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Biomedical subjects

K Yoshioka

Publications and source records attributed to K Yoshioka.

At least 127 records · Page 7Linked to original sources
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 1st communication: phosphodiesterase III inhibitory effect and class III antiarrhythmic effect in guinea-pig heart.

In order to clarify the mechanism of action of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel cardiotonic agent with Ca++ sensitizing action, its effects on contractile force, atrial rate and action potential, and on the activity of Na+, K(+)-ATPase and phosphodiesterase (PDE) I-IV were studied in the guinea-pig heart. SCH00013 exerted a positive inotropic effect (PIE) on isolated right ventricular papillary muscles in a concentration-dependent manner (EC50 = 9.2 mumol/l): the relative potency was milrinone > SCH00013 > vesnarinone. The PIE of SCH00013 was not influenced by propranolol, a beta-blocker, and SCH00013 did not affect the activity of cardiac Na+, K(+)-ATPase. The PIE of SCH00013 was partially inhibited by carbachol, a muscarinic receptor agonist, which implies a partial contribution of the cAMP-dependent mechanism to the PIE. SCH00013 inhibited the activity of PDE III selectively, but the potency was weak: the IC50 value was 64.9 mumol/l, which was 46 and 3.9 times less potent than those of milrinone and vesnarinone, respectively. SCH00013 and vesnarinone elicited a moderate decrease in the rate of beating of isolated right atria, while milrinone increased it. SCH00013 markedly prolonged the action potential duration and the effective refractory period with no change in the resting membrane potential and dV/dtmax, an indication that SCH00013 may suppress the activity of delayed rectifying K+ channels. These results indicate that SCH00013, that primarily acts as a Ca++ sensitizer, possesses a weak selective PDE III inhibitory effect. The potential positive chronotropic effect of SCH00013 due to PDE III inhibition may be offset by its effect on K+ channels.

Action Potentials↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs.

In vivo cardiovascular effects and bioavailability of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel cardiotonic agent, were investigated. In anesthetized dogs, intravenous administration of SCH00013 (0.3-10 mg/kg) increased maximum rate of rise in left ventricular pressure (LVdP/dtmax) in a dose-dependent manner with no change in heart rate (HR) and, at the dose of 3 mg/kg or higher, at which the increase in LVdP/dtmax reached the maximum, it decreased blood pressure. In conscious dogs, oral administration of SCH00013 (1-10 mg/kg) also increased LVdP/dtmax dose-dependently with no change in HR. The increase in the plasma concentration of orally administered SCH00013 (3 mg/kg) was parallel to the increase in LVdP/dtmax. The areas under the plasma concentration versus time curve (AUC0-24 h) after oral and intravenous administration of SCH00013 (3 mg/kg) were essentially identical (15.3 +/- 2.0 micrograms.h/ml and 16.5 +/- 2.1 micrograms.h/ml, respectively). These results suggest that oral bioavailability of SCH00013 is notably high. In conclusion, the positive inotropic effect of SCH00013 with neither elevation of HR nor excessive hypotension, as well as the high oral bioavailability of this compound, may provide a beneficial pharmacological treatment of the patients with congestive heart failure.

Administration, Oral↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 3rd communication: stereoselectivity of the enantiomers in cardiovascular effects.

