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Biomedical subjects

T Matsubara

Publications and source records attributed to T Matsubara.

At least 433 records · Page 24Linked to original sources
PubMed1987

Effect of N-methyltetrazolethiol on liver microsomal gamma-glutamylcarboxylation: modification of the in vitro action of N-methyltetrazolethiol.

Vitamin K-dependent gamma-glutamylcarboxylation activity in rat liver microsomes was monitored using the incorporation of 14CO2 into exogenous pentapeptide and endogenous protein substrates as indicators. Detergent solubilization of the microsomal enzymes was required for the activity to develop, but higher concentrations of detergent inhibited the enzymatic reaction. Pyridoxal-5'-phosphate (PAL-P) and dithiothreitol (DTT) stimulated the enzyme activity. The enzyme activity was observed when the hydroquinone form of vitamin K or the quinone form plus NADH was employed as the cosubstrate, but little activity was detected in the reaction system containing vitamin K-epoxide plus NADH plus DTT. N-Methyltetrazolethiol (NMTT), the substituent at the 3'-position of several beta-lactam antibiotics, inhibited the enzyme activity in vitro only in the reaction system containing NADH. Addition of DTT diminished the in vitro action of NMTT, while PAL-P and detergent did not affect it. The results indicate that the in vitro inhibitory action of NMTT is observable under some specific and restricted assay conditions. This paper also discusses the differences between the in vitro action and the in vivo effect of NMTT.

Animals↗
PubMed1987

Effects of beta-lactam antibiotics on the acetaldehyde-metabolizing system in germ-free rats.

Effects of several beta-lactam antibiotics on the acetaldehyde-metabolizing system were studied using germ-free rats. Administration of cefamandole (CMD) to the rats caused a decrease in liver mitochondrial low Km aldehyde dehydrogenase activity and an increase in blood acetaldehyde level during ethanol metabolism, similar to the case in conventional rats. Oral administration of CMD produced a pronounced increase in blood acetaldehyde level compared to the subcutaneous administration of the antibiotic. When the animals were given various beta-lactam antibiotics subcutaneously, only the antibiotics having an N-methyltetrazolylthiomethyl group at the 3-position of the cephalosporin nucleus exhibited the disulfiram-like effects on the acetaldehyde-metabolizing system. The results indicate that intestinal bacteria do no participate in the development of the disulfiram-like reaction of several beta-lactam antibiotics.

Acetaldehyde↗
PubMed1987

Pharmacokinetics of latamoxef and N-methyltetrazolethiol in rats associated with the development of disulfiram-like effects.

The disulfiram-like effect of beta-lactam antibiotics, having an N-methyltetrazolethiol (NMTT) as a 3'-position substituent of the cephalosporin nucleus, was determined in rats using latamoxef (LMOX) as a model. Intravenous and subcutaneous administrations of these antibiotics caused a decrease in the low Km aldehyde dehydrogenase (ALDH) activity in liver mitochondria and an increase in blood acetaldehyde level during ethanol metabolism, as in the case of disulfiram. When the antibiotic was administered intravenously to biliary fistula rats, the blood acetaldehyde level did not increase. On the other hand, oral administration of antibiotic to normal and biliary fistula rats caused pronounced development of disulfiram-like effects in both animals. When LMOX was injected to normal rats, the rapid and slow eliminations of LMOX and NMTT, respectively, were observed from blood and liver. After oral administration of LMOX, NMTT remained in the blood and liver for a long time with higher concentrations, although LMOX could not be detected in the body. With biliary fistula rats, intravenous injection of LMOX led to rapid urinary excretion of both LMOX and NMTT. These results indicate that the development of disulfiram-like effects of NMTT-containing antibiotics is closely related to the pharmacokinetic profile of NMTT released from its parent drugs.

Acetaldehyde↗
PubMed1987

Effects of adrenergic agonists and antagonists on glycogenolysis in isolated perfused rat liver.

