Biomedical subjects

Y Yamanaka

Publications and source records attributed to Y Yamanaka.

At least 19 recordsLinked to original sources

PubMed2000

Protective effect of fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on MPP(+)-induced hydroxyl radical in the rat striatum.

We examined whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist 1-methyl-4-phenylpyridine (MPP(+))-induced hydroxyl radical generation (.OH) in the extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microliter/min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) (5 mM; total dose 75 nmol) clearly produced an increase in.OH formation. However, fluvastatin (100 microM) reduced the.OH formation by the action of MPP(+). These results indicated that fluvastatin, a potent inhibitor of LDL oxidation, may resist the formation of.OH products of MPP(+).

1-Methyl-4-phenylpyridinium↗

PubMed2000

Reserpine attenuates interstitial adenosine-mediated activation of ecto-5'-nucleotidase in rat hearts in vivo.

We examined whether reserpine-induced norepinephrine (NE) depletion attenuated the products of adenosine in rat heart. A flexibly mounted microdialysis technique was used to measure the concentration of interstitial adenosine and to assess the activity of ecto-5'-nucleotidase in rat hearts in situ. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused with Tyrode solution containing adenosine 5'-monophosphate (AMP) at rate of 1.0 microliter/min. The baseline level of dialysate adenosine was 0.51 +/- 0.09 microM. The introduction of AMP (100 microM) through the probe increased markedly the dialysate adenosine to 8.95 +/- 0.86 microM, and this increase was inhibited by ecto-5'-nucleotidase inhibitor, alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP, 100 microM), to 0.66 +/- 0.38 microM. Thus, the level of dialysate adenosine is a measure of the ecto-5'-nucleotidase activity in the tissue in situ. AMP concentration for the half-maximal effect of adenosine release (EC(50)) was 107.3 microM. The maximum attainable concentration of dialysate adenosine (E(max)) by AMP was 21.1 microM. However, the EC(50) and E(max) values with reserpinized animals were 106.9 and 7.1 microM, respectively. Electrical stimulation of the left stellate ganglion increased significantly dialysate adenosine concentration, from the control level of 8.66 +/- 0.96 microM to 12.38 +/- 1.11 microM. After stimulation, dialysate adenosine returned to near the prestimulation level. When corresponding experiments were performed with reserpinized animals, the effect of electrical stimulation was abolished. Tyramine (endogenous catecholamine trigger) increased the adenosine concentration in a concentration-dependent manner. However, the elevation of adenosine concentration with reserpinized animals was not observed. These results suggest that reserpine attenuates NE-induced adenosine via stimulation of alpha(1)-adrenoceptor and protein kinase C mediated activation of ecto-5'-nucleotidase in rat heart.

5'-Nucleotidase↗

PubMed2000

Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish.

In vertebrates, specification of the dorso-ventral axis requires Wnt signaling, which leads to formation of the Nieuwkoop center and the Spemann organizer (dorsal organizer), through the nuclear accumulation of beta-catenin. Zebrafish bozozok/dharma (boz) and squint (sqt), which encode a homeodomain protein and a Nodal-related protein, respectively, are required for the formation of the dorsal organizer. The zygotic expression of boz and sqt in the dorsal blastoderm and dorsal yolk syncytial layer (YSL) was dependent on the maternally derived Wnt signal, and their expression at the late blastula and early gastrula stages was dependent on the zygotic expression of their own genes. The dorsal organizer genes, goosecoid (gsc) and chordin (din), were ectopically expressed in wild-type embryos injected with boz or sqt RNA. The expression of gsc strictly depended on both boz and sqt while the expression of din strongly depended on boz but only partially depended on sqt and cyclops (cyc, another nodal-related gene). Overexpression of boz in embryos defective in Nodal signaling elicited the ectopic expression of din but not gsc and resulted in dorsalization, implying that boz could induce part of the organizer, independent of the Nodal proteins. Furthermore, boz; sqt and boz;cyc double mutants displayed a severely ventralized phenotype with anterior truncation, compared with the single mutants, and boz;sqt;cyc triple mutant embryos exhibited an even more severe phenotype, lacking the anterior neuroectoderm and notochord, suggesting that Boz/Dharma and the Nodal-related proteins cooperatively regulate the formation of the dorsal organizer.

