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Biomedical subjects

M Hirobe

Publications and source records attributed to M Hirobe.

At least 55 records · Page 3Linked to original sources
PubMed1993

4-Phenyltetrahydroisoquinoline, but not nomifensine or cocaine, inhibits methamphetamine-induced dopamine release.

The inhibitory effect of 4-phenyltetrahydroisoquinoline (4-PTIQ) on methamphetamine-induced dopamine release in the rat nucleus accumbens was investigated using a brain microdialysis method. Methamphetamine (10(-6) M) infusion through a microdialysis probe induced the release of dopamine. Although the uptake inhibitors, cocaine (3 x 10(-6) M) and nomifensine (10(-6) M), failed to block dopamine release, 4-PTIQ (10(-6 M) inhibited the dopamine-releasing effect of methamphetamine. 4-PTIQ did not affect the elevation of the extracellular dopamine level induced by high concentrations of nomifensine (10(-5) M) and cocaine (3 x 10(-5) M). 4-PTIQ was the weakest inhibitor of [3H]dopamine uptake by rat striatal synaptosomes. These results suggest that 4-PTIQ is a selective antagonist against the dopamine-releasing effect of methamphetamine in the nucleus accumbens.

Animals↗
PubMed1993

Detection of nitric oxide production from a perfused organ by a luminol-H2O2 system.

Nitric oxide, thought to be the endothelium-derived relaxing factor (EDRF), is involved in intra- and intercellular signalling in various tissues. A system for the continuous detection of NO in the picomolar range from a perfused organ is described. The detection is based upon the chemiluminescence reaction between NO and the luminol (5-amino-2,3-dihydro-1,4-phthalazinedione)-H2O2 system. The chemiluminescence is due to the formation of peroxynitrite from NO and H2O2. The luminol-H2O2 system is specifically reactive to NO, so that other nitrogen-containing compounds, (organic nitrite, organic nitrate, and thio-nitroso compounds) or endothelium-derived compounds do not interfere. The limit of determination was approximately 100 fM. This system has been used to measure continuous NO release from isolated perfused rat kidney and the simultaneous changes of perfusion pressure. In Wistar rats basal NO release was 85 +/- 11 fmol/min-1 (g of kidney weight)-1 (39 pM in the perfusate), and acetylcholine increased NO release dose dependently with a concomitant pressure reduction. The changes in NO release were always associated with mirror image changes in the perfusion pressure. Simple pressure reduction did not interfere with the chemiluminescence. Precise titration data as well as results of some preliminary experiments using this method are presented.

Animals↗
PubMed1993

Unusual substituent effects in the hydroxylation of phenols by a Cu(2+)-ascorbic acid-O2 system, gamma-radiolysis, and microsomes.

Aromatic ring hydroxylation of phenolic compounds proceeded selectively in a Cu(2+)-ascorbic acid-O2 system. In contrast to usual oxidation systems, unusual substituent effects were observed: electron-withdrawing groups accelerate and electron-donating groups retard the hydroxylation. Hydroxyl radicals generated by gamma-radiolysis also converted phenols into catechols and hydroquinones. The close resemblance of these two systems led us to presume that the active intermediate in the Cu(2+)-ascorbic acid-O2 system is hydroxyl radical or an equivalent species. The unusual substituent effects were also observed in the hydroxylation of p-substituted phenol by microsomes, a cytochrome P-450-dependent reaction. These results imply that the Cu(2+)-ascorbic acid-O2 system is an effective biomimetic oxidation system.

Animals↗
PubMed1993

Application of chemical cytochrome P-450 model systems to studies on drug metabolism. VI. N,N-coupling reaction of N-methylaniline catalyzed by polypeptide-bound porphyrinatoiron(III) and cytochrome P-450.

Polypeptide-bound porphyrinatoiron(III) effectively catalyzed the N,N-coupling reaction of N-methylaniline in the presence of NaBH4/O2/tetramethyl-ammonium hydroxide or cumenehydroperoxide, whereas the corresponding non-bound monomer porphyrinatoiron(III) had little catalytic activity. Rat liver microsomes also catalyzed the N,N-coupling which was inhibited by cytochrome P-450 specific inhibitors, SKF-525A and metyrapone. The polypeptide-bound porphinatoiron(III) appears to be an excellent cytochrome P-450 model for drug metabolism studies.

