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Biomedical subjects

Y Satoh

Publications and source records attributed to Y Satoh.

At least 109 records · Page 6Linked to original sources
PubMed2000

QT-prolonging effects of sparfloxacin, a fluoroquinolone antibiotic, assessed in the in vivo canine model with monophasic action potential monitoring.

Sparfloxacin, a fluoroquinolone antibacterial agent, prolongs cardiac repolarization, which may predispose to torsades de pointes. This study was designed to assess simultaneously the hemodynamic and electrophysiologic effects of sparfloxacin using the halothane-anesthetized, closed-chest in vivo canine model (n = 6). Sparfloxacin was intravenously administered in the following two doses with a pause of 20 min, a clinically relevant dose of 3.0 mg/kg/10 min and a 10 times higher dose of 30 mg/kg/10 min. After the low dose of sparfloxacin, cardiac output increased, heart rate decreased, and ventricular repolarization and refractory periods were prolonged. After the high dose, cardiac output increased, whereas heart rate and mean blood pressure decreased, and ventricular repolarization and effective refractory periods were prolonged. The increment was greater in repolarization than in refractoriness, indicating an increase of electrical vulnerability. Because sparfloxacin prolonged repolarization in a reverse use-dependent manner, its negative chronotropic effect may have potentiated the QT prolongation. Left ventricle preload, left ventricular contraction, and AV nodal as well as intraventricular conduction were minimally affected. These results suggest that caution should be used when administering sparfloxacin to patients having risk factors for QT prolongation.

Action Potentials↗
PubMed2000

Can PET data differentiate Alzheimer's disease from vascular dementia?

The present study endeavored to differentiate Alzheimer's disease (AD) from vascular dementia (VaD) by comparing the metabolic and hemodynamic parameters. Positron emission tomographic (PET) studies were carried out in 13 patients with probable AD and 20 patients with VaD. PET findings were not included in the diagnostic criteria of AD or VaD. Using oxygen-15 labeled compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), cerebral blood volume, and vascular transit time (VTT) were measured quantitatively during the resting state. To evaluate vascular reactivity (VR), CBF was also measured during 7% CO2 inhalation. Regional CBF from the parietal cortex positively correlated with the neuropsychological scores in both AD and VaD groups. The typical parietotemporal pattern of hypoperfusion and hypometabolism was observed in the AD group, whereas the frontal lobe including the cingulate and superior frontal gyri were predominantly affected in the VaD group. The occipital cortex was preserved in both groups. A significant increase of the OEF was found in the parietotemporal areas in the AD group. No significant prolongation was seen with VTT. There was a marked difference in VR between the two groups: VR was depleted in the VaD group, whereas VR was normal in the AD group. The increased OEF with preserved vascular reserve seen in AD may implicate participation of a vascular factor in the pathogenesis of AD, possibly at the capillary level. Thus, PET provides important functional information in discriminating AD from VaD by comparing the patterns of hypoperfusion and/or hypometabolism, and in the understanding of the underlying hemodynamic pathophysiology.

Aged↗
PubMed2000

Dual CCK-A and CCK-B receptor antagonists (II). Preparation and structure activity relationships of 5-alkyl-9-methyl-1,4-benzodiazepines and discovery of FR208419.

In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of pancreatitis, we have prepared various 5-alkyl-9-methyl-1,4-benzodiazepines. From the compounds prepared, 1-cyclohexyl-carbonylmethyl-5-ethyl-9-methyl-3- (m-tolylureido)-2-oxo-1,4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receptor and 8-fold more potent CCK-B receptor binding activity than (S)-40. The biological activity after p.o. administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.

Animals↗
PubMed2000

Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential.