Animals↗

PubMed2000

Potassium chloride depolarization enhances MPP+-induced hydroxyl radical generation in the rat striatum.

We determined that extracellular potassium ion concentration, [K+]o-induced depolarization, enhances 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of high concentration KCl (70 mM) drastically increased formation of *OH trapped as DHBA by the action of MPP+. When dopamine (DA) was administered to the high KCl-treated animals, a marked elevation of DHBA was observed, compared with MPP+-only-treated animals, that showed a positive linear correlation between DA and *OH formation trapped as DHBA (R2 = 0.979) in the dialysate. When corresponding experiments were performed with iron (II), the same results were obtained: a positive linear correlation between the release of iron (II) and DHBA (R2 = 0.988) in the dialysate. These results suggest that [K+]o-induced depolarization enhances the formation of *OH products of efflux/oxidation due to MPP+.

1-Methyl-4-phenylpyridinium↗

PubMed2000

Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation.

We identified a zebrafish homologue of Dickkopf-1 (Dkk1), which was previously identified in Xenopus as a Wnt inhibitor with potent head-inducing activity. Zebrafish dkk1 is expressed in the dorsal marginal blastoderm and also in the dorsal yolk syncytial layer after mid-blastula transition. At later blastula stages, the expression expands to the entire blastoderm margin. During gastrulation, dkk1-expressing cells are confined to the embryonic shield and later to the anterior axial mesendoderm, prospective prechordal plate. Embryos, in which dkk1 was ectopically expressed, exhibited enlarged forebrain, eyes, and axial mesendoderm such as prechordal plate and notochord. dkk1 expression in the dorso-anterior mesendoderm during gastrulation was prominently reduced in zebrafish mutants bozozok (boz), squint (sqt), and one-eyed pinhead (oep), which all display abnormalities in the formation and function of the Spemann organizer and axial mesendoderm. dkk1 expression was normal in these embryos during the blastula period, indicating that zygotic functions of these genes are required for maintenance but not establishment of dkk1 expression. Overexpression of dkk1 suppressed defects in the development of forebrain, eyes, and notochord in boz mutants. Overexpression of dkk1 promoted anterior neuroectoderm development in the embryos injected with antivin RNA, which lack most of the mesoderm and endoderm, suggesting that Dkk1 can affect regionalization of neuroectoderm independently of dorso-anterior mesendoderm. These data indicate that Dkk1, expressed in dorsal mesendoderm, functions in the formation of both the anterior nervous system and the axial mesendoderm in zebrafish.

Amino Acid Sequence↗

PubMed2000

Conformational behavior of C alpha,alpha-diphenyl glycine: extended conformation in tripeptides containing consecutive D phi G residues.

Recent studies on the conformational preferences of the Dphig (C(alpha,alpha)-diphenylglycine) residue showed that this C(alpha,alpha)-disubstituted glycine has a structural versatility. In fact, depending on the nature of the following or preceding residue, Dphig can assume either folded or extended conformations. We have carried out the analysis of the conformational preferences of the Dphig residue in tripeptides containing consecutive Dphig residues. The crystal structures of Z-Dphig-Dphig -Dphig-OMe (a; Z = benzyloxycarbonyl; OMe = methyl ester), Z-Aib-Dphig-Dphig-OMe (b; Aib = alpha-aminoisobutyric acid), and Z-Ac(3)c-Dphig-Dphig-OMe (c; Ac(3)c = alpha-amino-cyclopropan carboxylic acid), are here reported. The Dphig residues adopt the fully extended conformation in the three tripeptides examined. Together with our previous findings on Dphig containing peptides, the structures of the peptides here examined, indicate that the presence of adjacent Dphig residue in the sequence further stabilizes the extended conformation.

Crystallography, X-Ray↗

PubMed1999

Protective effect of imidaprilat, an angiotensin-converting enzyme inhibitor on *OH generation in rat myocardium.