The cardiovascular effects of the enantiomers, (+)-SCH00013 and (-)-SCH00013, of a novel cardiotonic agent 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) were investigated in vitro and in vivo. The enantiomers of SCH00013 elicited an equipotent positive inotropic effect in isolated guinea-pig papillary muscles. Both of the enantiomers had a modest negative chronotropic effect in isolated guinea-pig right atria and the difference in the chronotropic effects of the enantiomers was not significant. In anesthetized dogs, both enantiomers increased LVdP/dtmax without change in heart rate and slightly decreased blood pressure. These hemodynamic effects of the enantiomers were not significantly different from each other. (+)-SCH00013 and (-)-SCH00013 increased the extent of cell shortening in association with only a small increase in the Ca++ transients in indo-1-loaded rabbit cardiomyocytes, and both the increases in cell shortening and Ca++ transients were not significantly different between the enantiomers. Both isomers equally shifted the relationships between the increases in the cell shortening and Ca++ transients to the left and upward as compared with the relationships for the elevation of extracellular Ca++ concentration and isoproterenol, which indicates that the effectiveness of the Ca++ sensitizing effects of the enantiomers are almost equivalent. The enantiomers of SCH00013 showed equipotent inhibitory effect on the phosphodiesterase (PDE) III activity. The maximal extent and the potency of prolonging effect of the two enantiomers on the effective refractory period were also the same. Thus, the efficacy and potency of the effects on the cardiovascular parameters such as myofibrillar Ca++ sensitivity, PDE III activity and the effective refractory period for the both enantiomers of SCH00013 are equivalent, indicating that the cardiovascular effects of SCH00013 may be due to equal contribution of both enantiomers.

Anesthesia↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Animals↗
PubMed1999

Characterization of a new Arabidopsis mutant exhibiting enhanced disease resistance.

In many plant-pathogen interactions, resistance is associated with the synthesis and accumulation of salicylic acid (SA) and pathogenesis-related (PR) proteins. At least two general classes of mutants with altered resistance to pathogen attack have been identified in Arabidopsis. One class exhibits increased susceptibility to pathogen infection; the other class exhibits enhanced resistance to pathogens. In an attempt to identify mutations in resistance-associated loci, we screened a population of T-DNA tagged Arabidopsis thaliana ecotype Wassilewskija (Ws) for mutants showing constitutive expression of the PR-1 gene (cep). A mutant was isolated and shown to constitutively express PR-1, PR-2, and PR-5 genes. This constitutive phenotype segregated as a single recessive trait in the Ws genetic background. The mutant also had elevated levels of SA, which are responsible for the cep phenotype. The cep mutant spontaneously formed hypersensitive response (HR)-like lesions on the leaves and cotyledons and also exhibited enhanced resistance to virulent bacterial and fungal pathogens. Genetic analyses of segregating progeny from outcrosses to other ecotypes unexpectedly revealed that alterations in more than one gene condition the constitutive expression of PR genes in the original mutant. One of the mutations, designated cpr20, maps to the lower arm of chromosome 4 and is required for the cep phenotype. Another mutation, which has been termed cpr21, maps to chromosome 1 and is often, but not always, associated with this phenotype. The recessive nature of the cep trait suggests that the CPR20 and CPR21 proteins may act as negative regulators in the disease resistance signal transduction pathway.

Arabidopsis↗
PubMed1999

Drug sensitivities of the primary afferents and their changes after inflammation.

This study explored the possibility that altered sensitivities of the dorsal root and dorsal root ganglion to neuroactive substances released in inflamed tissue may be involved in radicular pain. The chemical sensitivities of the dorsal root and ganglion of rats were examined by monitoring nerve membrane potential. Endogenous pain inducing substances such as bradykinin, serotonin, acetylcholine, and histamine caused depolarizations of the dorsal root and the ganglion. Application of bradykinin or capsaicin to the dorsal root and ganglion on the isolated spinal cord preparation evoked spinal reflex activities in the lumbar ventral root. These results suggest that, when pain inducing substances are released at the dorsal root or its ganglion, they may initiate action potentials and cause pain. As an inflammation model, chromic gut was tied loosely around the lower lumbar nerve root. The dorsal root of the surgically treated rats showed an increased sensitivity to bradykinin when compared with sham operated rats. In contrast, the sensitivity of the dorsal root to gamma-aminobutyric acid, a major inhibitory transmitter in the spinal cord, was decreased. This result suggests that these reciprocal changes in the sensitivities of the dorsal root may play an important role in the pathogenesis of chemical radiculitis.

Afferent Pathways↗
PubMed1999

The role of intrahepatic gammadelta-T cells for liver injury induced by Salmonella infection in mouse.