Aniline Compounds↗
PubMed1993

Selective release of serotonin by endogenous alkaloids, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, (R)- and (S)salsolinol, in the rat striatum; in vivo microdialysis study.

Dopamine-derived 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, (R)- and (S)salsolinol, released an enormous amount of serotonin in the rat striatum; the concentration of serotonin increased from undetectable level to 2.53 +/- 0.12 and 3.69 +/- 0.01 microM after perfusion of (R)- and (S)salsolinol, respectively. Salsolinols increased extracellular dopamine level, but to a much lesser degree than serotonin. Other naturally occurring isoquinolines with catechol structure released serotonin and dopamine, but salsolinols were the most potent and selective releaser of serotonin. Serotonin release by salsolinols may be involved in some psychiatric symptoms in L-DOPA therapy or alcoholism.

Alkaloids↗
PubMed1993

Cytochrome P450-like substrate oxidation catalyzed by cytochrome c and immobilized cytochrome c.

Cytochrome c (cyt.c) was shown to catalyze cytochrome P450 (P450)-like oxidative reactions, such as N-, and O-demethylation, S-oxidation, and epoxidation of olefins. A more detailed examination showed that (i) N-methylcarbazole and thioanisole oxidation with H2(18)O2 catalyzed by cyt.c resulted in introduction of 18O into the product, and (ii) during the epoxidation of cis-stilbene catalyzed by cyt.c, the stereochemistry of the substrate was retained and 18O was introduced when H2(18)O2 was used as an oxidant. These results show that cyt.c catalyzed N-demethylation, S-oxidation, and epoxidation in the same manner as P450. To utilize these P450-like reactivities effectively, cyt.c was immobilized on poly-gamma-methyl-L-glutamate. Up to 99% of the cyt.c used was immobilized. This immobilized cyt.c catalyzed N-demethylation, S-oxidation, and epoxidation in the same manner as both P450 and free cyt.c, and the activities of these reactions were increased by the immobilization. In N-demethylation of N,N-dimethylaniline with cumene hydroperoxide (CHP) catalyzed by cyt.c, the Vmax for CHP was increased by 4.4-fold by the immobilization of the enzyme, while the Km remained unchanged. Since P450 is involved in the metabolism of many xenobiotics, the above results suggest that immobilized cyt.c may be useful in drug metabolism research.

Aniline Compounds↗
PubMed1993

Effect of 4-phenyl-1,2,3,4-tetrahydroisoquinoline on ambulation induced by injection of methamphetamine into the nucleus accumbens in rats.

4-Phenyl-1,2,3,4-tetrahydroisoquinoline (4-PTIQ) has previously been shown to have antagonistic properties to methamphetamine in the spinal cord. Administration of 4-PTIQ (5 mg/kg, s.c.) reduced the ambulation induced by methamphetamine (0.5 mg/kg, s.c.) in rats. Methamphetamine (3 micrograms), injected unilaterally into the nucleus accumbens, increased ambulation. Alone, 4-PTIQ (10 micrograms) failed to elicit ambulation; however, it inhibited the methamphetamine-induced increase in ambulation. The alpha 1-antagonist prazosin (0.5 micrograms) or the beta-antagonist propranolol (3 micrograms) showed no effect on ambulation induced by methamphetamine. Haloperidol (5 ng), which possesses strong dopamine-blocking activity, abolished the ambulation induced by methamphetamine. The drug 4-PTIQ had weak affinity for dopamine D1 and D2 receptors. These results support the possibility that the inhibitory effects of 4-PTIQ on the ambulation-stimulating effects of methamphetamine, are due to blocking of the dopamine-releasing effect of methamphetamine but not due to dopamine blocking effects.

Animals↗
PubMed1993

Inhibitory effect of 4-phenyltetrahydroisoquinoline on locomotion and dopamine release induced by micro-injection of methamphetamine into the nucleus accumbens of the rat.

