Biomedical subjects

N Yamazaki

Publications and source records attributed to N Yamazaki.

At least 181 records · Page 10Linked to original sources

PubMed1989

Effects of idebenone on memory impairment induced in ischemic and embolization models of cerebrovascular disturbance in rats.

Two rat models of memory impairment in passive avoidance learning induced by cerebrovascular disturbance, were established to estimate the effects of a cerebral metabolic enhancer, idebenone. Transient and global cerebral ischemia in rats, produced by 4-vessel occlusion for 200 s immediately after the acquisition trial of passive avoidance learning, shortened the latencies in the retention test trial performed 24 h later. This retrograde amnesia was reversed significantly by idebenone administered orally or intraperitoneally at the doses of 10 and 30 mg/kg before the retention test trial. Idebenone at a dose of 10 mg/kg, given intraperitoneally before or immediately after the ischemia, also markedly inhibited the appearance of amnesia. In the second model, permanent and cerebral hemisphere embolization produced by injecting 2,000 microspheres into the internal carotid artery, significantly impaired passive avoidance learning performed 7 days later. The repeated administration of idebenone (30 mg/kg, i.p.). once a day after the embolization, significantly improved the impairment of passive avoidance learning in the embolized rats. Furthermore, physostigmine and arginine-vasopressin as reference compounds improved the impairment of passive avoidance learning in these models. These findings suggest that idebenone ameliorates memory impairment induced by cerebral vascular disturbance in rats.

Administration, Oral↗

PubMed1989

Idebenone improves learning and memory impairment induced by cholinergic or serotonergic dysfunction in rats.

The effects of idebenone, a cerebral metabolic enhancer, on learning and memory impairment in two rat models with central cholinergic or serotonergic dysfunction were investigated using positively reinforced learning tasks. A delayed alternation task using a T maze was employed to test the effect of idebenone on short-term memory impairment induced by a cholinergic antagonist, scopolamine. A correct response, defined as a turn toward the arm opposite to that in the forced run, was rewarded with food pellets. Scopolamine (0.2 and 0.5 mg/kg, i.p.) significantly decreased the correct responses to the chance level in the 60-s-delayed alternation task. The scopolamine (0.2 mg/kg, i.p.)-induced impairment of short-term memory was improved by idebenone (3-30 mg/kg, i.p.) or an acetylcholinesterase inhibitor, physostigmine (0.1 and 0.2 mg/kg, i.p.), administered simultaneously. The central serotonergic dysfunction model was produced by giving rats a diet deficient in tryptophan, a precursor of serotonin. The rats fed on a tryptophan-deficient diet (TDD) showed a slower learning process in the operant brightness discrimination task (mult V115 EXT) than did rats fed on a normal diet. Idebenone (60 mg/kg/day) admixed with the TDD decreased the number of lever-pressing responses emitted during the extinction periods. The percentage of correct responses was significantly higher in the idebenone-treated group than in the control TDD group. These results suggest that idebenone may improve both the impairment of short-term memory induced by a decreased cholinergic activity and the retardation of discrimination learning induced by central serotonergic dysfunction.

Acetylcholine↗

PubMed1989

Effects of idebenone on the levels of acetylcholine, choline, free fatty acids, and energy metabolites in the brains of rats with cerebral ischemia.

Cerebral ischemia was induced by a 200-s occlusion of both common carotid arteries in rats in which both vertebral arteries had been permanently cauterized. In the ischemic rats, a significant decrease in acetylcholine (ACh) and a marked increase in choline were observed in the cerebral cortex, hippocampus, striatum, and diencephalon. A slight increase in choline was also observed in the cerebellum and brain stem. Pretreatment with idebenone (10 mg/kg, i.p.) inhibited the decrease in ACh and the increase in choline in the forebrain regions. In addition, the same dose of idebenone inhibited the increments of lactate and free fatty acid contents and tended to inhibit the decrement of the ATP content in the cerebral cortex of the cerebral ischemic rats. These results indicate that idebenone inhibits the alteration of the ACh level and the disruption of membrane phospholipids in the brain of ischemic rats; these effects may be mediated by improved cerebral energy metabolism.