Liver injury was induced after infection with Salmonella choleraesuis 31N-1. In T-cell receptor-delta knockout mice, serum alanine transferase level was significantly decreased in comparison with normal control mice after Salmonella infection. On the contrary, in vivo administration of anti-gammadelta T-cell receptor monoclonal antibody (UC7-13D5) to stimulate gammadelta-T cells in infected mice significantly increased serum alanine transferase level but decreased bacterial growth compared with infected mice given control antibody (UC8; hamster IgG). These data suggest that gammadelta-T cells have effector activities not only for protection but also for liver injury during Salmonella infection.

Alanine Transaminase↗
PubMed1999

Randomized controlled trial of lymphoblastoid interferon alpha for chronic hepatitis C (comparison of 9-MU and 6-MU doses). IFN Treatment Group of Affiliated Hospitals of the Third Department of Internal Medicine at Nagoya University School of Medicine.

OBJECTIVE: We conducted a randomized controlled trial to compare the efficacy of two different dosages of lymphoblastoid interferon alpha (IFN) for the treatment of chronic hepatitis C. METHODS: Eighty-four patients with chronic hepatitis C were enrolled and randomly assigned into the two groups; group A was treated with 6 million units (MU) and group B with 9 MU daily for the first 2 wk, and then thrice weekly for an additional 14 or 22 wk. RESULTS: Eighty patients were evaluated (39 patients in group A and 41 in group B); 14 patients in group A (35.9%) and 15 in group B (36.6%) obtained sustained response. The percentages of patients who became negative for HCV RNA at the end of the second wk differed slightly between the groups, without statistical significance (56.4% and 68.3%). When assessed in detail, patients with genotype 1 and < 1 Meq/ml of viral load became negative for HCV RNA significantly more frequently in group B (eight of eight) than in group A (three of seven) (p < 0.05) at the end of the second week, whereas the sustained response rate was similar between the groups (five of eight and four of seven). Predictors of sustained response by multivariate analysis were low viral load (< 1.0 Meq/ml) and negativity of HCV RNA at the end of the second wk of IFN. CONCLUSIONS: The results indicated that there was no difference in sustained response rate between the 6-MU and 9-MU doses. The earlier disappearance of HCV RNA, at the end of the second wk or at least by the end of the fourth week, is an essential condition for sustained response.

Antiviral Agents↗
PubMed1999

TT virus infection in hemodialysis patients.

OBJECTIVE: Recently, TT virus (TTV), associated with posttransfusion hepatitis, was discovered. Prevalence of TTV infection in maintenance hemodialysis (HD) units and its pathogenicity to liver was investigated. METHODS: A total of 115 patients on HD were assessed for presence of serum TTV. DNA was purified from sera, and nested polymerase chain reaction was done for the detection of TTV DNA. RESULTS: TTV was detected in 59 patients on HD (51.3%), as compared with healthy blood donors (15 of 91 [16.5%], p < 0.0001). Serum HCV RNA and HBs antigen were positive in 16 and three patients, respectively. The prevalence rate of TTV was already 58.3% in the patients on HD for only 1 yr, and did not change according to the duration of HD until 15 yr on HD. TTV was positive in 51.2% (43 of 84) of the patients with history of blood transfusion, and in 51.6% (16 of 31) of those without it. In HCV-negative patients, alanine aminotransferase (ALT) levels of TTV-positive patients were similar to those of TTV-negative patients. Contrarily, in HCV-positive patients, ALT levels were more frequently > or =15 IU/L in TTV-positive patients (14 of 18) than in TTV-negative patients (five of 15) (p < 0.05). CONCLUSIONS: TTV infection is remarkably prevalent in patients on HD and in healthy blood donors. It is suggested that TTV generally does not cause liver disease by itself, but there remains the possibility that TTV may aggravate liver disease caused by HCV.

Aged↗
PubMed1999

JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway.

