The effect of electrical stimulation of cerebral cortex on neuronal activity in the subnucleus caudalis of the spinal trigeminal nucleus (STNcd) was examined electrophysiologically in the cat. The nociceptive neuronal firing in the STNcd was suppressed by electrical stimulation of contralateral cerebral cortex (primary motor: Msl or primary somatosensory: Sml cortical area). The high amplitude spontaneous and continuous neuronal hyperactivity (deafferentation hyperactivity: DH), which was provoked in the left STNcd after complete ablation of left Gasserian ganglion, was conspicuously suppressed by the electrical stimulation of the cerebral cortex (Msl stimulation: 5/36; Sml stimulation: 12/36). Almost all neurons (nociceptive and DH neuron), the neuronal activity of which was suppressed by electrical stimulation of cerebral cortex, were located in the dorsal and ventral reticular subnuclei of STNcd. On the other hand, the injection of wheat germ agglutinin labeling horseradish peroxidase into the cerebral cortex (Msl) demonstrated that the efferent fibers passed through the internal capsule (IC) and projected directly to the dorsal and ventral reticular subnuclei of the STNcd of the contralateral side. This study suggested that the neuronal firing in STNcd (nociceptive neuronal firing and DH) was suppressed by stimulation of the inhibitory efferent fibers from the cerebral cortex to STNcd by electrical stimulation of IC and cerebral cortex.
Developmental change of blood flow velocity and pulsatility index (PI) of the basilar artery (BA) were studied, using transcranial Doppler sonography on 137 healthy subjects (68 males and 69 females) from 1 month to 30 years old. Blood flow velocity of the basilar artery increased with age during infancy and childhood, reached the maximum at the age of 5, and then gradually decreased. Its ratio to blood flow velocity of the middle cerebral artery (MCA) i.e. MCA/BA showed a constant value irrespective of age. On the other hand, PI of the basilar artery showed a maximum value at infancy, and decreased during 1-2 years of age thereafter, it showed a constant value. Physiological variation of the blood flow velocity of MCA and BA during natural sleep and hyperventilation was also investigated. There is a close correlation between the optimal pulsed signal depth for the measurement of blood flow velocity of the basilar artery and head circumference, or occipito- frontal diameter.
Most antipsychotic drugs share similar pharmacological properties in that they cause anti-dopaminergic, anti-noradrenergic and anti-serotonergic activities. Using a radioreceptor assay, these anti-aminergic activities were measured in the serum of 34 schizophrenics receiving haloperidol medication. The anti-dopaminergic activity was determined as a value of haloperidol equivalent and chlorpromazine equivalent. The anti-noradrenergic and anti-serotonergic activities were based on the chlorpromazine equivalent. The schizophrenics were divided into two groups (group 1:16 out-patients, group 2:18 hospitalized acute psychotic patients). Most of the patients in group 1 showed low anti-dopaminergic activity (below 10 ng/ml haloperidol equivalent or 100 ng/ml chlorpromazine equivalent). Anti-noradrenergic and anti-serotoninergic activities could be measured in only two patients. Fifteen patients in group 2 responded well to haloperidol. There was a positive correlation between anti-dopaminergic activity, plasma HPD concentration and daily haloperidol dose in all the group 2 patients. Clinical improvement was positively correlated with anti-noradrenergic activity, but not with anti-dopaminerigic activity in the group 2 patients. These findings suggest that anti-noradrenergic activity plays an important role in clinical improvement of schizophrenic patients in an acute psychotic state.