The effects of adrenergic agonists and antagonists on hepatic glycogenolysis were investigated using isolated perfused rat liver. Comparative studies on the glucose output by various adrenergic agonists and the inhibitory action of various antagonists on epinephrine-induced glycogenolysis indicated that this glycogenolysis was mediated by alpha 1-adrenergic receptors. Epinephrine-induced glucose output from the liver was detected repetitively when epinephrine was repeatedly added to the perfused liver, while the glucose output decreased gradually when epinephrine was infused repetitively to the liver perfused with Ca2+-free buffer. Infusion of epinephrine to the perfused liver caused a release of Ca2+ associated with the glucose output, and a close correlation was found between the amounts of glucose and Ca2+ released from the liver with the infusion of epinephrine at various concentrations. The amounts of glucose production induced by epinephrine in the absence of extracellular Ca2+ were smaller than in the presence of extracellular Ca2+ when the liver received a large or sustained stimulation of epinephrine. These results suggest that the epinephrine mobilizes Ca2+ from the intracellular store to activate glycogenolysis, while entry of extracellular Ca2+ into the cell is required in order to obtain a large or sustained hormonal stimulation of glycogenolysis and to supply the intracellular Ca2+ store.

Animals↗
PubMed1987

Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats.

The disulfiram-like effect of various beta-lactam antibiotics containing N-methyltetrazolethiol (NMTT) on the alcohol-metabolizing system was studied using rats. Their administration caused decreased activities in low Km aldehyde dehydrogenase (ALDH) and acetaldehyde oxidation in the liver, with marked depression from several hours to 2 days after the treatment. Blood acetaldehyde level increased markedly when ethanol was administered 18-24 hr after pretreatment with antibiotics. A similar time course change in the effect was obtained when disulfiram was administered. The following results obtained in the present study indicate that the disulfiram-like effect associated with these antibiotics was not mediated by the whole molecular structures of these drugs: Firstly, the antibiotics were eliminated rapidly from the plasma and liver, and the disulfiram-like effect was followed by a disappearance of the drugs. Secondly, the concentration of antibiotics required to inhibit mitochondrial low Km ALDH activity in vitro was very high compared with their liver concentration. Thirdly, rapid onset of disulfiram-like effects occurred after administration of NMTT itself, and a pronounced elevation of blood acetaldehyde level was observed when ethanol was administered 3-5 hr after the NMTT injection. Fourthly, almost the same amounts of NMTT were released in the body after the intravenous administration of various NMTT-containing antibiotics, as judged by the urinary excretion. These results suggest that the disulfiram-like effect of beta-lactam antibiotics is mediated by NMTT released from them.

Acetaldehyde↗
PubMed1987

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats.

The in vivo effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics upon the ethanol elimination rate were examined in rats. Intravenous administration of ethanol caused a dose-dependent increase in blood ethanol level, and the ethanol elimination could be well described by a two compartment model. Pretreatment of rats with enzyme inhibitors caused a marked decrease in the ethanol elimination rate associated with the depression of the enzyme activities. Fasting of the animals caused a decrease in the ethanol elimination rate per animal associated with a decrease in the liver weight. However, no alteration was evident when the rate was expressed as the rate per g of liver. When animals were pretreated with a high dose of N-methyltetrazolethiol (NMTT)- containing beta-lactam antibiotics or NMTT itself, which causes a disulfiram-like reaction, the ethanol elimination rate per animal was depressed concomitant with an increase in the blood acetaldehyde level. The ethanol elimination rate in these animals showed lower values even when expressed as the rate per g liver. On the other hand, administration of cephems without NMTT, which cause no disulfiram-like reaction, led to a slight decline in the elimination rate per animal, although no alteration was detected when the rate was expressed as the rate per g liver. The findings indicated that the ethanol elimination in vivo per animal is regulated by the total capacity of the alcohol-metabolizing enzyme activities in the whole liver.

Acetaldehyde↗
PubMed1987

Effects of corticotropin-releasing factor (CRF) on aldosterone and 18-hydroxycorticosterone in essential hypertension and primary aldosteronism.