The major components of the mitogen-activated protein kinase (MAPK) cascades are MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). Recent rapid progress in identifying members of MAPK cascades suggests that a number of such signaling pathways exist in cells. To date, however, how the specificity and efficiency of the MAPK cascades is maintained is poorly understood. Here, we have identified a novel mouse protein, termed Jun N-terminal protein kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), by a yeast two-hybrid screen, using JNK3 MAPK as the bait. Of the mammalian MAPKs tested (JNK1, JNK2, JNK3, ERK2, and p38alpha), JSAP1 preferentially coprecipitated with the JNKs in cotransfected COS-7 cells. JNK3 showed a higher binding affinity for JSAP1, compared with JNK1 and JNK2. In similar cotransfection studies, JSAP1 also interacted with SEK1 MAPKK and MEKK1 MAPKKK, which are involved in the JNK cascades. The regions of JSAP1 that bound JNK, SEK1, and MEKK1 were distinct from one another. JNK and MEKK1 also bound JSAP1 in vitro, suggesting that these interactions are direct. In contrast, only the activated form of SEK1 associated with JSAP1 in cotransfected COS-7 cells. The unstimulated SEK1 bound to MEKK1; thus, SEK1 might indirectly associate with JSAP1 through MEKK1. Although JSAP1 coprecipitated with MEK1 MAPKK and Raf-1 MAPKKK, and not MKK6 or MKK7 MAPKK, in cotransfected COS-7 cells, MEK1 and Raf-1 do not interfere with the binding of SEK1 and MEKK1 to JSAP1, respectively. Overexpression of full-length JSAP1 in COS-7 cells led to a considerable enhancement of JNK3 activation, and modest enhancement of JNK1 and JNK2 activation, by the MEKK1-SEK1 pathway. Deletion of the JNK- or MEKK1-binding regions resulted in a significant reduction in the enhancement of the JNK3 activation in COS-7 cells. These results suggest that JSAP1 functions as a scaffold protein in the JNK3 cascade. We also discuss a scaffolding role for JSAP1 in the JNK1 and JNK2 cascades.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Creatinine clearance as a substitute for the glomerular filtration rate in the assessment of glomerular hemodynamics.

A method for the clinical assessment of glomerular hemodynamics has been published previously. We here examined whether, when using this method, renal creatinine clearance (Ccr) can be substituted for the glomerular filtration rate (GFR). The study subjects comprised 57 inpatients from Osaka City General Hospital: 30 with type 2 diabetes mellitus and 27 with chronic glomerulonephritis. During the 2-wk study, patients received a high-salt diet for 1 wk and a low-salt diet for 1 wk. Urinary sodium excretion and systemic blood pressure were measured daily. The renal plasma flow, Ccr, and plasma total protein concentration were also evaluated simultaneously on the last day of the high-salt diet. The GFR was also calculated from the fractional renal accumulation of 99mTc-diethylenetriaminepentaacetic acid (DTPA). Glomerular hemodynamics, represented by the glomerular capillary hydraulic pressure and the resistance of afferent and efferent arterioles, were calculated using the renal clearance, the plasma total protein concentration, and the pressure-natriuresis relationship. Values for renal hemodynamics with the Ccr-derived GFR were compared with those from the 99mTc-DTPA-derived GFR. Ccr values of 53 to 169 ml/min correlated with the 99mTc-DTPA-derived clearance of 39 to 179 ml/min (n=57, r=.71, p<.001). Values for the glomerular pressure and the resistances of afferent and efferent arterioles calculated using the Ccr-derived GFR correlated significantly with those calculated using the 99mTc-DTPA-derived GFR (r=.99, p<.001 and r=.99, p<.001, respectively). These results indicate that the Ccr is an accurate representation of the GFR for use in glomerular hemodynamic analysis of the pressure-natriuresis relationship.

Chronic Disease↗
PubMed1999

Peritonitis due to Mycobacterium fortuitum infection following gastric cancer surgery.

Mycobacterium fortuitum is a well-documented cause of nosocomial infection. However, no studies have reported peritonitis with M. fortuitum as a postoperative complication. We describe a case of peritonitis with M. fortuitum biovariant peregrinum following gastric cancer surgery. Gram-positive bacterial infection coexisted. Although the source of the infection was unclear, the patient was successfully treated with drainage tube exchange and combination therapy consisting of sparfloxacin, clarithromycin, and imipenem/cilastatin sodium. Thus for postoperative infectious pathogens, not only bacteria but also nontuberculous mycobacteria should be considered.