The inhibitory effects of 4-phenyl-1,2,3,4-tetrahydroisoquinoline (4-PTIQ) on methamphetamine-induced increases in dopamine and locomotion were investigated. Methamphetamine hydrochloride (10 micrograms) microinjected into the nucleus accumbens increased both locomotor activity and extracellular dopamine levels, measured by the brain microdialysis method. 4-PTIQ hydrochloride (20 micrograms) co-injected with methamphetamine inhibited both the increase in dopamine and the locomotor activity. The uptake blocker cocaine hydrochloride (20 micrograms) co-injected with methamphetamine failed to inhibit the effect of methamphetamine. Thus 4-PTIQ but not cocaine inhibited the dopamine-releasing effect of methamphetamine, and 4-PTIQ is suggested to block methamphetamine-induced locomotion by inhibition of dopamine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats.

To study mechanisms for attenuated endothelium-dependent vasorelaxation in hypertension, we examined the effects of acetylcholine (ACh) on renal vascular resistance (RVR) and release rates of endothelium-derived relaxing factor (EDRF) in kidneys isolated from spontaneously hypertensive rats (SHR), deoxycorticosterone acetate (DOCA) salt-hypertensive (DOCA salt) rats, and Dahl salt-sensitive (Dahl S) rats. Decreases in RVR by ACh were smaller in hypertensive rats than in their normotensive controls. The release rate of nitric oxide into the perfusate, which was estimated using nitrite-nitrate as an index, did not differ between SHR and Wistar-Kyoto rats (WKY). However, the release rate of EDRF was markedly decreased in both DOCA salt rats and Dahl S rats compared with their normotensive controls (10(-7) M ACh: DOCA salt 45 +/- 6 vs. control 410 +/- 60 pmol.min-1.g-1 kidney wt, P < 0.001). In SHR, high-K+ perfusion or pretreatment with glibenclamide, inhibitors of endothelium-derived hyperpolarizing factor (EDHF), significantly reduced ACh-induced vasorelaxation only in WKY, resulting in no differences in the RVR reduction between SHR and WKY. Thus attenuated ACh-induced vasorelaxation in the SHR kidney may be attributed to a decrease in EDHF, but to a decrease in EDRF in DOCA salt rats and Dahl S rats.

Acetylcholine↗
PubMed1993

Inter-individual differences of (+)-4-[4-(4-methylphenyl)phenylmethoxy-1-piperidinyl]butyric acid ((+)-MPPB) disposition in rats.

Inter-individual differences of drug plasma concentration were recognized in male Sprague-Dawley (SD) rats after a p.o. or i.v. administration of (+)-MPPB. Rats could be divided into two phenotypes, the rapid-metabolizing group (RM) and the slow-metabolizing group (SM). The hepatic clearance (CLliver) of RM was about 10 times larger than that of SM. Outbred SD(male, female), and Wistar(male) rats were mixtures of RM and SM. On the other hand, all inbred Lewis(male) rats were RM, and all inbred F344(male) and ACl(male) rats were SM.

Animals↗
PubMed1993

A novel metabolite of 3,4-methylenedioxyamphetamine (MDA): formation of 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and its pharmacological effect.

In 3,4-methylenedioxyamphetamine (MDA)-treated rat brain and urine, 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (3Me6,7MDTIQ) was detected as a new metabolite. The content of 3Me6,7MDTIQ in (R)-MDA-treated rat was significantly higher than that in (S)-MDA-treated brain and urine. This result suggests that this metabolism of MDA contains stereoselective pathways. The pharmacological effects of 3Me6,7MDTIQ on behavior differed from those of MDA. The ambulation score of 3Me6,7MDTIQ was significantly decreased compared to the control, and the rearing score of 3Me6,7MDTIQ was moderately decreased compared to the control in an open-field test.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Toxicity of 1-methyl-4-phenylpyridinium derivatives in Escherichia coli.