Acetylcholine↗

PubMed1989

Effects of idebenone on metabolism of monoamines and cyclic AMP formation in rats.

Idebenone, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, at a dose of 100 mg/kg (i.p.) markedly increased the level of 5-hydroxyindole-3-acetic acid (5-HIAA) in several brain regions without affecting monoamine contents in normal rats. In rats with cerebral ischemia, idebenone (10 mg/kg, i.p.) normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-hydroxytryptamine (serotonin, 5-HT) biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) decreased the levels of 5-HT to one-third of the control level 24 h after administration. Idebenone (10, 30, or 100 mg/kg, i.p.), administered 24 h after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreased in the hippocampus, diencephalon and brain stem in a dose-dependent manner. Idebenone (100 mg/kg, i.p.) stimulated the release of 5-HT in the dorsal hippocampus as determined by in vivo differential pulse voltammetry. Idebenone, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of hippocampus and diencephalon, and the formation of cyclic AMP in a concentration-dependent manner in rat diencephalon slice. This stimulation was almost completely blocked by methysergide, a 5-HT receptor blocker. Idebenone slightly and PCA markedly inhibited 5-HT uptake into hippocampus slices. The mechanism of the 5-HT releasing actions of idebenone in the hippocampal slices may be mediated through endogenous calcium. These results suggest that idebenone has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon, and brain stem of rats.

Animals↗

PubMed1989

Effects of strophanthidin on intracellular Ca2+ concentration and cellular morphology of guinea pig myocytes.

To study the role of cytosolic calcium concentration [( Ca2+]i) in the pathophysiology of Ca2+ overload, we used a digital image of calcium indicator signals (fura-2 fluorescence) from guinea pig myocytes. [Ca2+]i increased from 69(SEM 5) nmol.litre-1 (n = 15) to 204(45) nmol.litre-1 (n = 14) after 10 min perfusion with 100 mumol.litre-1 strophanthidin. The effects of strophanthidin on cellular morphology were associated with variable increases in [Ca2+]i of myocytes. [Ca2+]i was 263(9) nmol.litre-1 in the spontaneous contracting cells with "Ca2+ wave", and 784(103) nmol.litre-1 in rounded cells. There was a significant relationship (r = 0.77, p less than 0.001) between elevation of [Ca2+]i and shortening of longitudinal length of the cells. After 20 min pretreatment with 10 mumol.litre-1 ryanodine, strophanthidin (100 mumol.litre-1) did not cause spontaneous contractile activity, and induced a slower increase in [Ca2+]i than found previously with strophanthidin alone. We suggest that [Ca2+]i played a primary role in mediating irreversible injury in this study, and that the absolute value of [Ca2+]i was correlated with morphological changes. We also suggest that the Ca2+ release from the sarcoplasmic reticulum was related to the increase in [Ca2+]i and the spontaneous contracting activity.

Animals↗

PubMed1989

Mechanism of arrhythmias induced by palmitylcarnitine in guinea pig papillary muscle.

Long chain acyl carnitines, intermediates of free fatty acid metabolism, have been implicated in malignant arrhythmias occurring during myocardial ischaemia. To investigate the mechanism of arrhythmia induced by these compounds the electrophysiological effects of palmitylcarnitine (30, 100 and 300 mumol.litre-1) on guinea pig papillary muscles was examined using the microelectrode technique. Palmitylcarnitine caused a time and concentration dependent shortening of action potential duration, with an increase in both developed and resting tension. After attaining the peak value of developed tension, delayed afterdepolarisations and/or aftercontractions were observed in three out of eight muscles on exposure to 100 mumol.litre-1 palmitylcarnitine and in all 13 muscles on exposure to 300 mumol.litre-1, while arrhythmia occurred in one out of eight muscles and in seven out of 13 muscles during these exposures. The amplitude and the coupling interval of delayed afterdepolarisations were dependent on basic cycle length. Delayed afterdepolarisations, aftercontractions and arrhythmias were completely abolished by ryanodine (1 mumol.litre-1). Though low Ca2+ (0.1 mmol.litre-1) abolished these activities, verapamil (4 and 10 mumol.litre-1) did not suppress them. Palmitylcarnitine (300 mumol.litre-1) shortened action potential duration to the same degree during metabolic block of either oxidative phosphorylation or glycolysis as it did in muscles exposed to oxygenated Krebs solution. Under these conditions, delayed afterdepolarisation and/or aftercontractions appeared in all muscles. We conclude that palmitylcarnitine could cause Ca2+ overload and trigger activity due to delayed afterdepolarisations and could act on the cell membrane independently of cardiac metabolism. We suggest that palmitylcarnitine is a factor in arrhythmogenesis during myocardial ischaemia.

