 3.8 mm3). Ketamine failed to significantly decrease damage (7.8 +/- 5.0 mm3).These results suggest that the factors elicited by the clotted blood contribute to the ischaemic damage after subdural haematoma, and that the glutamate receptor antagonist dizocilpine reduces the damage, while ketamine shows only a trend reduction of the damage.

Depressant effects of halothane, enflurane and isoflurane on isolated guinea-pig left atrial muscles bathed in Tyrode's solution at 30 degrees C were examined. Contractions were elicited by stimulation through external field electrodes while tension was recorded continuously. Frequency-force relationships at stimulation rates of 0.1, 0.2, 0.5 and 1 Hz were studied. The pD2 values of these volatile anesthetics at each stimulation rates were not different significantly, suggesting the frequency-independent depressions of these anesthetics. Interval-strength relationships at time intervals of 0.3-20 sec during 1 Hz-stimulation were also studied. Mechanical restitution curves after converting to logistic function reached a peak at 8-20 sec and were fitted well to double exponential functions with time constants of 200-600 msec (k1) and 2-6 sec (k2). All volatile anesthetics depressed the magnitude constants for fast response in a dose dependent manner. Accordingly, at high concentrations, mechanical resuscitation curves tended to fit single exponential function. Halothane and enflurane did not alter time constant k1, k2 significantly, while isoflurane increased k2 significantly. These results suggest that the mechanisms of myocardial depressant effects are different between these anesthetics.

Changes in pial vessel diameter combined with regional cerebral blood flow (CoBF) during infusion of vasodilating drugs, isosorbide dinitrate (ISDN) 5 micrograms/kg/min and nitroprusside (NTP) 5 micrograms/kg/min, compared with haemorrhagic hypotension were studied in cats anesthetized with halothane (1.0%). Pial arteries and veins were measured by image-splitting technique and were each divided into three groups according to the reference diameter: I;50 microns, II; 51microns100, III; 101microns. With either drug, the mean blood pressure (mBP) decreased by 10-20%. There was significant decrease in cerebral vascular resistance with ISDN compared with haemorrhagic hypotension while CoBF (H2 clearance) remained unchanged. Dilatation of pial arteries depending on vessel size with ISDN was two-hold compared with haemorrhagic hypotension without any change in all veins. Consistent and significant dilation of veins (I and II) was observed only during NTP infusion. These findings indicate the differential effect of ISDN and NTP on pial arteries and veins.

Effects of ergot alkaloids, nicergoline (NIC), on survival rate, brain water content, local cerebral blood flow (LCBF: 14C-iodoantipyrine) and glucose utilization (LCGU: 14C-2-deoxyglucose) were examined after bilateral carotid artery occlusion (BCAO) in spontaneously hypertensive rats. Two series of study were performed; the permanent BCAO and 3-hr-BCAO study. After permanent BCAO, the survival rate at 24 hrs of 32% (8 mg/kg, i.p.) or 38% (16mg/kg) in NIC group was higher than that in non-treated group (12%). At the end of 3-hr-BCAO, the increase in water content (dry-wet) in di-mesencephalon was less in NIC (100 micrograms/kg/min, i.v.) group than that in non-treated group. The decrease in LCBF in caudate-putamen (CP), parietal cortex (PC), thalamus (TH), hypothalamus (HT), and substantia nigra (SN) were less in NIC group than those in non-treated group. At the 2-hr-reperfusion after 3-hr-BCAO, the decrease in LCBF in TH and HT were less in NIC group than those in non-treated group. The LCGU in sensory motor cortex, CP, PC, HT, inferior colliculus and pons-reticular were higher in NIC group than those in non-treated group. From these results, it is concluded that nicergoline may have ameliorative effects on survival rate related to the prevention of decreased cerebral blood flow and metabolism following brain ischemia.

