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Biomedical subjects

Y Kasuya

Publications and source records attributed to Y Kasuya.

At least 307 records · Page 17Linked to original sources
PubMed1985

TEA prevents the decline of the duration of the action potential in hypoxic cardiac muscle.

Our study was designed to evaluate the effects of the K+ channel blocker tetraethylammonium TEA (20 mM), Ca++ ionophore A23187 (6.9 microM), the Ca++ channel blocker verapamil (2 microM), and CaCl2 (6 mM) on a model of heart damage, hypoxia/reoxygenation of isolated guinea-pig hearts. The right ventricular papillary muscles maintained at 37 degrees C and paced at 60 beats/min were perfused with Ringer solution equilibrated with 95% O2-5% CO2 (normoxia) or 95% N2-5% CO2 (hypoxia). After stabilization of the electrical and mechanical activity, 60 min of hypoxia was induced and then followed by 15 min of reoxygenation. During hypoxia, there was a significant decrease in the action potential duration (APD) and the contractile force (CF). The decrease in APD in the TEA-treated muscle was significantly less than that in the non-treated muscle. However, CF declined at the same rate in both groups. Neither A23187, CaCl2 nor verapamil prevented the decline in both APD and CF. To study the slow responses, the fast Na+ current was first voltage-inactivated by partial depolarization to about -40 mM using an elevated K+ solution. The rate of hypoxia-induced blockade of the slow response was not slower in the presence of 20 mM TEA. These data demonstrate that TEA significantly prevented the decline of APD in hypoxia, but this resistance in APD did not affect the rate of inhibition of mechanical activity.

Action Potentials↗
PubMed1985

Effects of nipradilol (K-351) on alpha-adrenoceptor mediated responses in various isolated tissues.

Nipradilol competitively antagonized norepinephrine- or phenylephrine-induced contractile responses of guinea-pig thoracic aorta. These actions of nipradilol were about 6 times less potent than those of phentolamine. Nitroglycerin showed a non-competitive antagonistic action on norepinephrine-induced contractions of aorta. Furthermore, nipradilol competitively inhibited norepinephrine-induced contractions of rat vas deferens and dose-dependently reduced the phenylephrine-induced inhibitory responses in rabbit ileum. These antagonistic actions of nipradilol were 30 to 100 times less potent than those of phentolamine. Nitroglycerin did not appreciably affect these alpha-adrenoceptor mediated responses in rat vas deferens and rabbit ileum. The inhibitory action of clonidine on the twitch contraction of rat vas deferens produced by intramural stimulation was only slightly antagonized by nipradilol (pA2 = 5.4). Nipradilol and nitroglycerin showed a non-competitive antagonistic action on clonidine-induced contractions of canine saphenous vein after the exposure to phenoxybenzamine, while phentolamine competitively inhibited the clonidine responses. These results suggest that nipradilol possesses an alpha 1-adrenoceptor blocking action; it possesses very weak or practically no presynaptic alpha 2-blocking activity but shows a non-competitive antagonistic action on postsynaptic alpha 2-adrenoceptor mediated contractile responses.

Adrenergic alpha-Antagonists↗
PubMed1984

Quantitative determination of dexamethasone in human plasma by stable isotope dilution mass spectrometry.

An analytical method for the quantitation of nanogram to subnanogram amounts of dexamethasone is described. Dexamethasone was isolated from human plasma using a C18-bonded reverse-phase cartridge, purified by subsequent normal-phase HPLC, and the corresponding trimethylsilyl derivative analyzed by gas chromatography-mass spectrometry (GC-MS). The quantitation by isotope-dilution MS was carried out by selected-ion monitoring on the (M + 1)+ ion of the trimethylsilyl derivative of dexamethasone and its stable isotopically labeled diluent, [ 13C6 ,2H3]dexamethasone (681 and 690 m/z, respectively). Methane was used as the GC carrier gas and as the chemical-ionization reagent gas. The sensitivity of the method, judged from the lower limit of detection of the mass spectrometer, was at approximately 100 pg. The inter- and intraassay coefficients of variation (CV) determined at two different concentrations were 3.83 and 3.78% for 2 ng/mL and 2.64 and 1.29% for 5 ng/mL, respectively. Plasma concentration profiles for dexamethasone following a single 1-mg iv and a 2-mg oral dose of dexamethasone administered 24 h apart to two healthy volunteers are presented. The mass fragmentographic method described here is useful for bioavailability and pharmacokinetic studies of the synthetic glucocorticoid.