The effects of plasma protein concentration (TP) on sevoflurane plasma protein/gas partition coefficient and of hematocrit values (Ht) on sevoflurane red cell/gas partition coefficient were examined in dogs. Furthermore, the effects of TP and inhalated nitrous oxide on sevoflurane MAC and sevoflurane concentration in blood at 1 MAC were studied in dogs during sevoflurane anesthesia. Significantly positive correlations were noted in vitro between TP and plasma/gas partition coefficient, and between Ht and red cell/gas partition coefficient. However, the change in blood/gas partition coefficient appeared to be affected by TP. Sevoflurane MAC and sevoflurane concentration in blood at 1 MAC rose in positive correlation with the rise of TP with or without nitrous oxide in combination, but there was no correlation with Ht. This seemed to be related to the predominancy of sevoflurane to dissolve into the plasma. The sevoflurane MAC and sevoflurane concentration in blood were significantly lower in the 33% nitrous oxide combined group than those in the oxygen alone group, but there was no significant difference between the 66% nitrous oxide combined group and the 33% nitrous oxide combined group. Furthermore, TP affected the sevoflurane MAC but not the nitrous oxide MAC.
A pressor effect of TRH in hemorrhagic hypotensive rats was studied. First, TRH (1mg/kg, 2mg/kg, 5mg/kg), its analogue MK771 (0.2mg/kg) and anti-TRH antibody were given intravenously. The change in the mean arterial blood pressure (MAP) was observed. After administration of TRH, MAP rose dose-dependently, and it also rose after administration of MK771. The anti-TRH antibody significantly suppressed the compensatory and reflective increase of MAP following the hemorrhage. This suggested that the endogenous TRH plays an important role in the maintenance of MAP in the hemorrhagic hypotensive state. Next, the same hypotention models were made using adreno-demedullated rats. TRH or anti-TRH antibody was given intravenously. TRH significantly increased MAP, while the anti-TRH antibody suppressed MAP. This indicates that the pressor effect of TRH is not mediated by the adrenal medulla. The endogenous TRH may play its maintenance role of blood pressure via medulla oblongata.
To clarify the pathophysiology of nocturnal enuresis and to establish its rational classification and treatment, clinical and electroencephalographic studies were made on 404 enuretic children, including an overnight polysomnographic investigation on 55 cases. EEG was normal in only 76 cases (18.8%). Background EEG abnormalities were observed in 226 cases (55.9%). This suggested the presence of brain immaturity or dysmaturity in enuretic children. Epileptic discharges were detected in 94 cases (23.3%), but not concomitant with the enuretic events. The epileptic mechanism may not play a primary role in the manifestation of enuresis. Specific EEG patterns of subcortical origin, i.e., 6 c/s wave-and-spike phantom, 14 & 6 c/s positive epikes, anterior theta burst, and mu rhythm, were detected in as many as 188 cases (46.5%). This indicates the importance of subcortical brain dysfunction in enuresis. During overnight polysomnographic recordings, 38 enuretic episodes were observed in 30 cases. Twenty eight episodes appeared in light sleep, 8 episodes in deep sleep, but only 2 episodes in REM sleep. According to the arousal response at the time of enuresis, enuretics were properly classified into arousal type (12 cases) and non-arousal type (18 cases). Prognosis was favourable in the cases whose enuresis appeared in light sleep and also in the arousal type enuretics.
Flow reserve of the right coronary artery (RCA) was studied in open-chest dogs and compared with that of the left anterior descending coronary artery (LAD). The maximum percent peak reactive hyperemia (%PRH) of the RCA was greater, and the duration of occlusion that produced one-half of the maximum coronary vasodilation (T1/2) in the RCA was about twice that in the LAD. With an increase in right ventricular MVO2 produced by constriction of pulmonary artery or isoproterenol infusion, T1/2 of the RCA was shortened significantly. For estimating the quantitative contribution of the perfusion pressure to coronary flow reserve, we occluded the RCA for 60 sec and the LAD for 30 sec, during which each vessel reached maximum vasodilation with various perfusion pressure in the range of 100 to 20 mmHg. %PRH decreased with a reduction in perfusion pressure, and perfusion pressure below which the RH abolished was significantly lower in the RCA than the LAD: 32.2±5.7 VS 41.5±5.0 mmHg. Thus, the RCA has a greater flow reserve than the LAD, and lower cardiac work and less extravascular artery compression of the right ventricle would account for this finding.