Haloperidol has been reported to induce polymorphic ventricular arrhythmias associated with QT prolongation. The present study examined the effects of magnesium sulfate on the cardiovascular system suffering from haloperidol overdose. Beagle dogs were anesthetized with halothane inhalation under the monitoring of monophasic action potential (n=6). After intravenous administration of an intentionally high dose of haloperidol (3 mg/kg), the heart rate (HR), left ventricular contraction and mean blood pressure (BP) decreased, and the ventricular repolarization phase and effective refractory period (ERP) were prolonged, the increment in the former being than in the latter, indicating an increase in electrical vulnerability. However, preload of the left ventricle, cardiac output (CO) and cardiac conduction were hardly affected. An additional intravenous dose of 100 mg/kg of magnesium sulfate increased the preload of the left ventricle, and decreased the HR, mean BP, left ventricular contraction and CO, suppressed atrioventricular as well as intraventricular conduction, and prolonged the ventricular repolarization phase and ERP, in which the increment of the repolarization phase was similar to that of ERP. These results suggest that magnesium sulfate hardly affects the electrical vulnerability of the heart during haloperidol overdose, but may block the calcium, potassium and sodium channels, which may explain its antiarrhythmic action.

Action Potentials↗
PubMed2000

Comparison of the electropharmacological effects of verapamil and propranolol in the halothane-anesthetized in vivo canine model under monophasic action potential monitoring.

The cardiovascular profile of verapamil was assessed in the halothane-anesthetized canine model and compared with that of propranolol. Verapamil was infused at the rates of 1, 3 and 10 microg x kg(-1) x min(-1) (n=6), whereas propranolol was administered at a fixed rate of 10 microg x kg(-1) x min(-1) (n=6). Each infusion was performed over 30 min, and the parameters were assessed for 20-30 min after the start of each infusion. Verapamil in a dose of 10 microg x kg(-1) x min(-1) significantly suppressed atrio-ventricular (AV) node conduction and slightly decreased the mean blood pressure, but no significant change was detected in the left ventricular end-diastolic pressure, maximum upstroke velocity of the left ventricular pressure, sinus automaticity, double product, cardiac output, intraventricular conduction, and ventricular repolarization phase and refractoriness. Propranolol suppressed AV node conduction to an extent similar to that of verapamil, but it also inhibited intraventricular conduction, sinus automaticity and ventricular contraction, increased the ventricular refractoriness, and decreased the double product and cardiac output, without any significant change in the other variables measured. These results suggest that verapamil can selectively affect the AV node, and that the greater part of the suppressive action of propranolol on the multiple cardiovascular performance is through a beta-blocking action and direct membrane effect, although the halothane inhalation itself might have modified each of the drug's effects. The abbreviation of the relative refractory period of the ventricle by propranolol may show its potential utility for re-entry type ventricular tachycardia.

Action Potentials↗
PubMed2000

Effects of mexiletine on the canine cardiovascular system complicating cisapride overdose: potential utility of mexiletine for the treatment of drug-induced long QT syndrome.

The purpose of this study was to test the potential utility of mexiletine for the treatment of drug-induced long QT syndrome in vivo. Beagle dogs were anesthetized with halothane inhalation (n =7). Monophasic action potential (MAP) of the right ventricle, ECG, systemic and left ventricular pressure, cardiac output and effective refractory period (ERP) of the right ventricle were measured. The electrically vulnerable period was estimated by the difference between MAP duration and ERP. An intentionally high dose of 1 mg/kg, i.v. of cisapride decreased the heart rate, mean blood pressure, left ventricular contraction and cardiac output and prolonged the ventricular repolarization phase and ERP, in which the increment was greater in the former than in the latter, indicating the increase of electrical vulnerability. The left ventricular end-diastolic pressure and atrioventricular as well as intraventricular conduction were hardly affected. Additional administration of an antiarrhythmic dose of 3 mg/kg, i.v. of mexiletine increased the heart rate, decreased the left ventricular contraction and cardiac output, suppressed the atrioventricular as well as intraventricular conduction, and prolonged the ERP, but shortened the ventricular repolarization phase. There was no change in the afterload and preload of the left ventricle. Thus, mexiletine decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced long QT syndrome.