Administration, Oral↗
PubMed1984

Nature of N-nitrosodimethylamine demethylase in hepatic microsomes of rats.

The nature of enzymes involved in demethylation of N-nitrosodimethylamine (NDMA) was investigated in hepatic microsomes of rats. Compared to the other cytochrome P-450-dependent enzymes. NDMA demethylase had anomalous properties as reported in the literature. However, kinetic analysis suggested a qualitative change in NDMA demethylase induced by phenobarbital (PB) and 3-methylcholanthrene (MC) pretreatment. The inhibition of demethylase by alpha-naphthoflavone in MC-treated microsomes also suggested that cytochrome P-450 species induced by MC are active in demethylating NDMA. The enhancement of NDMA demethylase activity by metyrapone in PB-treated microsomes was greater than in non-treated ones, and was not observed in MC-treated ones. The result is almost the same as in acetanilide hydroxylation, depending on cytochrome P-450. Pyrazole, tranylcypromine, and aminoacetonitrile, which are selective inhibitors of NDMA demethylation, interacted with cytochrome P-450 species to produce type-II spectra, and typical type-II compounds (aniline, imidazole, and nicotinamide) were inhibitors of the NDMA demethylation. Tranylcypromine irreversibly inhibited microsomal monoamine oxidase [EC 1.4.3.4], but not NDMA demethylase. Semicarbazide (a copper- and pyridoxal-containing amine oxidase [EC 1.4.3.6] inhibitor) had no effect on demethylation. From these results it is concluded that NDMA demethylation depends only on cytochrome P-450-dependent monooxygenases.

Aminoacetonitrile↗
PubMed1984

Synthesis of deuterium labeled 17-methyl-testosterone.

The synthesis of two forms of selectively deuterated 17-methyl-testosterone is described. 17-Methyl-d3-testosterone was prepared by the Grignard reaction of dehydroepiandrosterone with deuterium labeled methyl magnesium iodide followed by an Oppenauer oxidation. 17-Methyl-d3-testosterone-19,19,19-d3 was prepared by treating 3,3-ethylenedioxy-5,10-epoxy-5 alpha, 10 alpha-estran-17-one with deuterium labeled methyl magnesium bromide followed by hydrolysis and dehydration of the 5 alpha-hydroxyandrostane derivative.

Chemical Phenomena↗
PubMed1984

Comparison of hepatic drug-metabolizing enzymes induced by 3-methylcholanthrene and phenobarbital between pre- and postnatal rats.

Effects of 3-methylcholanthrene (3MC) and phenobarbital (PB) on the hepatic drug-metabolizing enzyme system in fetal liver of rats were investigated. Intraperitoneal administration of 3MC (25 mg/kg, 72 and 48 hr before death) to pregnant rats significantly increased hexobarbital (HB) and aminopyrine (AM)-metabolizing activities in fetuses on the 21st day of gestation to 148.0 and 150.6% of control fetuses, respectively. In contrast, HB and AM-metabolizing activities in 4-day-old neonates and mothers were decreased by administration of 3MC on the 21st day of gestation. Benzo[a]pyrene (BP)-metabolizing activity, NADPH-cytochrome c reductase activity, and cytochrome P-450 content in 3MC-treated fetuses were significantly increased to 2143.6, 137.6, and 323.8% of the control, respectively. Following 3MC administration, the maximum absorption of the cytochrome P-450-CO difference spectra in liver microsomes of fetuses was observed at 449-450 nm. The induction profile following 3MC administration in the fetal livers was different from that in the neonatal and the maternal livers. On the other hand, intraperitoneal administration of PB (60 mg/kg, 72, 48, and 24 hr before death) significantly increased HB, AM, and BP-metabolizing activities in fetal livers to 263.7, 231.0, and 151.2% of the respective controls. The profile induced by PB in the fetal livers was similar to that in maternal livers. These results suggest that HB and AM-metabolizing enzymes in fetal livers treated with 3MC or PB possess the capacity to be induced, and the responsiveness of the drug-metabolizing enzyme system to 3MC during the prenatal stage may differ from the postnatal stage.