Several derivatives of 1-methyl-4-phenylpyridinium (MPP+), i.e., 1-methyl-4-(4'-nitrophenyl)pyridinium (1), 1-methyl-4-(4'-cyanophenyl)pyridinium (2), 1-methyl-4-(3'-nitrophenyl)pyridinium (3), 1-methyl-4-(4'-chlorophenyl)pyridinium (4), 1-methyl-4-(4'-acetamidophenyl)pyridinium (5), and 1-methyl-4-(4'-aminophenyl)pyridinium (6), were synthesized in order to compare their toxicity with that of paraquat (PQ2+) in Escherichia coli. Addition of compounds 1, 2, and 3 to aerobic E. coli cell suspensions caused extracellular ferricytochrome c reduction, which was inhibited by superoxide dismutase in the same manner as that in the case of PQ2+. The rate of the ferricytochrome c (cyt. c) reduction was in the order of PQ2+ greater than 1 greater than 2 greater than 3, which is the same as that of the redox potentials of these compounds. On the other hand, MPP+, 4, 5, and 6, which have more negative potentials, had no effect on the cyt. c reduction. Compound 1 inhibited the growth of E. coli under aerobic conditions, but not under anaerobic conditions. The results show that compound 1 can act as a mediator for production of superoxide (O2-.), which seriously injures E. coli cells. However, though compounds 2 and 3 catalyzed the production of O2-. in E. coli cells, their activity of O2-. production was much lower than that of compound 1 or PQ2+. Thus, compound 3 had no effect on growth or survival of E. coli at 1 mM, while compounds 2 and 4 had both bacteriostatic and bacteriocidal effects which were independent of dioxygen (O2). The results show that the toxic mechanism is different from that of compound 1. MPP+, 5, and 6 had no effect on growth of E. coli. This paper shows that compound 1 is a novel enhancer of intracellular superoxide production, though the mechanism of toxicity of compounds 2 and 4 is not clear yet. The results suggest that the redox potential is a crucial factor for manifestation of the activity.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Difference in superoxide toxicity between 4,7-dicyanobenzofurazan and paraquat.

The O2-. production by aerobically cultured Escherichia coli in the presence of benzofurazan (1), 4,7-dimethylbenzofurazan (2), 4,7-dibromobenzofurazan (3), 4-bromo-6-cyanobenzofurazan (4), and 4,7-dicyanobenzofurazan (5) was examined by using the cytochrome c reduction method in order to elucidate the mechanism of cytotoxicity of benzofurazans. Adding compound 5 to E. coli cell suspension caused cytochrome c reduction, which was completely inhibited by superoxide dismutase. The rate of cytochrome c reduction was in the order of 1 = 2 = 3 less than 4 less than 5, which correlates well with that of the reduction potentials of these benzofurazans. Adding glucose to the E. coli cell suspension-compound 5-cytochrome c system accelerated the rate of cytochrome c reduction. The formation of 4,7-dicyanobenzofurazan anion radical in the cell suspension-compound 5-glucose system in the absence of O2 was followed by ESR spectroscopy. The ESR signal of the anion radical disappeared when O2 was added. Compound 5 was shown to have an approximately 10-fold greater increasing effect on the flux of O2-. by E. coli than paraquat (PQ) by the cytochrome c reduction method. The results were confirmed by the electrochemical method with an oxygen electrode. However, compound 5 had a bacteriostatic, but not lethal, effect, while PQ had both effects. The effect of compound 5 and PQ on lethality of E. coli showed a dramatic difference when E. coli was exposed to these two compounds and washed prior to testing the effects of that exposure. This difference probably arose because compound 5 readily leaked from the cells during dilution and plating. Also, the reduced form of compound 5 exits from the cells more readily than the reduced form of PQ and then generates O2-. in the medium by autoxidation. This suggests the importance of the intracellular production of O2-., rather than the extracellular production of O2-., for lethal effect.

Benzoxazoles↗
PubMed1992

Cytochrome P450 isozymes catalyzing 4-hydroxylation of parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline in rat liver microsomes.