Action Potentials↗
PubMed2000

Different domains of Sgs1 are required for mitotic and meiotic functions.

The SGS1 of Saccharomyces cerevisiae is a homologue for human Bloom's syndrome, Werner's syndrome, and Rothmund-Thomson's syndrome causative genes. Disruptants of SGS1 show high sensitivity to methyl methanesulfonate (MMS) and hydroxyurea, and hyper recombination phenotypes including interchromosomal homologous recombination in mitotic growth. In addition, sgs1 disruptants show poor sporulation and a reduced level of meiotic recombination as assayed by return-to-growth. We examined domains of Sgs1 required for mitotic and meiotic functions of Sgs1 by transfecting variously mutated SGS1 into sgs1 disruptants. The N-terminal 1-401 amino acid region was required for complementation of MMS sensitivity and suppression of hyper heteroallelic recombinations of sgs1 disruptants in mitotic growth and for complementation of poor sporulation and of reduced meiotic recombination. Although the N-terminal 1-125 amino acid region was absolutely required for the complementation of MMS sensitivity and suppression of hyper heteroallelic recombinations in mitotic growth, it was dispensable for the meiotic functions. In contrast, the highly acidic region (400-596 amino acid) was dispensable for the mitotic functions but a deletion of this region affected the meiotic functions. The C-terminal 1271-1350 amino acid region containing a HRDC (helicase and RNaseD C-terminal) domain was dispensable for the mitotic and meiotic functions. Although DNA helicase activity of Sgs1 was not required for Sgs1 to complement the meiotic functions, a deletion of helicase motifs III-IV (842-1046 amino acid) abolished the complementing activity of Sgs1, indicating that a structurally intact helicase domain is necessary for Sgs1 to fulfill its meiotic functions.

Alleles↗
PubMed2000

Prevention of nephrotoxicity of cisplatin by repeated oral administration of ebselen in rats.

The ability of ebselen, which exhibits glutathione peroxidase (GSH-Px)-like activity, to prevent cisplatin (CDDP)-induced nephrotoxicity was examined in rats. CDDP (6 mg/kg [20 micromol/kg] body weight) was injected intraperitoneally. In subgroups, daily ebselen doses of 2.75 (10 micromol), 5.5 (20 micromol), or 11.0 mg (40 micromol)/kg body weight were administrated orally 1 hour prior to CDDP treatment. Treatment with CDDP alone resulted in significantly increased plasma creatinine (Cr) and blood urea nitrogen (BUN) levels. Repeated administration of 5.5 and 11.0 mg/kg ebselen prevented the CDDP-induced elevation of plasma Cr and BUN levels and protected against kidney damage. Relative to controls, rat that received CDDP treatment displayed a decreased ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator directly related to oxidative stress, and elevated malondialdehyde (MDA) levels in the kidney. In comparison with controls, activity of GSH-Px activity, which antioxidant enzyme, was also reduced in the kidney of rats treated with CDDP. Repeated administration of 5.5 or 11.0 mg/kg ebselen prevented CDDP-induced alteration of GSH/GSSG ratios, MDA levels, and GSH-Px activity; however, no protection against CDDP was observed with administration of 2.75 mg/kg ebselen. Effective protection of CDDP-induced nephrotoxicity with ebselen was observed only when the molar amount of each daily ebselen treatment equaled or exceeded

Administration, Oral↗
PubMed2000

Effect of low temperatures on compound 48/80-induced intracellular Ca2+ changes and exocytosis of rat peritoneal mast cells.