Aminopyrine↗
PubMed1984

Renal aminopyrine demethylation in several species determined by a sensitive radiometric method.

Renal microsomal aminopyrine demethylation activities of several species were measured by a sensitive radiometric method using [dimethylamino-14C-]aminopyrine as a substrate and 2,4-dinitrophenylhydrazine as a trapping agent for the formaldehyde formed. The activity was highest in hamsters (0.75 nmol min-1 mg-1 protein) and that in rabbits, rats, mice, and guinea-pigs was 19.7, 7.0, 4.5 and 3.7%, respectively, of the hamster values. These species differences did not correlate with species differences in cytochrome P-450 content or in NADPH cytochrome c reductase activity. Aminopyrine demethylation activities in sliced renal tissues of several species were also compared. This activity was also found highest in hamsters (0.54 nmol min-1 g-1 wet tissue) and the activities in rabbits, rats, and guinea-pigs were 9.2, 1.8 and 2.5%, respectively, of the hamster values.

Aminopyrine↗
PubMed1984

Post-natal change and regional variation of the response of the vas deferens of new-born rats to autonomic drugs.

The vas deferens isolated from rats of different ages (11-60 d old) was bisected to provide an epididymal and a prostatic half. The contractile responses of both halves to potassium ions, adrenergic agents (noradrenaline, isoprenaline and tyramine), cholinergic agents (acetylcholine, methacholine and tetramethylammonium), histamine and serotonin were measured. The response to 150 mM potassium, which was regarded as an approximate measure of full contractility of the preparation, increased in parallel with the organ weight. Most of the agonists could induce the full contractility in both halves until 3-4 weeks of age, but thereafter they could produce only smaller responses than the full contractility in either or both halves, resulting in a differentiation of the halves in the response to agonists. A regional variation of the post-natal development of alpha-adrenergic, muscarinic and nicotinic responses is discussed.

Animals↗
PubMed1984

Post-natal change in the effect of denervation on the rat vas deferens.

The vas deferens of 14-54 d old rats was denervated, isolated after 7 d, divided into prostatic and epididymal halves, and denervation supersensitivity to noradrenaline, acetylcholine, methacholine and tetramethylammonium (TMA) was examined. The supersensitivity to any of these agonists did not appear in rats younger than 21 d of age. Thereafter a leftward shift of the dose-response curve and an increase in the maximum contraction to noradrenaline were observed. The maximum contraction became progressively greater with development in the prostatic half but was approximately constant in the epididymal half. Supersensitivity to methacholine distinctly developed with age in the epididymal half. Only a subsensitivity to TMA was observed, suggesting that TMA acts on the nerve. The effect of denervation on the response to acetylcholine in the epididymal half resembled that to methacholine, and in the prostatic half resembled that to TMA. The developmental change in the effect of denervation on noradrenaline was discussed in relation to the full contractile ability of the vas halves, and that to cholinergic drugs was discussed in relation to nicotinic and muscarinic receptor population.

Acetylcholine↗
PubMed1984

Possible role of endothelium in the vasodilator response of rat thoracic aorta to platelet activating factor (PAF).

As the endothelium has an important role in the vasodilating effect of acetylcholine, we investigated the possible role of the endothelium in the vasodilating effect of platelet activating factor (PAF). Experiments were done on spirally cut rat thoracic aorta either containing or denuded of endothelial cells. It was demonstrated that relaxation by PAF and acetylcholine of pre-contracted strips required the presence of endothelial cells. The results strongly suggested the possible involvement of endothelium in the vasodilation produced by PAF as well as by ACh.

Acetylcholine↗
PubMed1984

Effects of hypoxia and reoxygenation on tissue ATP level and electrical and mechanical function of isolated guinea pig ventricular muscles.