The effects of isosorbide dinitrate (ISDN) on regional cerebral blood flow (rCBF) and intracranial pressure (ICP) were examined in cats. A low dose of ISDN (2.5 micrograms/kg/min) infusion did not show any changes in cerebral hemodynamics. During high dose of ISDN (5.0 micrograms/kg/min) or NTP (5.0 micrograms/kg/min) infusion, mean blood pressure (mBP) decreased by 10 to 20% accompanied by decreased cerebral perfusion pressure (CPP: mBP-ICP), however, rCBF or ICP did not change. It is concluded that intravenous administrations of ISDN in a dose of 2.5-5.0 micrograms/kg/min that produce slight decrease in blood pressure did not influence on cerebral hemodynamics.

We studied the effects of lidocaine and MEGX on the sodium current, using Vmax as an indicator, at an extracellular potassium concentration ([K]o) of 10 mmol.l-1, and compared the present results with those obtained at 5.4 mmol.l-1 [K]o in our previous study. At 10 mmol.l-1 [K]o, both lidocaine (10 micrograms.ml-1) and MEGX (10 micrograms.ml-1) significantly decreased the Vmax at the steady-state of 1 Hz, caused a significant rate-dependent decrease in Vmax, and slowed the recovery kinetics of Vmax. These effects of both agents were more prominent than those obtained at 5.4 mmol.l-1 [K]o, suggesting that MEGX as well as lidocaine produce voltage-or [K]o-dependent blocking effects on Vmax.

The cerebral effects of hypotension induced by inhalation of increasing concentrations of isoflurane or intravenous administration of prostaglandin E1 (PGE1) were studied in 15 dogs anesthetized with 1% isoflurane and 50% nitrous oxide during normocarbic (PaCO2 approximately 39 mmHg) and normothermic (37.5 degrees C) condition. Mean arterial pressure (MAP) was decreased stepwise to 25, 40, and 55% of its baseline values. Cerebral blood flow (CBF) was measured using the venous outflow technique. Cerebral metabolic rate for oxygen (CMRO2), cerebral metabolic rate for glucose (CMRgl) and oxygen/glucose index (OGI) were calculated, and cerebrospinal fluid pressure (CSFP) and EEG were also recorded at each decrement in MAP and after resuming the control condition. The CBF, CMRO2, CMRgl, OGI and CSFP responses related to hypotension showed no significant changes from baseline values in both methods. However, CBF values in isoflurane-induced hypotension at 25% and 40% reduction of MAP were significantly higher than those in PGE1-induced hypotension. By increasing concentration of isoflurane, EEG changed from continuous fast wave to high amplitude (100 microV) slow wave (4-6 Hz) and typical burst suppression observed in 3 of 8 dogs. In contrast, no significant EEG changes were seen during PGE1-induced hypotension. These results suggest no adverse effect of isoflurane- and PGE1-induced hypotension on cerebral metabolism or function.

The effects of ONO-1016, as an inhibitor of C1-/HCO3-exchange, on the brain edema and circulatory failure following cerebral ischemia were examined in stroke-prone spontaneously hypertensive rats (SHR-SP). SHR-SP were divided into three groups: control (sham-operation), non-treated, ONO-1016 group, respectively. Cerebral ischemia was produced by bilateral carotid artery occlusion (BCAO) for 1 hr and then following reperfusion. The brain water content and local cerebral blood flow (LCBF) were determined by dry-wet method and 14C-iodoantipyrine method 2 hr after start of reperfusion. ONO-1016 was given intravenously at a dose of 100 micrograms/kg/min prior to ischemia. The brain water content increased in septum (SP), amygdala (AM) in both non-treated and ONO-1016 groups compared from those in control group. However, brain water contents in SP and midbrain were lower in ONO-1016 group than those in non-treated group. LCBFs decreased to 50-80% in SP, cerebral cortex (CT), striatum (ST), hippocampus (HC) and AM in non-treated group, while LCBFs decreased to 60-80% in SP, CT, ST, AM in ONO-1016 group when compared from those in control group. Decrease of LCBF in ST and HC in ONO-1016 group were less severe than those in non-treated group. From these results, ONO-1016 may prevent the brain edema formation associated with hypoperfusion during reperfusion period after ischemia in SHR-SP.