Action Potentials↗

PubMed1989

Effects of hydrogen peroxide on action potentials and intracellular Ca2+ concentration of guinea pig heart.

Oxygen free radicals and Ca2+ overload have been implicated in the genesis of reperfusion induced arrhythmia and injury. Effects of hydrogen peroxide (H2O2) on action potentials and intracellular Ca2+ concentration ([Ca2+]i) were studied using guinea pig papillary muscles and ventricular myocytes. High concentration of H2O2 (10 mmol.litre-1) caused delayed afterdepolarisations in all six papillary muscles, and induced triggered activity in 3/6 preparations. Pretreatment with ryanodine (1 mumol.litre-1) abolished delayed afterdepolarisations and triggered activity induced by H2O2. [Ca2+]i and morphological changes in isolated ventricular myocytes of guinea pig were measured using fura-2. Quiescent and rod shaped myocytes became shortened and rounded (contracture) after the application of 0.1 and 1 mmol.litre-1 H2O2. [Ca2+]i increased from the control values of 53 (SEM 4) and 62(8) nmol.litre-1 to 110(29) and 105(24) nmol.litre-1 (p less than 0.05 v control) when cells were shortened during perfusion with 0.1 and 1 mmol.litre-1 H2O2, respectively. The values were 130(26) nmol.litre-1 (p less than 0.05 v control) and 100(18) nmol.litre-1 (p less than 0.05 v control) when the cells became rounded during perfusion with 0.1 and 1 mmol.litre-1 H2O2. We suggest that the arrhythmia caused by Ca2+ overload was induced by H2O2, possibly by lipid peroxidation of cell membrane. H2O2 was also shown to shorten cells and cause cell contracture (rounding). The mechanism of cell injury is not likely to be due to the Ca2+ overload, since the increase in [Ca2+]i during perfusion with H2O2 was not large.

Action Potentials↗

PubMed1989

The role of the fibrinolytic system in acute myocardial infarction after a normal exercise test.

A 67-year-old man had an acute myocardial infarction with thrombosis in the left anterior descending artery shortly after normal exercise. We were able to measure the fibrinolytic components in this patient just prior to his developing acute myocardial infarction as well as during convalescence. In this case, marked increase in total plasminogen activator inhibitor-1 (PAI-1) antigen, mainly due to free PAI-1 antigen, was observed in basal conditions before the onset of acute myocardial infarction. On the appearance of ischaemia, plasminogen activator activity was suppressed, probably due to decreased tissue plasminogen activator antigen release and increased PAI activity, compared with that during convalescence. This suggests that some patients with coronary artery disease who have a high level of free PAI-1 antigen in basal conditions may have a strong tendency to develop acute myocardial infarction, due to further impaired fibrinolysis on the induction of ischaemia.

Acute Disease↗

PubMed1989

Patent ductus arteriosus with Eisenmenger's syndrome detected by first-pass study.

The case of a 20-year-old man with patent ductus arteriosus complicated with Eisenmenger's syndrome is described. Radionuclide angiocardiography characterized the abnormal pattern of blood flow through the central circulation to establish a diagnosis of patent ductus arteriosus with a significant right-to-left shunt, which had not been indicated by other clinical findings.

Adult↗

PubMed1989

Current status of melanoma treatment with interferon, cytokines and other biologic response modifiers in Japan.