We used a flexibly mounted microdialysis technique to the hearts of rats and examined the protective effect of imidaprilat, an angiotensin-converting enzyme (ACE) inhibitor, on the production of hydroxyl free radical (*OH) generation. A microdialysis probe was implanted into the left ventricular myocardium, and dialysate norepinephrine (NE) concentrations were measured as an index of myocardial interstitial NE levels. Sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was directly infused through a microdialysis probe to detect the generation of *OH reflected by the formation of dihydroxybenzoic acid (DHBA) in rat myocardium. When tyramine (1 mM) was directly infused through the microdialysis probe, the level of NE significantly increased in the dialysate and the level of NE increased by 128 +/- 43%. Imidaprilat (5, 25 and 50 microM) decreased the level of tyramine (1 mM)-induced NE in a concentration-dependent manner. Tyramine clearly produced an increase in *OH formation. In the presence of imidaprilat (50 microM), tyramine failed to increase both 2,3- and 2,5-dihydroxylation. Therefore, the effects of imidaprilat on the *OH generation in the sympathetic nerve blockaded hearts by reserpine treatment were not observed. Moreover, to examine the effect of imidaprilat on *OH formation by ischemia/reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, elevation of NE and 2,3- and 2,5-DHBA in imidaprilat (50 microM)-pretreated animals was not observed in the heart dialysate. Imidaprilat 2.5 mg/kg i.p. pretreatment at 5 h before coronary occlusion significantly blunted the rise of serum creatine phosphokinase and improved the electrocardiogram 2 h after coronary occlusion. These results suggest that imidaprilat, an ACE inhibitor, is associated with cardioprotective effect due to the suppression of NE-induced *OH generation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Prazosin attenuates hydroxyl radical generation in the rat myocardium.

The present study examined whether tyramine-induced hydroxyl radical (*OH) generation via noradrenaline release was attenuated by prazosin. A flexibly mounted microdialysis technique was used to detect the generation of *OH in in vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anaesthetized rats and Ringer's solution was used. To measure the level of *OH, sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused directly through a microdialysis probe to detect the generation of *OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA). Tyramine (0.1, 0.5 and 1.0 mM) increased the level of 2,3-DHBA in a concentration-dependent manner. However, in the presence of prazosin (10 microM), the effect of tyramine was abolished. To confirm the generation of *OH by a Fenton type reaction, iron (II) was infused through a microdialysis probe. A positive linear correlation between iron (II) and the formation of 2,3-DHBA (R2 = 0.982) was observed. To examine the effect of prazosin on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, in the presence of prazosin (10 microM), the elevation of 2,3-DHBA was not observed in ischemic/reperfused rat heart. Prazosin was shown to have a *OH scavenging effect. These results suggest that tyramine-induced noradrenaline causes *OH generation, an effect which is inhibited by prazosin as Na+ channel blocker, but not through its alpha1-adrenoceptor antagonistic action of prazosin.

Adrenergic alpha-Agonists↗

PubMed1999

Tyramine produces interstitial adenosine-mediated activation of ecto-5'-nucleotidase in rat heart in vivo.

We examined the effect of tyramine on the production of adenosine in rat heart. A flexibly mounted microdialysis setup was used to measure the concentration of interstitial adenosine and to assess the activity of ecto-5'-nucleotidase in in vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused with Tyrode solution containing adenosine 5'-monophosphate (AMP) at a rate of 1.0 microl/min. The concentration of adenosine in the effluent (dialysate) was measured by high-performance liquid chromatography (HPLC). Dialysate adenosine obtained during perfusion with the AMP-containing solution through the probe originated from the hydrolysis of AMP by endogenous ecto-5'-nucleotidase, and the level of adenosine reflected the activity of ecto-5'-nucleotidase in the tissue. Tyramine (0-4 mM) increased the adenosine concentration measured during the perfusion of AMP (100 microM) in a concentration-dependent manner. Alpha,beta-methyleneadenosine 5'-diphosphate (alpha,beta-meADP, 100 microM), an inhibitor of ecto-5'-nucleotidase, abolished the AMP-induced increase in dialysate adenosine. Tyramine (1 mM) increased the adenosine concentration measured in the presence of 100 microM AMP (i.e., the activity of ecto-5'-nucleotidase) by 65.8 +/- 19.9% (n = 6, P < 0.05), an increase which was inhibited by an antagonist of the alpha1-adrenoceptor (prazosin, 50 microM) or of protein kinase C (chelerythrine, 10 microM). These data provide the first evidence that alpha1-adrenoceptor stimulation and the subsequent activation of protein kinase C can increase adenosine concentrations in the interstitial space of ventricular muscle in vivo, through activation of endogenous ecto-5'-nucleotidase. To examine the effect of tyramine on the production of adenosine by ischemia-reperfusion of the rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, elevation of the level of adenosine in the ischemic zone was observed, but this change was not significant. However, when corresponding experiments were performed with a subsequent systemic administration of tyramine (1 mM), a marked elevation in the level of adenosine was observed. The results suggest that tyramine elevates adenosine via stimulation of alpha1-adrenoceptors and protein kinase C-mediated activation of ecto-5'-nucleotidase in rat heart.