The effects of ovine corticotropin releasing factor (o-CRF) on plasma aldosterone, 18-OH-corticosterone (18-OHB), plasma adrenocorticotropin (ACTH) and cortisol were determined in eight patients with primary aldosteronism, six with aldosterone-producing adenoma (APA) and two with idiopathic hyperaldosteronism (IHA). The results were compared with those in six normal subjects and eleven patients with essential hypertension (EHT, 5 with low renin and 6 with normal renin). In patients with APA, the peak plasma aldosterone and 18-OHB responses to 100 micrograms iv of o-CRF (226% and 113% increase from baseline, respectively) were greater than those in EHT and normal subjects. The net integrated aldosterone and 18-OHB responses (840 +/- 156, and 419 +/- 121 ng/dl.hr, respectively) were also significantly greater (p less than 0.01) in APA than those in normals and EHT. In two patients with IHA, both the peak and net integrated aldosterone response were smaller than those in APA, in spite of nearly identical plasma ACTH and cortisol responses. These results suggest that augmented responses of mineralocorticoids to o-CRF may be characteristic of aldosteronism due to APA, mediated by CRF-induced ACTH, and possibly other proopiomelanocortin (POMC)-derived peptides.

18-Hydroxycorticosterone↗
PubMed1987

Effect of diltiazem on acute myocardial ischemia. Study of the relationship between regional myocardial blood flow and myocardial energy metabolism.

To examine the effects of diltiazem on myocardial ischemia, 200 micrograms/kg of diltiazem were injected intravenously into anesthetized open-chest mongrel dogs 10 min after coronary ligation. This was followed by a continuous infusion of diltiazem at 10 micrograms/kg/min for 50 min. Regional myocardial blood flow (MBF) was measured by the hydrogen gas clearance method. Sixty minutes after ligation, myocardial specimens were taken from the areas where MBF was measured, and the ATP and CP contents were determined by the bioluminescence method. Simultaneously, mitochondria were isolated from the ischemic and nonischemic areas, and both the respiratory control index (RCI) and the rate of oxygen consumption in state III (QO2 III) were calculated. The aortic systolic pressure and heart rate of diltiazem treated and untreated dogs were not significantly different, and diltiazem did not increase the MBF in the area with a MBF below 40 ml/min/100 g. When MBF was 10 to 30 ml/min/100 g, the ATP content in the diltiazem treated hearts was significantly higher than that in the untreated dogs, whereas the CP content was not significantly changed. Thus, diltiazem administered after ischemia preserved ATP content in the ischemic myocardium with a MBF of 10 to 30 ml/min/100 g without significantly affecting the hemodynamics or MBF. This suggests that diltiazem exerts a cardioprotective effect by acting directly on the ischemic myocardium if it has an MBF above a certain level, even when the drug is administered after the onset of ischemia.

Adenosine Triphosphate↗
PubMed1987

[The influence of smoking on the development of various subtypes of pulmonary carcinoma].

The influence of smoking on the development of pulmonary carcinoma of various histological subtypes was analyzed in 244 primary and 84 metastatic lung cancer patients. The new WHO classification was used for histological diagnosis. The relative risk was calculated by the odds ratio. It was found that all the squamous, small-and large-cell carcinomas were derived from smokers with relative risks of 27.8, 7.5 and 5.6, respectively. On the other hand, adenocarcinoma had very little, if any, relationship with smoking, the relative risk being 1.5 in men and 1.3 in women. The high-risk group for squamous cell carcinoma in men was defined with a regression line of y (duration of smoking) on x (number of cigarettes per day) as y = -0.24 x + 48.6.

Adenocarcinoma↗
PubMed1987

Incidence of squamous metaplasia in large bronchi of Japanese lungs: relation to pulmonary carcinomas of various subtypes.

The incidence of bronchial squamous metaplasia in Japanese lungs was investigated in order to clarify the significance of this lesion for the development of lung cancer of various histological subtypes. The bronchi of 104 and 32 lungs resected, respectively, for primary or metastatic tumors were step-sectioned and examined histologically. The incidence of squamous metaplasia was particularly high (83% of cases, 8-11% of sections) in male lungs bearing primary squamous or small cell carcinoma whereas it was low (43% of cases, 3% of sections) in lungs of both sexes with adenocarcinoma, the latter figures being about the same as those for lungs with secondary metastatic tumors. Although the overall incidence of lung squamous metaplasia in Japanese is much lower than in the U.S., the present data demonstrate a high level in association with squamous or small cell carcinoma, directly comparable to that of Americans. However, atypical metaplasia, or dysplasia, was encountered much less frequently than in the U.S. A topographical study of 7 minute or small squamous cell carcinomas revealed 3 to have adjacent and 2 to have nearby areas of squamous metaplasia. However, 2 cases were found to be completely free of squamous metaplastic lesion. Thus, squamous metaplasia may be associated with the development of squamous cell carcinoma but would appear not to be an obligatory step in the development of this neoplasm.

