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Biomedical subjects

E Sakurai

Publications and source records attributed to E Sakurai.

At least 91 records · Page 5Linked to original sources
PubMed1995

The role of HMT (histamine N-methyltransferase) in airways: a review.

Histamine N-methyltransferase (HMT) expressed in the epithelial and endothelial cells of the airways is a principal enzyme degrading histamine in the body. This brief review summarizes the recent advances in molecular biology related to the pathophysiological role of HMT in regulating airway functions.

Animals↗
PubMed1995

Allergic airway response and potassium channels: histamine release and airway inflammation.

The possible involvement of potassium (K) channels in allergic airway responses was examined in ovalbumin (OA)-sensitized guinea pigs. An ATP-sensitive K channel opener (BRL-38227) inhibited OA inhalation-induced bronchoconstriction and airway plasma leakage. BRL-38227 also had an inhibitory effect on exogenous histamine- and leukotriene-induced responses. In contrast, BRL-38227 did not affect OA-induced histamine release from minced lung tissues. Therefore, the ATP-sensitive K channel opener inhibits allergic bronchoconstriction and plasma leakage as a result of its effect on airway smooth muscle and postcapillary venules. Apamin, a small conductance Ca2+ -activated K channel (PK,Ca) blocker, significantly inhibited both OA-induced tracheal contraction and histamine release from lung tissues, suggesting that this compound reduces allergic airway responses via a mast cell stabilizing effect. We conclude that ATP-sensitive K channel opening and small conductance PK,Ca closure may be beneficial for preventing allergic airway responses.

Adenosine Triphosphate↗
PubMed1995

Effects of the histamine H3 agonist (R)-alpha-methylhistamine and the antagonist thioperamide in vitro on monoamine oxidase activity in the rat brain.

The effects of an H3 agonist, (R)-alpha-methylhistamine (alpha-MeHA), and an H3 antagonist, thioperamide, on monoamine oxidase (MAO) activity in rat hypothalamus were studied in vitro. Thioperamide was more potent in inhibiting MAO-B than MAO-A activity; MAO-B activity in rat hypothalamic homogenates was competitively inhibited by thioperamide with a Ki value of 175 micronM. From this in vitro experiment, the conversion of N-telemethylhistamine to N-tele-methylimidazoleacetic acid may be inhibited by thioperamide, suggesting that thioperamide may affect the regulation of histamine metabolism within histaminergic neurons. In contrast with the results obtained with thioperamide, alpha-MeHA inhibited MAO-A more potently than MAO-B activity; the Ki values for MAO-A and -B of hypothalamic homogenates were estimated to be 1.1 and 3.3 mM, respectively. The weak inhibitory effect of alpha-MeHA for MAO-B does not seem to be a major cause of changes in N-tele-methylhistamine concentrations.

Animals↗
PubMed1994

Histamine depletion in brain caused by treatment with (S)alpha-fluoromethylhistidine enhances ischemic damage of gerbil hippocampal CA2 neurons.

The effect of (S)alpha-fluoromethylhistidine (FMH), a specific inhibitor of histamine synthesis from histidine, on ischemic damage was examined in gerbil brain after forebrain ischemia. Two h after subcutaneous FMH injection, the histamine content of the brain was significantly reduced. Neuronal loss in the CA2 region of the hippocampus 7 days after 3 min ischemia was enhanced by treatment with FMH. These results indicate that depletion of brain histamine aggravates neuronal death of hippocampal CA2 neurons after 3 min ischemia.

Animals↗
PubMed1994

Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice.

The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

Animals↗
PubMed1994

Clinical significance of glucocorticoid pharmacodynamics assessed by antilymphocyte action in kidney transplantation. Marked difference between prednisolone and methylprednisolone.