This paper introduces the current status of melanoma treatment with various biologic response modifiers (BRMs) in Japan, with an emphasis on the clinical results of Interferon therapies. The authors also refer briefly to the current situation of interleukin-2 (IL-2) and tumor necrosis factor (TNF) in Japan. Many BRMs have been used in treatment of melanoma, e.g., IFN, IL-2, TNFs, BCG, MY-1 (DNA extracted from BCG), WPG (CWs of Bifidobacterium infantis, ATCC 15697), OK-432 (Picibanil, Streptococcus pyogenes preparation), bestatin, and forphenicinol. Some of these have completed clinical trials, while others are still undergoing clinical testing. Among IFN-alpha, beta, and gamma, intralesional administration of natural IFN-beta was found to be more effective than IFN-alpha for metastatic skin melanoma, the survival time of patients being prolonged by the administration of IFN-beta. IFN-gamma appeared to have lower efficacy than IFN-alpha and beta. The frequency of BRM application to melanoma treatment will increase. The authors foresee that combinations with radio- and/or other chemotherapy will be more common than the single use of a BRM, especially in the case of IFN.

Biological Factors↗

PubMed1989

Mechanical properties of poly(alkyl alpha-fluoroacrylate)s as denture-base materials.

alpha-Fluoro-substituted acryl polymers, poly(methyl alpha-fluoroacrylate) (PMFA) and poly(2,2,2-trifluoroethyl alpha-fluoroacrylate) (P3FFA) were investigated for extension to denture-base resins. PMFA, in which fluorine attaches to the polymer chain, had excellent mechanical properties: For instance, compressive and bending strength and bending modulus were 50% higher than those of PMMA. P3FFA, in which fluorines are substituted at the end of the pendant alkyl ester, showed poor mechanical properties. Contrary to expectations, the amount of water sorption of PMFA was about twice that of PMMA, while that of P3FFA was almost zero. Copolymers of MFA and 3FFA were prepared in an attempt to optimize the mechanical properties and the water sorption. The copolymer with 40% of 3FFA showed higher compressive, diametral tensile, and bending strength; in particular, the bending modulus and water resistance were about 35% and 20% higher, respectively, than those of PMMA. Improvement of the mechanical properties and increase of the water sorption of PMFA may be due to intermolecular forces induced by polarizability of the fluorine and carboxy group along the polymer chain. Decrease of the water sorption by fluorine substituted on the alkylester group as in P3FFA may be due to higher hydrophobicity and steric effect of the fluoroalkyl substitute.

Acrylic Resins↗

PubMed1989

Oxygen-derived free radicals related injury in the heart during ischemia and reperfusion.

It has been suggested recently that oxygen-derived free radicals may play an important role in the genesis of reperfusion injury and arrhythmias. Free radicals have a very short half-life (ranging from mili- to microseconds), hence almost all the reports supporting the free radical hypothesis of reperfusion cell injury have been indirect. We have applied electrone spin resonance spectrometry to measure directly the amount of free radicals generated during ischemia and reperfusion. The concentration of free radicals in mitochondria increased significantly during ischemia (for 20 and 40 min). The concentration of free radicals after reperfusion was higher than that during ischemia, and a large amount of free radical generation occurred within the first 60 sec of reperfusion and returned to the level of prereperfusion at 5 min after reperfusion. The concentration of free radicals in the reperfusion-induced ventricular fibrillation group was significantly higher than that in the non-occurrence group. The administration of liposomal superoxide dismutase reduced the incidence of reperfusion-induced ventricular fibrillation and that prevented the free radical generation during reperfusion. This study showed that enhanced generation of free radicals occurred at the onset of ventricular fibrillation and that free radical scavenger prevented the development of arrhythmias and free radical generation during reperfusion. We have obtained more circumstantial evidence for an involvement of free radicals in the genesis of reperfusion injury and arrhythmias.

Animals↗

PubMed1989

Acute myocardial infarction shortly after negative exercise test and reperfusion by intracoronary thrombolysis.

A 67-year-old man developed an acute myocardial infarction shortly after normal exercise testing. His clinical history and findings from emergency coronary arteriography suggested that coronary artery spasm followed by intraluminal thrombosis might have been responsible for the myocardial infarction. Although intracoronary thrombolysis two hours after the onset of chest pain provided continued patency of an occluded vessel, serial myocardial perfusion scintigraphies documented myocardial injury, which was probably induced by reperfusion, rather than myocardial salvage.

Aged↗

PubMed1989