The myocardial ATP level in guinea pig ventricular muscles was determined during hypoxia and reoxygenation and compared with the cardiac electrical and mechanical function. The action potential duration (APD), contractile force (CF) and tissue ATP level were depressed gradually depending on the N2 concentration in the medium. Time course studies revealed that the membrane electrical activity and the ATP content did not show parallel evolution, although changes in CF coincided with changes in ATP level.

Action Potentials↗
PubMed1984

Renal microsomal N-nitrosodimethylamine demethylase determined by a sensitive radiometric method.

Renal microsomal N-nitrosodimethylamine (NDMA) N-demethylation was measured in several species by a sensitive radiometric method using [14C]NDMA as a substrate and 2,4-dinitrophenylhydrazine (DNPH) as a trapping agent of the [14C]formaldehyde formed. The activities were the highest in mice and lowest in hamsters. The activities in rats could not be detected. Among several strains of mice studied the DDY strain was the highest in its activities. Although nicotinamide adenine dinucleotide supported NDMA demethylation by about 32% of nicotinamide adenine dinucleotide phosphate in kidney and only 16% in liver, other properties (pH profiles, km values, and effects of inhibitors) exhibited almost similar results in liver as compared to kidney.

Animals↗
PubMed1983

Pharmacokinetic approach for reconstruction of predetermined plasma insulin profiles by continuous subcutaneous insulin infusion in depancreatized dogs.

A preprogrammable insulin delivery system which can provide the flexibility of varying plasma insulin concentration in a physiological manner has been developed. This system involves a program of continuous subcutaneous infusion of insulin at variable rates to reproduce arbitrarily selected plasma insulin concentration-time profiles. The desired insulin infusion rate profile was calculated from the desired insulin pattern using pharmacokinetic parameters experimentally determined by measurement of immunoreactive plasma insulin following a subcutaneous bolus dose to depancreatized dogs.

Absorption↗
PubMed1983

New method for quantitative measurement of N-nitrosodimethylamine formation in the whole mouse.

A simple method for the quantitative estimation of the formation of N-nitrosodimethylamine (NDMA) in mice has been developed. Mice were frozen in liquid nitrogen and homogenized. NDMA was then extracted and analyzed by a gas chromatograph equipped with a thermal energy analyzer. In normal mice NDMA (100 nmole) administered orally was rapidly metabolized and recovery of NDMA was about 10% after 60 min. However, when pyrazole (300 mg/kg) was injected i.p. to mice 60 min before the administration of NDMA, more than 80% of the administered NDMA could be recovered within 60 min. This result suggested that in pyrazole pretreated mice the accurate amount of NDMA formed could be estimated. Therefore the NDMA formation was measured in the pyrazole pretreated mice. When 0.25 mumole of aminopyrine and from 0.25 to 2.0 mumole of sodium nitrite were simultaneously administered orally, the amount of the NDMA formation in 20 min was found to be from 8.2 to 60.3 nmole. These values are equal to about from 30 to 200 micrograms/kg of body weight which are nearly daily doses expected to cause the carcinogenic effect on mice or rats. This method of measuring NDMA in pyrazole pretreated mice appears to be useful for investigating the in vivo formation of NDMA quantitatively.

Aminopyrine↗
PubMed1983

Effect of phenobarbital and 3-methylcholanthrene on the hepatic microsomal metabolism of N-nitrosodimethylamine, N-nitrosomethylbutylamine and N-nitrosomethylbenzylamine.

The effect of phenobarbital (PB) and 3-methylcholanthrene (MC) pretreatment on dealkylations of N-nitrosodimethylamine (NDMA), N-nitrosomethylbutylamine (NMBuA) and N-nitrosomethylbenzylamine (NMBeA) was investigated in rat hepatic microsomes. PB increased the demethylation and the debutylation of NMBuA and the debenzylation of NMBeA. MC increased the debutylation of NMBuA and the debenzylation of NMBeA. However, MC decreased the demethylation of NMBeA. The demethylation of NDMA was not changed by the pretreatment of the inducers. These results suggest that the dealkylations of these nitrosamines are catalyzed by several enzymes, which probably depend on different cytochrome P-450 species.

Animals↗