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Biomedical subjects

E Sakurai

Publications and source records attributed to E Sakurai.

At least 55 records · Page 3Linked to original sources
PubMed1998

Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization.

With gene targeting, one can practically knock out a gene in vivo and create a mutant organism that completely lacks the gene product. The mutant mice lacking histamine H1 receptors was generated by the method of gene targeting. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen. The mutant mice showed impaired locomotor activity and exploratory behavior in an open field and activity wheel. Behaviors of the mutant mice were examined with several other tasks such as passive avoidance test, resident-intruder aggression test and formalin test to clarify the role for the H1 receptors in behaviors. Behavioral changes observed in the mutant mice are almost compatible with those obtained by the classical pharmacological tools. In correlation to the behavioral changes in the mutant mice, 5-hydroxytryptamine release was significantly increased in the brains of mutant mice.

Animals↗
PubMed1998

Kinetics of buccal absorption of propafenone single oral loading dose in healthy humans.

Buccal absorption has an advantage when compared with other administration routes because of its rapid onset of action. We examined the pharmacokinetics of buccal-absorbed propafenone in healthy humans. 1. After a single oral administration of 150 mg of propafenone, the average peak concentration of propafenone was 27.9+/-2.5 ng/ml, and that of 5-hydroxypropafenone was 61.7+/-6.6 ng/ml (n=5). The times to reach peak serum concentrations of propafenone and 5-hydroxypropafenone were 1.8+/-0.1 hr and 1.5+/-0.2 hr, respectively. 2. After a buccal absorption of 150 mg of propafenone, the time to reach peak serum concentration of propafenone was 16.9+/-2.3 min (n=8). The average peak concentration of propafenone was 30.4+/-1.4 ng/ml (n=8), and the concentrations of 5-hydroxypropafenone were below the detection limit in all subjects. The rapid upstroke of serum concentrations of propafenone by buccal administration may cause rapid onset of pharmacological conversion.

Absorption↗
PubMed1998

Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors.

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice. These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

Aggression↗
PubMed1998

[Effect of carbon tetrachloride-induced hepatic injury on stereoselective N-demethylation of chlorpheniramine by rat hepatic cytochrome P450 2C11 isozyme].

We examined the effect of a carbon tetrachloride (CCl4)-induced hepatic injury on the stereoselective N-demethylation of RS-(+/-)-chlorpheniramine (Chp) by cytochrome P450 (CYP) 2C11 isozyme. In the non-treated rat liver microsomes, the stereoselective N-demethylation of racemic Chp was observed. However, in the CCl4-treated (0.5 ml/kg, i.p.) rat liver microsomes, the N-demethylation activities of S-(+)- and R-(-)-Chp decreased continuously up to the third day after the treatment with CCl4, and reached about 9 and 13% of control values, respectively, and the stereoselective N-demethylation of Chp was not observed. Moreover, in the liver microsomes at the 7th day after the treatment with CCl4, the N-demethylation activities of both enantiomers recovered to an original level, and the stereoselective N-demethylation of Chp was again observed. The addition of 30 microliters of the anti-rat CYP2C11 serum to the reaction mixture containing 1 mg of microsomal protein inhibited the formation of monodesmethylchlorpheniramine (DMChp) from both enantiomers to 74 and 57% of the control values for S-(+)- and R-(-)-Chp, respectively. In the liver microsomes of a male rat at the 1st day after the treatment of CCl4, the addition of the anti-rat CYP 2C11 serum (30 microliters) also caused 25% inhibition of the formation of DMChp from S-(+)-Chp, but anti-rat CYP2C11 had no inhibitory effect on the rates of microsomal N-demethylation of R-(-)-enantiomer. On the other hand, in the liver microsomes of a male rat at the 7th day after the treatment with CCl4, the anti-rat CYP2C11 serum had an inhibitory effect on the rates of microsomal N-demethylation of either S-(+)- or R-(-)-enantiomers again. Moreover, it was confirmed by Western blotting analysis that the density of the stained bands of CYP2C11 in the liver microsomes from male rats at the 1st, 2nd and 3rd days after the treatment with CCl4, was thinner than that from non-treatment male rats. These results indicated that the changes of N-demethylation activities of Chp in the CCl4-induced hepatic injury were due to the variation of microsomal CYP2C11.

Animals↗
PubMed1998

Inhibition by [Arg8]-vasopressin of long term potentiation in guinea pig hippocampal slice.