5'-Nucleotidase↗

PubMed1999

Changes in monoamine metabolites concentrations in rat cerebrospinal fluid after acute and long-term administration of a selective serotonin reuptake inhibitor, trazodone.

In order to clarify the mechanism of the antidepressive effects of trazodone, a selective serotonin reuptake inhibitor, we investigated the dynamics of monoamine metabolites in cerebrospinal fluid (CSF) of free-moving conscious rats by acute and long-term treatment with trazodone. When 100 mg kg-1 p.o. of trazodone were administered, a significant increase of 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration was soon observed in the light period of the light/dark cycle, and a significant decrease of dihydroxy phenyl acetic acid (DOPAC) concentration was observed during the 2 days after administration of trazodone; in contrast, the homovanilic acid (HVA) level was increased. However, we detected no significant changes in the 5-hydroxy indole-3-acetic acid (5-HIAA) concentration during the 3 days. In the case of long-term treatment with 50 mg kg-1, p.o. of trazodone, the levels of MHPG, DOPAC and HVA exhibited no difference when compared with values obtained during saline treatment in either the light or dark period, whereas the levels of 5-HIAA showed a significant increase during the light period. These findings suggest that a long-term treatment with trazodone enhances the serotonergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Preoperative concurrent chemoradiotherapy plus radical surgery for advanced squamous cell carcinoma of the oral cavity: an analysis of long-term results.

Locoregionally advanced squamous cell carcinomas of the head and neck continue to be a major clinical problem. We demonstrated in 1996 that preoperative concurrent cisplatin- or carboplatin-based chemotherapy and radiotherapy plus radical surgery in advanced oral cancer had minimal toxicity, had high clinical tumor response rates, was well tolerated and produced impressive complete response rates and a high 5-year survival rate. The purpose of the present study was the long-term follow-up of this treatment regimen for advanced oral carcinoma. Forty-eight patients with squamous cell carcinoma of the oral cavity (including soft palate) were treated preoperatively with cisplatin- or carboplatin-based chemotherapy in combination with simultaneous irradiation to a target volume of 40 Gy, and 2-6 weeks later underwent curative surgery. All patients with advanced Stage II (n=7), Stage III (n=22) and Stage IV (n=19) were treated and followed for an average of 7.2 years (range: 61-144 months). The overall actuarial survival of all patients was 81.3% at 5 years and also at 10 years. Progression-free survival at both 5 and 10 years was 84.8% for all patients, and 85.7% for Stage II, 90.0% for Stage III, and 78.9% for Stage IV patients. Progression-free survival rates according to the histopathologic regression grade of primary tumor following preoperative chemoradiotherapy at 10 years were 40. 0% for Grade IIa, 88.9% for Grade IIb, 100% for Grade III, and 87.5% for Grade IV. Patients who achieved good responses histopathologically (Grades IIb, III, IV) had superior survival rates in comparison to patients with extensive residual tumor (Grade IIa) in surgically resected specimens (p=0.0012). A better histologic regression grade was also associated with a higher survival rate even in the long-term analysis. This treatment regimen for advanced oral cancer produced high clinical and pathologic complete response and survival rates with an acceptable acute toxicity profile and lack of late therapeutic complications. The long-term follow-up showed gratifying results even for advanced oral cancers without a substantial increase in distant metastasis and second primary malignancy.