Adenocarcinoma↗
PubMed1999

Phytol induces programmed cell death in human lymphoid leukemia Molt 4B cells.

The exposure of human lymphoid leukemia Molt 4B cells to phytol which was isolated from Lolium multiflorum Lam and identified by MS, and 1H- and 13C-NMR, led to both growth inhibition and the induction of programmed cell death (apoptosis). Morphological change showing apoptotic bodies was observed in the cells treated with phytol. The fragmentation by phytol of DNA to oligonucleosomal-sized fragments that are characteristics of apoptosis was observed to be concentration- and time-dependent. These findings suggest that growth inhibition by phytol of Molt 4B cells results from the induction of apoptosis in the cells.

Apoptosis↗
PubMed1999

Hyaluronan activates mitogen-activated protein kinase via Ras-signaling pathway.

Hyaluronan (HA) triggers a wide variety of cellular functions, yet its signaling pathway remains largely unclear. We found that HA-treatment of 3Y1 cells activated tyrosine phosphorylation of cellular proteins and mitogen-activated protein (MAP) kinase in a time- and dose-dependent manner, and, subsequently, stimulated cell growth. This HA-activity was resistant to boiling at 100 degrees C but completely abolished by treatment with hyaluronidase, suggesting that HA itself, but not any HA-associated proteins, has the activity. In addition, we found that HA-dependent activation of MAP kinase was strongly suppressed by the expression of dominant negative ras (S17N ras). These results suggest that Ras-MAP kinase pathway is activated by HA and may play an important role in HA-dependent signaling.

Adjuvants, Immunologic↗
PubMed1999

[Evaluation of thrombomodulin and tumor necrosis factor-alpha levels in patients with hemolytic uremic syndrome caused by enterohemorrhagic Escherichia coli O157:H7 infection].

To investigate the role of thrombomodulin (TM) and tumor necrosis factor-alpha (TNF-alpha) in hemolytic uremic syndrome (HUS), serum and urinary levels of TM and TNF-alpha were determined in patients with hemorrhagic enterocolitis (HC) of enterohemorrhagic E. coli O157:H7 infection. These patients were divided into two groups: an HUS group consisting of patients with HUS; an HC group consisting of patients without HUS. In the 10 days after the onset of diarrhea, the serum TM and TNF-alpha levels in the HUS group were significantly elevated compared with those in the control group but decreased after 11 days. The serum TM and TNF-alpha levels in the HC group were not elevated compared with those in the control group except for one case of TNF-alpha. It is suggested that the serum TM elevation showed the severity of endothelial cell damage. Urinary TM and TNF-alpha levels in the HUS group were significantly elevated in the first 10 days. The urinary TNF-alpha levels rapidly decreased after 11 days, while the urinary TM levels were persistently high. From these results, the sustained elevation of the urinary TM levels suggested the persistent presence of renal endothelial cell damage, and the decrement of urinary TNF-alpha levels suggested that TNF-alpha acted as a trigger of the renal endothelial cell damage in the first 10 days.

Biomarkers↗
PubMed1999

[The prevalence of TTV infection and the route of TTV transmission in hemodialysis patients--compared with HCV infection].

Recently a novel virus named TT virus (TTV), associated with posttransfusion hepatitis, was isolated. The prevalence of TTV infection and the route of TTV transmission in HD units was investigated. TTV was detected in 51.3% of patients on HD (59/115), as compared with 16.5% of healthy blood donors (15/91). The prevalence rate of TTV in the patients without history of blood transfusion was similarly high (51.6%), compared with that of those with history of blood transfusion (51.2%). The prevalence rate of TTV did not differ according to the duration of HD. These suggest that the risk of TTV infection is very high in HD units and there is another major route of TTV transmission than blood transfusion.

Biomarkers↗