We examined the effects of [Arg8]-vasopressin (AVP) on long term potentiation (LTP) of the field excitatory postsynaptic potentials at CA1 and CA3 synapses in adult guinea pig hippocampal slices. AVP (10 nM) depressed the magnitude of LTP without any effects on basal responses at both synaptic pathways. The depressive effect by AVP at CA1 synapses appears to be receptor-mediated since it was inhibited by an AVP V1-receptor antagonist, [Pmp1,Tyr(Me)2]-AVP. From these results, AVP may play an inhibitory role on the induction of LTP via V1 receptors in the guinea pig hippocampus.

Animals↗
PubMed1998

Histamine-induced calcium mobilization in single cultured cells expressing histamine H1 receptors: a relationship between its sensitivity and the density of H1 receptors.

Stimulation of histamine H1 receptors initiates the hydrolysis of phosphatidylinositides and results in the production of inositol (1, 4,5)-triphosphate and intracellular Ca2+ mobilization. Although the mechanism for signal transduction via the H1 recptor has been extensively investigated, little is known about the correlation between the sensitivity of histamine-induced Ca2+ mobilization and the density of H1 receptors in cultured cells. Cytosolic free Ca2+ concentration ([Ca2+]i) after stimulation by histamine was monitored in single CHO and rat C6-glioma cells stably expressed with H1 receptors and astrocytoma 1321N1 cells using the Ca2+-sensitive dye Indo-1 and dynamic single cell imaging techniques (ACAS 570 laser cytometer). Both of the H1 receptor-expressed CHO cells and C6-glioma cells were over 10 times more sensitive to histamine than astrocytoma 1321N1 cells in which H1 receptors were naturally present. The density of H1 receptors in the transfected cells was also more than 10-fold that of 1321N1 cells. In addition, inhibition of intracellular Ca2+-ATPase by thapsigargin elicited an increase in [Ca2+]i in H1 receptor-overexpessed cells and astrocytoma 1321N1 cells with similar sensitivity. These data suggest that the sensitivity of Ca2+ mobilization by histamine in these cells was correlatively augmented with the increase in the density of H1 receptors.

Animals↗
PubMed1998

Role of machine perfusion preservation in kidney transplantation from non-heartbeating donors.

The shortage of kidneys for transplantation is a universal problem. If the viability of the kidney can be assured, organ procurement from non-heartbeating donors will be greatly enhanced. This study evaluates the usefulness of machine perfusion preservation parameters as an index of kidney graft viability. We report our experience with 77 non-heartbeating donor kidneys preserved with machine perfusion technique. Sixty-eight grafts demonstrated excellent perfusion (mean flow 0.79 ml/min/g) with low vascular resistance (55.4 mmHg/ml/min/g). Early graft function occurred in all of these kidneys. Nine kidneys demonstrated poor perfusion (mean flow 0.35 ml/min/g) and elevated pressures with high vascular resistance (132.5 mmHg/ml/min/g). Four kidneys with poor perfusion and elevated pressures was discarded after perfusion. The four mates of these discarded at our center were primarily non-functional when transplanted at another transplant center. All five of the poorly perfused kidneys experienced primary non-function. We conclude that the use of quantitative values of perfusion flow (> 0.4 ml/min/g) and no increased pressure pattern allow safe utilization of grafts from non-heartbeating donors and can predict early postoperative function.

Graft Survival↗
PubMed1998

Induction of L-histidine decarboxylase in a human mast cell line, HMC-1.

Histamine is an important mediator in allergic reactions, gastric acid secretions, and neurotransmission in the central nervous system. Basophils and mast cells are the main sources of histamine, which is formed from L-histidine by histidine decarboxylase (HDC). However, the regulatory mechanism of HDC in these cells remains unclear. We examined the regulation of HDC activity and gene expression using a unique human mast cell line, HMC-1, after stimulation with phorbol 12-myristate 13-acetate (PMA) or ionomycin. HDC activity was increased from 52.1+/-0.4 (mean+/-standard deviation) to 154+/-6.9, or 105.6+/-6.2 pmol/min/mg protein (n = 3), 4 hours after stimulation with PMA (10 ng/mL) or ionomycin (10[-6] M). Although actinomycin D had no effect on this increase, cycloheximide completely inhibited the increase caused by these stimuli. The population of HMC-1 cells containing HDC protein was increased after stimulation with either PMA or ionomycin as evaluated by immunocytochemical analysis with anti-HDC antibody as a marker. HMC-1 constitutively expressed HDC mRNA, and its level was not increased with these stimuli. These results suggest that the increase of HDC activity in HMC-1 induced by PMA or ionomycin is regulated at the translational level.

Cell Line↗
PubMed1998

[Pulmonary thromboembolism that developed during an airplane flight "economy-class syndrome"].