Adult↗

PubMed1999

Characterization of insulin-like growth factor binding protein-3 (IGFBP-3) binding to human breast cancer cells: kinetics of IGFBP-3 binding and identification of receptor binding domain on the IGFBP-3 molecule.

Insulin-like growth factor binding protein-3 (IGFBP-3) binds to specific membrane proteins located on human breast cancer cells, which may be responsible for mediating the IGF-independent growth inhibitory effects of IGFBP-3. In this study, we evaluated IGFBP-3 binding sites on breast cancer cell membranes by competitive binding studies with IGFBP-1 through -6 and various forms of IGFBP-3, including synthetic IGFBP-3 fragments. Scatchard analysis revealed the existence of high-affinity sites for IGFBP-3 in estrogen receptor-negative Hs578T human breast cancer cells (dissociation constant (Kd) = 8.19 +/- 0.97 x 10(-9) M and 4.92 +/- 1.51 x 10(5) binding sites/cell) and 30-fold fewer receptors in estrogen receptor-positive MCF-7 cells (Kd = 8.49 +/- 0.78 x 10(-9) M and 1.72 +/- 0.31 x 10(4) binding sites/cell), using a one-site model. These data demonstrate binding characteristics of typical receptor-ligand interactions, strongly suggesting an IGFBP-3:IGFBP-3 receptor interaction. Among IGFBPs, only IGFBP-5 showed weak competition, indicating that IGFBP-3 binding to breast cancer cell surfaces is specific and cannot be attributed to nonspecific interaction with glycosaminoglycans. This was confirmed by showing that synthetic IGFBP-3 peptides containing IGFBP-3 glycosaminoglycan-binding domains competed only weakly for IGFBP-3 binding to the cell surface. Rat IGFBP-3 was 20-fold less potent in its ability to compete with human IGFBP-3(Echerichia coli), as well as 10- to 20-fold less potent for cell growth inhibition than human IGFBP-3, suggesting the existence of species specificity in the interaction between IGFBP-3 and the IGFBP-3 receptor. When various IGFBP-3 fragments were evaluated for affinity for the IGFBP-3 receptor, only those fragments that contain the midregion of the IGFBP-3 molecule were able to inhibit 125I-IGFBP-3(Escherichia coli) binding, indicating that the midregion of the IGFBP-3 molecule is responsible for binding to its receptor. These observations demonstrate that specific, high-affinity IGFBP-3 receptors are located on breast cancer cell membranes. These receptors have properties that support the notion that they may mediate the IGF-independent inhibitory actions of IGFBP-3 in breast cancer cells.

Amino Acid Sequence↗

PubMed1999

Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF-binding protein-3 concentrations in normal children and children with growth hormone deficiency.

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0-40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71 +/- 0.26 microg/L, mean +/- SD; females, 1.05 +/- 0.49 microg/L), increased during puberty (males, 5.84 +/- 2.18 microg/L; females, 5.80 +/- 1.49 microg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95-2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77 +/- 0.60%; females, 2.02 +/- 0.87%). 3) The SD scores of serum free IGF-I in the 21 GHD children ranged from -3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than -2 SD below those of age-matched normal subjects. 4) There was a significant correlation between the SD scores of free IGF-I and those of total IGF-I (r = 0.715; P < 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05). These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.

Adolescent↗

PubMed1999

The zebrafish bozozok locus encodes Dharma, a homeodomain protein essential for induction of gastrula organizer and dorsoanterior embryonic structures.