The influence of hypothermia (27°C) on the action of nondepolarizing neuromuscular blocking drugs was investigated using rat phrenic nerve-hemidiaphragm preparations. The pH of modified Krebs' solution was maintained constant by reducing the concentration of CO2 aerating the solution to 4% at 27°C from 5% at 37°C. Log dose-response curves were constructed for pancuronium, vecuronium, pipecuronium, d-tubocurarine (d-Tc), metocurine and gallamine at 37°C and 27°C, respectively. The slopes were not influenced by temperature. The ED50 of pancuronium, vecuronium and pipecuronium at 27°C were significantly smaller than that at 37°C. However, the ED50 of gallamine increased and that of d-Tc and metocurine did not change when temperature was lowered. In addition, the effects of lowering temperature (27°C) on the partial neuromuscular blockade produced by pancuronium, vecuronium and their 3-deacetyl, 17-deacetyl and 3, 17-deacetyl metabolites were studied. Neuromuscular blockade produced by pancuronium, vecuronium and their 3-deacetyl metabolites increased, while that by 17-deacetyl and 3, 17-deacetyl metabolites decreased when temperature was lowered. In conclusion, the difference in the influence of hypothermia among the neuromuscular blocking drugs, is not attributed to their steroidal structure, but may be due to the differences in their mechanism of action.
The effects of acute respiratory acidosis and alkalosis on the activated coagulation time (ACT) of both pre-heparinized and post-heparinized blood samples were studied in adult mongrel dogs. The ACT of pre-heparinized samples, compared with the ACT at a normal pH, was significantly shortened with the progression of acidosis. The correlation coefficient between the ACT of pre-heparinized samples and the pH values during acidosis was 0.55 (p<0.01). During alkalosis, however, the ACT of pre-heparinized samples showed no significant changes. On the other hand, the ACT of post-heparinized samples, compared with the ACT at a normal pH, showed significant prolongation with the progression of both acidosis and alkalosis. The correlation coefficient between the ACT of post-heparinized samples and the pH values was -0.74 (p<0.001) during acidosis, and was 0.55 (p<0.01) during alkalosis. These results indicate that, although the mechanism of the alteration of ACT due to the acute respiratory pH changes seemed to be multifactorial, the ACT in the presence of pH abnormality does not reflect the actual blood concentration of heparin correctly.
1-Methyl-4-phenyl-1, 2, 3, 6, -tetrahydropyridine (MPTP) has been shown to destroy the nigrostriatal dopaminergic system, inducing biochemical and histopathological changes resembling Parkinson's disease. Biochemical changes, especially changes of neuropeptides were determined 1, 2 or 6 weeks after MPTP treatment in various regions of the mice brain. The dopamine (DA) concentration decreased to 22% of the control level in the striatum 1 week after MPTP treatment, but recovered to 50% of the control level 6 weeks after MPTP treatment. The decrease in the noradrenaline concentration was less than that of DA. Amine fluorescence histochemistry revealed, markedly decreased amine fluorescence in the striatum 6 weeks after MPTP treatment, and this decrease in amine fluorescence was recovered after levodopa treatment. The results of a pole test revealed the bradykinesia of MPTP-treated mice and it was attenuated by levodopa and amantadine hydrochloride treatments. Among the neuropeptides tested, somatostatin (SOM) increased 1 week after MPTP treatment in the striatum and the thalamus+midbrain but decreased 6 weeks after MPTP treatment in the striatum and the hippocampus. In the striatum the decreased SOM recovered with levodopa treatment. Thus, the SOM might be regulated by a dopaminergic system. On the other hand, in the cerebral cortex, while no changes appeared in the SOM concentration after MPTP treatment, the concentration decreased significantly with levodopa treatment. Other neuropeptides such as substance P, cholecystokinin-octapeptide and thyrotropin releasing hormone did not show any significant changes up to 6 weeks after MPTP treatment.