The occurrence of thromboembolic phenomena during long-duration airplane flights is called "economy-class syndrome". Recently it has become more popular for Japanese to go abroad by airplane, and an increase in the prevalence of pulmonary thromboembolism should be expected. However, there are few reports of the economy-class syndrome in Japan. A 52-year-old woman was admitted to our hospital because of chest discomfort and dyspnea that developed during an airplane flight. We suspected pulmonary thromboembolism, on the basis of a chest X-ray film and on electrocardiogram. A ventilation-perfusion lung scan disclosed mismatching between ventilation and perfusion in the right upper lung field. Pulmonary thromboembolism was confirmed by pulmonary arteriography. The patient was treated with heparin and urokinase. A phlebogram of the legs showed no significant findings. There was no history of thromboembolic disease or of consumption of oral contraceptives. We conclude that the pulmonary thromboembolism might have been caused by stasis of blood in the lower limb veins during the airplane flight. We emphasize the importance of including pulmonary thromboembolism in the differential diagnosis of patients with chest discomfort and dyspnea that develop during airplane flights. No noninvasive test can lead to a definitive diagnosis of pulmonary thromboembolism. Early pulmonary angiography should be recommended when pulmonary thromboembolism is suspected.

Dehydration↗
PubMed1997

Glucocorticoid-resistance in peripheral-blood lymphocytes does not correlate with number of affinity of glucocorticoid-receptors in chronic renal failure patients.

Glucocorticoid (GC) resistance in patients with chronic renal failure (CRF) seriously impairs successive GC therapy after renal transplantation. We examined the relationship between GC-receptor (GC-R) parameters in peripheral-blood mononuclear cells (PBMC) and PBMC resistance to GC in 21 CRF patients and 18 healthy subjects. Each subject group was divided into two subgroups according to PBMC sensitivity to prednisolone in a mitogen assay procedure; i.e., sensitive (IC50 < 381 ng/mL) and resistant (IC50 > 381 ng/mL) groups. In healthy subjects, the mean GC-R Bmax and Kd in quiescent PBMC of the GC-sensitive group were 2.89 +/- 1.23 fmol/10(6) cells and 4.00 +/- 2.24 nM, respectively. The Bmax in these subjects significantly increased to 6.61 +/- 2.02 (257.7 +/- 107.8%) after 24 h stimulation with concanavalin A (p < 0.01), while the Kd change was not significant. The GC-R Bmax and Kd in quiescent PBMC of the GC-resistant group were 5.33 +/- 1.37 fmol/10(6) cells and 3.20 +/- 1.39 nM, respectively. Both of these parameters, however, did not change significantly after mitogen stimulation. There was a significant negative correlation between IC50S of prednisolone and increase-ratios (post/pre ratio) of Bmax after mitogen stimulation (p < 0.05). In CRF patients, Bmax and Kd in quiescent PBMC of the GC-sensitive group were 6.04 +/- 2.35 fmol/10(6) cells and 3.49 +/- 1.72 nM, respectively, while those in PBMC of the GC-resistant group were 5.13 +/- 2.31 fmol/10(6) cells and 4.04 +/- 1.62 nM, respectively. The Bmax and Kd were not significantly changed after mitogen stimulation in both subgroups of CRF. Moreover, in contrast to healthy subjects, there was no correlation between IC50 and GC-R parameters in CRF. We concluded that, in healthy subjects, decreased PBMC capacity to amplify GC-R numbers in response to mitogen is correlated with GC resistance, whereas in CRF patients the resistant mechanism is not correlated with GC-R parameters. An unknown event might be involved in GC-resistance of CRF.

Adult↗
PubMed1997

Glucocorticoids and cyclosporine induce apoptosis in mitogen-activated human peripheral mononuclear cells.

Induction of apoptosis by immunosuppressive agents such as glucocorticoids (GCs) and cyclosporine (CsA) in cultured lymphoid cells has been suggested. However, there are few studies which demonstrate the induction of apoptosis by these agents in the activation process of human peripheral blood mononuclear cells (PBMCs). Here we show that potent immunosuppressive GCs and CsA induce apoptosis in concanavalin A (con A)-activated human PBMCs. In this study, GCs and CsA suppressed human PBMC-blastogenesis when activated by con A in a dose-dependent manner, where healthy PBMCs treated with > 100 ng/ml of each immunosuppressive agent exhibited a DNA-ladder structure in electrophoretic analysis. In three chronic renal failure (CRF) patients, dose-dependency of the PBMC-apoptosis induction was confirmed by our quantification of fragmented DNA using ELISA. Furthermore, the enrichment of DNA fragmentation was significantly associated with the rate of PBMC-blastogenesis when treated with GCs or CsA (r = -0.466, P < 0.01). These results suggested that suppression of the mitogen-induced PBMC-blastogenesis by the immunosuppressive agents should be correlated with the induction of apoptosis.

Apoptosis↗