It has been well documented that compound 48/80-induced exocytosis of mast cells is accompanied by changes in intracellular Ca2+ concentration ([Ca2+]i) showing a biphasic pattern: an initial phase which constitutes an abrupt increase, followed by a plateau phase. The former is caused by Ca2+ release from intracellular Ca2+ stores, and the latter is the result of secondary Ca2+ influx. Low temperatures lead to the inhibition of exocytosis, but the precise mechanism remains unclear. The present study aims to reveal whether [Ca2+]i changes are affected by the environmental temperature. To this end, we developed a novel imaging method to record [Ca2+]i changes and exocytotic processes simultaneously. Rat peritoneal mast cells were loaded by Indo-1/AM or Fluo-3/AM for measuring [Ca2+]i, and the exocytosed granule matrices were stained by sulforhodamine-B. Cells were stimulated by compound 48/80, and [Ca2+]i changes and exocytosis were recorded by means of a real-time confocal microscope. At 37 degrees C, [Ca2+]i changes in stimulated mast cells showed a sustained plateau phase. Granule discharge was observed at the cell surface, and, in addition, most of the intracellular granule matrices were involved in compound exocytosis. The granule discharge and compound exocytosis proceeded over a period of a few minutes. At 4 degrees C, the plateau phase of [Ca2+]i changes declined rapidly, although the initial phase was not suppressed. Granule discharge occurred at the cell surface, but compound exocytosis ceased within a few minutes. These findings indicate that a low temperature inhibits compound exocytosis which can be caused by Ca2+ influx. The present imaging method represents a powerful tool for investigating the stimulus-secretion coupling of mast cells.

Aniline Compounds↗
PubMed2000

Effect of cilostazol on cerebral blood flows in chronic stage of cerebral circulation.

In order to find out the difference between cilostazol and ticlopidine hydrochloride in the cerebral vasodilating effect in the chronic stage of cerebral infarction, cerebral blood flows were measured while the patients were on ticlopidine hydrochloride and after ticlopidine hydrochloride was switched to cilostazol. Single photon emission computed tomography (SPECT) was performed using Prism 2000XP gamma camera system. Ultrasound examinations of the carotid artery was performed using Ultramark 9. The blood flows in the frontal white matter, temporal cortex and occipital cortex after cilostazol were significantly higher than those before cilostazol. The peak systolic velocity, time-averaged peak velocity and volume flow after cilostazol were significantly higher than those before cilostazol. The total cholesterol, triglyceride and apolipoprotein B concentrations after cilostazol were significantly lower than those before cilostazol. The present study suggests that cilostazol has better influence on cerebral circulation than ticlopidine hydrochloride in the chronic stage of cerebral infarction.

Aged↗
PubMed2000

[Three-channeled aortic dissection: selection of surgery based on the images].

Three patients with 3-channeled dissection were operated upon. Images of the dissection were enlargement of the false lumens, compression of the true lumen by enlarged false lumens and visceral arteries of false lumen origin. These prevent the use of cardiopulmonary bypass (CPB) and cause malperfusion of the viscera. Three-channeled dissecion is easy to rupture for its peculiar anatomy and total repair of the thoraco-abdominal aorta is mandatory. Fenestration brings functional recovery of malperfused viscera and enables the patients to be placed on CPB for total repair. Two patients underwent infrarenal and descending aorta fenestration followed by the total repair of thoraco-abdominal aorta successfully. A third patient has been placed on the strict CT follow-up following the infrarenal fenestration.

Adult↗
PubMed1999

Modulation of actomyosin ATPase by thiotetromycin is mediated through conformational change of actin.

Thiotetromycin isolated from the culture broth of Streptomyces sp. strain OM-674 slightly enhanced the superprecipitation and the ATPase activity of myosin B from skeletal muscle. The ATPase activity of troponin-tropomyosin-free myosin B was inhibited by thiotetromycin. The inhibitory effect of thiotetromycin was significantly attenuated by troponin-tropomyosin complex. The ATPase activity of actomyosin reconstituted from actin and myosin was inhibited by pretreatment of actin with thiotetromycin. Thiotetromycin induced a concentration-dependent decrease in the fluorescence intensity of actin and pyrenyl-F-actin. By using surface plasmon resonance (SPR), it was proved that thiotetromycin bound to actin. Thiotetromycin caused a concentration-dependent decrease in sedimentation of F-actin by hard centrifugation. This was a cross-correlation among the concentration-inhibition curves for thiotetromycin in the activity of actomyosin ATPase and the fluorescence intensity. These results suggest that thiotetromycin binds to actin to cause a conformational change, resulting in modulation of the interaction between actin and myosin, and in depolymerization of F-actin.