Microsomal 4-hydroxylase of 1,2,3,4-tetrahydroisoquinoline (TIQ), a possible candidate for causing Parkinson disease, was characterized by using rat hepatic microsomes and purified P450 isozymes. Kinetic analysis revealed that Km and Vmax values (mean +/- SE) for hepatic microsomal TIQ 4-hydroxylase of male Wistar rats were 319.6 +/- 26.8 microM and 12.13 +/- 1.43 pmol.min-1.mg-1 protein, respectively. When TIQ 4-hydroxylase activity was compared in Wistar (an animal model of extensive debrisoquine metabolizers) and Dark Agouti (an animal model of poor debrisoquine metabolizers) rats, significant strain (Wistar greater than Dark Agouti) and sex (male greater than female) differences were observed. The microsomal activity toward TIQ 4-hydroxylation was increased by pretreatment of male Wistar rats with P448 inducers (beta-naphthoflavone and sudan I), but not with phenobarbital. Pretreatment with propranolol, an inhibitor of P450 isozymes belonging to the P450 IID gene subfamily, decreased TIQ 4-hydroxylase activity. P450 BTL, a P450 isozyme belonging to the IID subfamily, showed TIQ 4-hydroxylase activity of 64.1 pmol.min-1.nmol P450(-1), which was 3.2-fold that of microsomes (20.9 pmol.min-1.nmol P450(-1)). Antibody (IgG) against this isozyme suppressed microsomal TIQ 4-hydroxylase activity concentration-dependently. A male-specific P450 ml (P450IIC11) catalyzed this reaction to a much lesser extent (10.0 pmol.min-1.nmol P450(-1)), and its antibody did not affect the microsomal activity. These results suggest that TIQ 4-hydroxylation in hepatic microsomes are catalyzed predominantly by a P450 isozyme (or isozymes) belonging to the IID gene subfamily in non-treated rats and its immunochemically related P450 isozyme (or isozymes), and that a P450 isozyme (or isozymes) belonging to the IA subfamily also participates in TIQ 4-hydroxylation in rats pretreated with P448-inducers.

Amino Acid Sequence↗
PubMed1992

Bacteriostatic effect of 4,7-dicyanobenzofurazan due to inactivation of 2,3-dihydroxyisovalerate dehydratase.

As part of our research on benzofurazans (BZs), we have reported the bacterioses of BZs in Escherichia coli, which may be due to O2-. produced within E. coli in the presence of dioxygen (O2). Incubation of E. coli with 4,7-dicyanobenzofurazan (1) lowered the 2,3-dihydroxyisovalerate dehydratase activity detectable in extracts from these cells. Addition of branched chain amino acids such as valine and leucine protected E. coli from growth inhibition by compound 1, though it could not protect E. coli from the damage by paraquat (PQ). Addition of Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl]amine (Fe-TPAA), a novel superoxide dismutase mimic, protected the dehydratase in a dose-dependent manner, which confirms that inactivation of the dehydratase is largely due to production of O2-.. The possibility was discussed that the bacteriostatic effect of compound 1 is due to the inactivation of 2,3-dihydroxyisovalerate dehydratase.

Bacteria↗
PubMed1992

New method of detecting nitric oxide production.

Nitric oxide (NO) reacts with H2O2 to produce a rise in potent luminol-dependent chemiluminescence under neutral pH conditions. We applied this reaction to the continuous detection of NO released from the rat isolated perfused kidney with simultaneous pressure changes. Acetylcholine increased NO release dose-dependently with the pressure reduction. An NO synthesis inhibitor, NG-monomethyl-L-arginine, abolished the release. This inhibition was reversed by the addition of L-arginine.

Animals↗
PubMed1992

Amphetamine-antagonistic property of 4-phenyltetrahydroisoquinoline: effect on noradrenaline release in spinal cord slices.

The amphetamine-related compounds methamphetamine, phenylethylamine and nomifensine increased the K(+)-evoked release of endogenous noradrenaline from rat spinal cord slices. 4-Phenyl-1,2,3,4-tetrahydroisoquinoline (4PTIQ), which alone did not affect the K(+)-evoked release of noradrenaline, inhibited the noradrenaline-releasing effects of methamphetamine, phenylethylamine and nomifensine. 4PTIQ revealed a weak noradrenaline-uptake inhibitory effect, and the effect was weaker than those of desipramine and nomifensine. These results showed that 4PTIQ is an antagonist against the amine-releasing effects of amphetamines.

Amphetamine↗