A number of studies have demonstrated the impact of glucocorticoid response of peripheral lymphocytes on kidney allograft survival, suggesting that the better the glucocorticoid selection, the better the clinical outcome. However, individual differences in pharmacodynamics of clinically important glucocorticoids have not been taken into account. Four glucocorticoids (hydrocortisone, prednisolone, methylprednisolone, and dexamethasone) were examined for their ability to suppress in vitro blastogenesis of mitogen-stimulated PBL obtained from 122 chronic renal failure (CRF) patients waiting for renal transplantation and 98 healthy volunteers. Concentrations of steroids that gave 50% inhibition of lymphocyte blastogenesis (IC50) were determined individually in order to compare steroids and subject groups. Graft outcomes in 36 kidney transplant recipients treated with prednisolone were compared retrospectively with the prednisolone pretransplant IC50 values. Lymphocyte response to each glucocorticoid showed wide deviations among the subjects. Prednisolone IC50 values of the CRF patients showed the largest deviation, ranging from 1.0 to 10,000 micrograms/L. Thus, a significantly large population of the CRF patients (26.2%), when compared with the healthy subjects (4.1%) showed a marked decrease in lymphocyte response to prednisolone (P < 0.01). The binding capacity and affinity of lymphocyte glucocorticoid receptors did not differ significantly between the responders and nonresponders, suggesting that steroid resistance is a post-receptor event. The antilymphocyte potency of prednisolone assessed by IC50 of the steroid was less than that of hydrocortisone, whereas methylprednisolone was > 12-fold superior to prednisolone. After kidney transplantation, CRF patients who showed impaired preoperative lymphocyte response to prednisolone had a significantly high incidence of acute allograft rejection under prednisolone/CsA therapy (P < 0.01). It is concluded from these results that methylprednisolone could be of benefit to prednisolone-resistant recipients, who can be identified by the preoperative lymphocyte culture.

Adolescent↗
PubMed1994

The disposition of thioperamide, a histamine H3-receptor antagonist, in rats.

An HPLC method using an ovomucoid-conjugated column has been developed for measurement of thioperamide, a histamine H3 antagonist, with a minimum quantitation limit of 0.05 micrograms mL-1. The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg-1), the plasma concentration decreased monoexponentially with a half-life of 26.9 min. The apparent total body clearance of thioperamide from rat plasma was 74.6 mL min-1 kg-1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.

Animals↗
PubMed1994

The disposition of (R)-alpha-methylhistamine, a histamine H3-receptor agonist, in rats.

Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-alpha-methylhistamine (alpha-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of alpha-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12.6 mg kg-1), the plasma concentration declined biexponentially with a half-life of 1.3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 micrograms min mL-1 and 97 mL min-1 kg-1, respectively. After administration, alpha-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of alpha-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that alpha-methylhistamine crosses the blood-brain barrier in rats with difficulty.

Animals↗
PubMed1993

In vivo microdialysis measurement of histamine in rat blood effects of compound 48/80 and histamine receptor antagonists.

An in vivo microdialysis method combined with a highly sensitive HPLC method which was developed for the analysis of the mediators in the CNS has been applied to assay histamine concentrations in the blood. The technique was used to study the effects of compound 48/80 and histamine receptor antagonists on histamine release in the blood of rats. The mean basal level of histamine in the blood measured by in vivo microdialysis was 177.8 +/- 11.1 pmol/mL. This level was not affected significantly by intraperitoneal (i.p.) injection of saline, and remained at the constant level for at least 8 hr after injection of saline. After i.p. injection of histamine (0.5 mg/kg), histamine was quickly detected in the blood of the jugular vein. Moreover, because the recovered histamine in the dialysate is directly proportional to the free fraction in the blood, the in vivo microdialysis method of blood is a reliable method of examining histamine release into the blood. In our experiments, the histamine level in dialysates from rat jugular vein was markedly increased by compound 48/80 (2.0 mg/kg, i.p.), demonstrating the histamine release into the blood from mast cells. However, there was no increase in histamine concentration after an i.p. injection of histamine receptor antagonists, such as pyrilamine (2.0 mg/kg), d-chlorpheniramine (2.0 mg/kg), cimetidine (10 mg/kg), or thioperamide (10 mg/kg). Thus, the present results suggested that these histamine receptor antagonists might not have an influence on histamine release into the blood.