We evaluated the relation between dose and response for the neuroprotective effect of propofol in a rat model with incomplete cerebral ischaemia. For clarification of the mechanism of neuroprotection, plasma catecholamines and tumour necrosis factor-alpha levels were measured. Three doses (low, moderate and high-dose) of propofol were tested. These produced, respectively, a low amplitude, slowing and a burst-suppression pattern of electroencephalographic activity. Incomplete cerebral ischaemia was produced by right carotid artery occlusion combined with haemorrhagic hypotension (35 mmHg) for 30 min. Neurological outcome at 72 h post-ischaemia in the high-dose group was significantly better than that in both low-dose and moderate-dose groups. Propofol exhibited a trend in the dose-related attenuation of the increases in plasma adrenaline and noradrenaline during ischaemia. Tumour necrosis factor-alpha increased during and after ischaemia in all groups with no intergroup differences. The results indicate that a burst-suppression dose of propofol provides neuroprotection. The protective effect can not be completely explained by the attenuating effect on circulating catecholamines.

The effects of diazepam, clomipramine, and chlorpromazine upon cerebral metabolism and blood flow were examined separately in 18 dogs. After the administration of diazepam or clomipramine, cerebral cortical oxygen consumption (CMRO2) decreased significantly by a maximum of 17% and 13% of control within 10 minutes and 15 minutes, and returned to control at 120 minutes and 90 minutes, respectively. Chlorpromazine, however, decreased by a maximum of 10% of control, a level which continued throughout the period of observation. It was observed that reduction in CMRglucose was followed by the reduction in CMRO2 at an interval during the early stages of CMRO2 depression. Diazepam produced a significant decrease in CBF accompanied by reduction in CMRO2, but neither clomipramine nor chlorpromazine had any effect on CBF in spite of reduction in CMRO2. Reduction in CMRO2 both with diazepam and clomipramine was accompanied by slow wave activities of EEG, but with chlorpromazine reduction in CMRO2 was accompanied with less pronounced slow wave activities. It was concluded that the three drugs examined were cerebral metabolic depressants.

In order to study the influence of hypoxia on cyclic nucleotides in the brain, we reduced arterial Po(2) for 15-30 min in lightly anaesthetised and artificially ventilated rats to obtain values ranging from about 45 to about 10 mm Hg. In an additional group (arterial Po(2) 18-22 mm Hg), the tissue hypoxia was aggravated by moderate arterial hypotension (mean arterial blood pressure about 80 mm Hg). In all animals, electrocortical activity was recorded. Cyclic GMP concentrations in cerebral cortex were unchanged in all groups but one. In that group, in which tissue hypoxia was severe enough to induce a suppression-burst EEG pattern and a measurable reduction in the adenylate energy charge, cyclic GMP concentrations were slightly increased (p less than 0.05). Cyclic AMP concentrations remained unaltered at all degrees of hypoxia studied. It is concluded that changes in cyclic nucleotides in brain tissue occur first at such severe degrees of hypoxia of the duration studied that function and metabolism are profoundly altered.

This paper reviews postischemic events which might influence the neurologic injury following cerebral ischemia. The influence of diverse calcium entry blockers (CEB) on postischemic cerebral blood flow (CBF) and neurologic outcome is presented. The role of intracellular calcium (Ca) accumulation in neuronal injury is discussed. Although a number of diverse experiments appear in the literature using several, different types of CEB, e.g., nimodipine, lidoflazine, flunarizine and nicardipine, they appear to have different cerebral effects. There is no solid consistent evidence that CEB prevent Ca loading following cerebral ischemia. At least one CEB appears promising, namely, nimodipine. Since the mechanisms of action of CEB in cerebral ischemia remain obscure, further studies appear necessary and warranted.