To clarify the acute-phase response in brain, we investigated the induction of metallothionein (MT) genes by administering an endotoxin (lipopolysaccharide) in rat intraperitoneum. We performed in situ hybridization on the serial brain sections to identify the cells expressing the MT genes in the acute-phase. After endotoxin administration, transcripts of MT genes were detected in the arachnoideal, ependymal cells and the Bergmann glia of the cerebellum, while no significant induction of the MT genes by zinc ion was observed in the brain. These results suggest that the acute-phase response occurs specifically in at least these three non-neuronal cells.
Deafferentation hyperactivity (DH) was provoked in the neurons of the subnucleus caudalis of the spinal trigeminal nucleus and the lateral reticular formation in cats by Gasserian ganglionectomy, and was used as a model of peripheral deafferentation pain. The influence of neurochemical substances upon DH was investigated. Neurotransmitters and their antagonists were applied topically around the soma of hyperactive neurons by the microiontophoretic technique, using a 7-barreled glass micropipette. Then the participation of inhibitory amino acids in the descending inhibitory systems, which were activated by deep brain stimulation (DBS), was investigated. Discharges of hyperactive neurons (n=75) were recorded extracellularly and analyzed using a spike density histogram. DH was suppressed by topically injected GABA and glycine, but not by met-enkephalin. The suppressive effects of GABA and glycine were almost completely antagonized by bicuculline and strychnine, respectively. Stimulation of the internal capsule or VPM suppressed DH, and this suppression was not affected by microiontophoretically injected bicuculline or strychnine. Intravenous injection of picrotoxin reduced the suppression, but intravenous strychnine did not. GABA may play an important role as an inhibitory neurotransmitter in the descending inhibitory systems activated by DBS.
To relieve deafferentation pain, electrophysiological assessment of target points was performed using deep cerebral SEPs. As a preliminary experiment, the relationship between the waveform of the SEP and the anatomical structure of the brain was examined in cats. The infraorbital nerve was stimulated and the SEP was recorded around the VPM. From the rostral edge of the medial lemniscus (ML), a high voltage positive wave was recorded, and from the ventral side of the VPM a wide negative wave with positive wavelets was recorded. For the treatment of three cases of thalamic pain, the deep cerebral SEP was recorded during the insertion of a chronic electrode for deep brain stimulation. By contralateral median nerve stimulation, the high voltage positive waves (peak latency; 13-15msec) from the ML and the subsequent uneven waves from the VPL were recorded along the trajectory. The later uneven waves were composed of wide negative waves and positive wavelets, which were thought to be derived from the synaptic activity of the VPL and thalamocortical radiation, respectively. Effective pain relief was obtained at the border zone of the ventral VPL and the ML, where the characteristic waves of the VPL changed to those of the ML. The deep cerebral SEP can be used for the identification of target points electrophysiologically.
The renal and hepatic metallothionein (MT) and serum zinc levels were studied in rats following renal ischemia, to clarify the effects of renal damage on the zinc metabolism. The serum zinc concentration began to decrease on the 4th day in the bilateral renal ischemic rat. The accumulation of hepatic MT was stimulated by sham operation and was augmented furthermore by renal ischemic damage. The renal MT level increased gradually and reached the maximum on the 3rd day in the bilateral renal ischemic rat. The MT level in the injured kidney was higher than that in the intact kidney in the unilateral renal ischemic rat. These results suggested that the mechanism of MT synthesis in the kidney was different from that in the liver, and that some local factor might induce MT in the injured kidney.
The effect of heparin-urokinase (H-U) on the prevention of brain damage induced by ischemia was evaluated in 31 dogs subjected to an 18 min of complete global brain ischemia. Complete brain ischemia was produced by clamping the ascending aorta with aorto-atrial and aorto-femoral bypass formation. Post-ischemic cerebral blood flow (CBF) and other hemodynamic parameters were measured for 7 hours after ischemia in 15 dogs (acute study). Neurologic outcome was eveluated for 7 days after ischemia in 16 dogs (chronic study). Fifteen minutes after restoration of circulation to the brain, an intravenous bolus of heparin 100 I. U./kg and urokinase 3000 I. U./kg, was given, followed by continuous intravenous infusion of heparin 0.25 I. U./kg/min and urokinase 8.3 I. U./kg/min for 6 hours. H-U significantly improved both post-ischemic CBF and neurologic outcome. H-U was effective in treating brain damage when given 15 min after ischemia. These results suggest that H-U improved both post ischemic CBF and neurologic outcome owing to amelioration of the deterioration of microcirculation.