Animals↗
PubMed1993

Comparison of adrenal functions in kidney transplant recipients with different long-term immunosuppressive treatments--prednisolone and azathioprine versus prednisolone and cyclosporine.

Adverse effects of cyclosporine on the adrenal cortex have been documented in animal experiments, but nothing has been reported in human subjects. Endogenous cortisol in peripheral blood was monitored for three years after transplantation, with 30 kidney recipients on two different immunosuppressive treatments. In the azathioprine group, 16 patients were treated with coadministration of prednisolone at an initial dose of 120 mg/day. In the cyclosporine group, 14 patients were also treated with prednisolone, using an initial dose of 60 mg per day. Short ACTH stimulation tests were performed to reconfirm the results obtained by basal cortisol monitoring. During the first year following transplant, cortisol concentrations in the cyclosporine group were higher, though not significantly so, than those in the azathioprine group, in accordance with cumulative amounts of prednisolone administered. At three years, however, the mean cortisol concentrations in the azathioprine group were 2-3 times higher than those in the cyclosporine group (P < 0.05). All patients in the azathioprine group responded well to ACTH, whereas 4 patients out of 14 in the cyclosporine group showed continuous severe suppression without considerable response to ACTH (P < 0.01). In conclusion, we would like to suggest that adrenocortical toxicity of long-term cyclosporine use may appear one year after transplant, resulting in chronic suppression of the adrenal cortex, and, accordingly, difficulty in further reduction of prednisolone use.

Adrenal Glands↗
PubMed1993

[Effects of selenium on the glycolysis and gluconeogenesis system in rat liver].

We studied the effect of selenium on the glycolysis and gluconeogenesis system in the rat liver. Significant decreases in glucose level in the serum were observed from the 4th day after daily intraperitoneal (i.p.) administration of selenite (173 micrograms/kg, 78.9 micrograms/kg of selenium base equivalent). Selenium was also effective in reducing a precursor of gluconeogenesis, lactate, alanine or glycerol, in the serum. Moreover, there were significant decreases in the activities of pyruvate carboxylase and glucose-6-phosphatase, a rate-limiting enzyme of gluconeogenesis, in the liver of selenium-treated rates. On the contrary, the activities of glycokinase and phosphofructokinase, a rate-limiting enzyme of glycolysis, in the liver of rat treated with selenium significantly increased in comparison with the control group. These data, therefore, indicated that the hypoglycemic effect of selenium might be due to the acceleration of glucose metabolism and the inhibition of glucose synthesis in the liver, suggesting a decrease in a source of precursor supply for the gluconeogenesis.

Alanine↗
PubMed1993

Proconvulsant effect of ketotifen, a histamine H1 antagonist, confirmed by the use of d-chlorpheniramine with monitoring electroencephalography.

Ketotifen produced seizures in a 5-year-old boy with secondary generalized epilepsy (SGE) and allergic rhinitis. To confirm that the seizures were due to histamine H1 receptors blockade, d-chlorpheniramine was administered with monitoring electroencephalography (EEG). Administration of d-chlorpheniramine significantly increased the number of epileptic discharges in the patient, compared with those before administration. Plasma noradrenaline and dopamine levels were not affected by treatment with d-chlorpheniramine. These findings indicate that histamine H1 receptors blockade produced convulsions and increased epileptic discharges on EEG. Recently, several experimental reports have shown that histamine has an inhibitory role on convulsions through histamine H1 receptors. Experimental findings and present results show that histamine H1 antagonists have proconvulsant effects, especially in the developmental period. Thus, it is recommended that centrally-acting histamine H1 antagonists should be avoided in epileptic patients, especially in children of pre-school age.

Child, Preschool↗