Bronchi↗
PubMed1987

Effects of a calcium entry blocker on cerebral circulation in essential hypertension.

The acute effects of the calcium entry blocker, nifedipine, on cerebral circulation were studied in 22 patients (56 +/- 5 years) with essential hypertension (EHT, WHO I-II) and 12 age-matched normal subjects. Cerebral effects were reevaluated in sixteen EHT patients after 8 weeks of treatment. The cerebrovascular resistance (Rp), cerebral capacitance (Cp), carotid velocity, and flow volume were measured by a newly developed ultrasonic volume flow meter coupled with a built-in computer which calculates Rp and Cp based on a simulated model. In EHT, acute administration of nifedipine (10 mg orally) decreased Rp from 13.5 +/- 1.8 to 8.0 +/- 0.3 (p less than 0.01) and increased Cp from 22.8 +/- 3.3 to 54.9 +/- 5.2 mFc (p less than 0.01). The carotid blood flow and velocity increased by 25.7% and 22.9%, respectively (p less than 0.05) in the face of lowered arterial pressure. In normal subjects, nifedipine also decreased Rp and increased Cp but to a lesser degree compared with EHT. The acute changes in cerebrovascular circulation in EHT were maintained at 8 weeks of treatment. These results suggest that nifedipine reduces Rp, possibly as the consequence of systemic hypotension and direct vasodilation of the cerebral arteries. This may be beneficial for hypertensive patients.

Adult↗
PubMed1987

[Spindle cell squamous carcinoma of the lung--two case reports].

Two cases of spindle cell squamous carcinoma of the lung are presented. Both cases were female heavy smokers aged 73 and 55. The carcinomas, 7.5 and 6.0 cm in diameter respectively, were located at the peripheral portion of the right lower lung lobes. Direct invasion to the diaphragma and metastasis to the chest wall were observed in the first case but no metastasis was observed in the second case. Histologically, both carcinomas showed a biphasic appearance due to the presence of a squamous cell carcinoma component and a spindle cell sarcomatous component with marked cellular pleomorphism, but no neoplastic bone, cartilage or muscle. Transitional area of two components were seen in the second case.

Aged↗
PubMed1986

Increased superoxide anion release from human endothelial cells in response to cytokines.

To study the effects of macrophage and lymphocyte-derived factors on superoxide anion (O2-) generation and release from human umbilical vein endothelial cells (EC), cultured EC were stimulated by ultrapure interleukin 1 (IL 1) and recombinant interferon-gamma (IFN-gamma), and the O2- released into the supernatant was measured. Both of these cytokines enhanced O2- release in a dose and time-dependent manner. Addition of a combination of IL 1 and IFN-gamma, each in submaximal concentration, produced an additive effect on O2- release. It would appear from these findings that cytokines released by macrophages and lymphocytes during inflammatory reactions can promote O2- generation and release from human EC. O2- released from EC may alter the basement membrane of blood vessels and the surrounding connective tissue, and in this way promote the vascular injury and angiogenesis associated with local inflammation.

Cells, Cultured↗
PubMed1986

Superoxide anion release by human endothelial cells: synergism between a phorbol ester and a calcium ionophore.

In order to study the signal transduction mechanism of human endothelial cells (EC), the regulation of superoxide anion (O2-)release in EC has been investigated using the calcium ionophore A23187 and phorbol myristate acetate (PMA), a potential activator of the Ca2+ activated, phospholipid-dependent protein kinase, designated "protein kinase C." PMA enhanced O2- release from EC, and this enhancement occurred regardless of the presence or absence of extracellular Ca2+. A similar increase was produced by A23187; omission of extracellular Ca2+ prevented this increase. Simultaneous stimulation with PMA and A23187 produced a large increase in O2- release at submaximal concentrations of these agents, which, when added separately, caused minimal effects. These findings indicate that the activation of protein kinase C and mobilization of Ca2+ evoked by PMA and A23187 respectively are synergistically effective for eliciting a full physiological response of EC in the generation and release of O2-.

Anions↗