The effects of a PGI2 analogue (OP-41483), a thromboxane A2 synthetase inhibitor (OKY-046) and a Ca blocker (nifedipine) on the diameter of constricted basilar arteries and on the regional cerebral blood flow (r-CBF) in the brain stem were investigated in the cat delayed spasm model. The experiment was performed three days (72 hours) after artificial subarachnoid hemorrhage. The basilar artery was exposed transclivally, and more advanced vasospasm was produced by topical application of a lysed erythrocyte solution for 5 to 6 hours which demonstrated no more vascular dilatation even by topical application of papaverine hydrochloride (0.01mg/ml). In the delayed spasm model, the intravenous administaration of neither OP-41483 (8μg/kg), OKY-046 (60mg/kg) nor nifedipine (0.003mg/kg) affected the vascular diameter. OP-41483 increased r-CBF in the brain stem in 3, and nifedipine increased it in 4 out of the 5 studied delayed spasm models, whereas OKY-046 never increased r-CBF (n=5). There was no significant difference in the amount of fatty acids including arachidonic acid between normal and constricted arteries. This study suggests that thromboxane A2 is not the major factor of cerebral vasospasm and OKY-046 might not be effective on vascular diameter or r-CBF at the late spasm stage. However, the PGI2 analogue (OP-41483) and Ca blocker (nifedipine) may be effective in increasing r-CBF even at the late spasm stage.
The influence of reperfusion after complete global brain ischemia (CGBI) on blood brain barrier (BBB) permeability to evans blue dye (EB) was studied in dogs. The various durations of CGBI, from 10 to 18 minutes, were produced by clamping the ascending aorta with the aorta to the right atrium and the aorta to the femoral vein bypass circuit. Dogs were divided into four groups according to the duration of CGBI: dogs in group A, B, C, and D (n=6, in each group) suffered 10, 12, 15, and 18 minutes of CGBI, respectively. EB was injected 15 minutes after the reperfusion, and extravasation of EB in the cerebral cortex, thalamus, hippocampus, cerebellum and the brain stem were observed 30 minutes after the reperfusion. In this study, cerebral blood flow (CBF) and intracranial pressure (ICP) were also measured for the first 20 minutes after the reperfusion. Extravasation of EB were observed in three groups except for group A, and a tendency toward extravasation of EB in the cerebellum was recognized in group C and D. Reactive hyperemia and increase in ICP within 20 minutes after the reperfusion were also observed. In conclusion, not only ischemia but also the reactive hyperemia might increase BBB permeability.
Toxicokinetic study on organic solvents was carried out using the data obtained by controlled exposure experiments. Organic solvents used in the present study were chlorobenzene, toluene, m-xylene, p-xylene and trichloroethylene. Molar ratio of urinary metabolites to organic solvents inhaled was different among solvents and was between 7.7% and 70.8%. The relationship between the amount of exposed toluene and the amount of hippuric acid was linear. However, for m-xylene, the amount of its urinary metabolites was not so much in comparison with the amount of exposed solvent at higher level exposure of 1400ppm×hour. Simulation of the excretion curves of urinary metabolites after cessation of exposure to organic solvents was fit for the two-compartment exponential model. Using the parameters of one compartment model of the single exposure to these organic solvents, the estimated metabolite level curve obtained by repeated exposures could be drawn, and relationship between biological half lives and critical sampling time was discussed. In respect to the urinary metabolites, the excretion rate of metabolites in the urine collected at the end of exposure depended on the period of time from the last urination to the end of exposure.