Actins↗
PubMed1999

Combined NK1 and NK2 tachykinin receptor antagonists: synthesis and structure-activity relationships of novel oxazolidine analogues.

We report herein the synthesis and structure-activity relationships of a series of novel oxazolidine analogues with regards to NK1 and NK2 tachykinin receptor binding affinity. Among this series of oxazolidine analogues, some compounds exhibited excellent high binding affinities for both NK1 and NK2 receptors. In addition, we describe the inhibitory effect in vivo on SP-induced airway vascular hyperpermeability and NKA-induced bronchoconstriction in guinea pigs.

Animals↗
PubMed1999

CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth.

We have recently demonstrated that murine and human tumors induce apoptosis of dendritic cells (DC). Here, we evaluated the effect of CD40 ligation on the survival of tumor-associated DC and tumor growth. Retroviral transduction of MC38 colon carcinoma cells with the CD154 gene resulted in inhibition of tumor growth. This effect was abrogated in IL-12 knockout mice. Immunohistochemical analysis revealed an increase in CD11c+ (N418) and CD8+ but not NLDC-145+ cells in CD154-transfected tumors in wild-type mice. This increase was less pronounced in IL-12-deficient mice. In vitro, overexpression of CD154 on tumor cells significantly decreased the level of tumor-induced DC apoptosis. Surprisingly, the CD154-induced protection of DC from tumor-induced apoptosis was IL-12 independent in vitro, suggesting an IL-12-dependent and an IL-12-independent mechanism of CD154-induced anti-tumor immunity. Thus, our data suggest a new strategy to improve immunotherapy of cancer by protecting DC from tumor-induced apoptosis.

Animals↗
PubMed1999

Effects of AIF4- and ATP on intracellular calcium dynamics of crypt epithelial cells in mouse small intestine.

Previous digital imaging analysis of intracellular calcium ion ([Ca2+]i) dynamics in the crypt of the small intestine showed little response by most columnar cells to cholinergic and adrenergic agonists. The objective of the present study was to demonstrate whether G-protein activators and other transmitters elicit [Ca2+]i changes in crypt cells. We used digital imaging to analyze spatiotemporal dynamics of [Ca2+]i in Fura-2/AM-loaded isolated crypts of mouse duodenum and ileum. A1F4- increased [Ca2+]i in crypt columnar cells. In many cases, we observed [Ca2+]i oscillations, which were synchronized throughout the entire crypt. The oscillations were blocked by octanol. ATP, but not adenosine, caused a [Ca2+]i increase in middle crypt-regions of the duodenum and upper regions of the ileum, and the [Ca2+]i wave propagated towards the crypt bottom. The ATP-induced [Ca2+]i increase was prevented by pretreatment with thapsigargin or suramin, but not by La3+ or an extracellular Ca(2+)-free environment. Neither dopamine, 5-hydroxytryptamine (5-HT), histamine, vasoactive intestinal peptide, substance P. cholera toxin, nor guanylin had significant effects. The [Ca2+]i dynamics of Paneth cells were independent of the AlF4(-)-induced synchronous oscillations of columnar cells and of the ATP-induced [Ca2+]i wave. In conclusion, crypt columnar cells have [Ca2+]i-dependent intracellular signaling mechanisms that are linked with G proteins, and by which the cells communicate with each other. ATP elicited [Ca2+]i mobilization from columnar cells via P2 receptors, although some regional differences were noted between the duodenum and ileum.

Adenosine Triphosphate↗