The dorsal gastrula organizer plays a fundamental role in establishment of the vertebrate axis. We demonstrate that the zebrafish bozozok (boz) locus is required at the blastula stages for formation of the embryonic shield, the equivalent of the gastrula organizer and expression of multiple organizer-specific genes. Furthermore, boz is essential for specification of dorsoanterior embryonic structures, including notochord, prechordal mesendoderm, floor plate and forebrain. We report that boz mutations disrupt the homeobox gene dharma. Overexpression of boz in the extraembryonic yolk syncytial layer of boz mutant embryos is sufficient for normal development of the overlying blastoderm, revealing an involvement of extraembryonic structures in anterior patterning in fish similarly to murine embryos. Epistatic analyses indicate that boz acts downstream of beta-catenin and upstream to TGF-beta signaling or in a parallel pathway. These studies provide genetic evidence for an essential function of a homeodomain protein in beta-catenin-mediated induction of the dorsal gastrula organizer and place boz at the top of a hierarchy of zygotic genes specifying the dorsal midline of a vertebrate embryo.

Animals↗

PubMed1999

Protective effect of histidine on hydroxyl radical generation induced by potassium-depolarization in rat myocardium.

We investigated the efficacy of histidine on potassium-depolarization induced hydroxyl radical (*OH) generation in the extracellular fluid of rat myocardium by a flexibly mounted microdialysis technique (O system). After the rat was anesthetized, a microdialysis probe was implanted in the left ventricular myocardium, and then sodium salicylate in Ringer's solution (0.5 nmol/microl per minute) was infused to detect the generation of *OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA). Infusion of KCl (70 mM) clearly produced an increase in *OH formation. However, when KCl in the presence of a high concentration of histidine (25 mM) was infused through the microdialysis probe, KCl failed to increase the 2,3-DHBA formation. To examine the effect of histidine on ischemia-reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, a marked elevation of the levels of 2,3-DHBA was observed in the heart dialysate. However, when corresponding experiments were performed with histidine (25 mM)-pretreated animals, histidine prevented the ischemia-reperfusion induced *OH formation trapped as 2,3-DHBA. These results indicate that histidine may protect against K+-depolarization-evoked *OH generation in rat myocardium.

Animals↗

PubMed1999

Monitoring of radical scavenging activity of peroral administration of the Kampo medicine Sho-saiko-to in rats.

The Kampo medicine Sho-saiko-to scavenged superoxide anion radicals (O2-), hydroxyl radicals (*OH) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals in a dose-dependent fashion. We attempted to investigate the transition of free radical scavenging activity in plasma after oral administration of Sho-saiko-to in rats. From the response-time profile, kinetic parameters including values for Ka (absorption rate constant), Tmax (peak concentration time), T1/2 (half life) and MRT (mean residence time) of radical scavenging activity in plasma could be calculated for the O2-, *OH and DPPH radicals. These parameters calculated from the dynamics of antioxidation are considered a very meaningful procedure to examine the effects of Sho-saiko-to.

Animals↗

PubMed1999

The inhibition of monoamine oxidase activity by various antidepressants: differences found in various mammalian species.

The effects of the antidepressant drugs zimeldine, imipramine, maprotiline or nomifensine on mitochondrial monoamine oxidase (MAO) activity in mouse, rat, dog and monkey brains were compared in vitro. Mouse, rat, dog and monkey brain MAO-B activities were inhibited by zimeldine more potently than MAO-A activity. Imipramine inhibited MAO-B more potently than MAO-A activity in mouse and rat brains. When dog and monkey brains were investigated, MAO-A activity was inhibited more potently than MAO-B activity at high concentrations of imipramine, while at low concentrations, MAO-B activity was more potently inhibited. Maprotiline and nomifensine inhibited mouse and rat brain MAO-B activity more potently than MAO-A activity, while the inverse was true for dog and monkey brains. All four drugs are competitive inhibitors of MAO-A, but noncompetitive inhibitors of MAO-B in all animal brains. The respective Ki values of these reagents for monkey brain MAO-A and MAO-B were low compared to those of mouse, rat and dog. These results indicate that monkey brain MAOs are more sensitive to antidepressant drugs than those in rodent brain.

Animals↗

PubMed1999

NO contribution to lipopolysaccharide-induced hepatic damage in galactosamine-sensitized mice.

To investigate the role of nitric oxide (NO) in hepatitis-induced endotoxemia, we injected mice intraperitoneally with 250 mg/kg galactosamine (GalN) and 1 mg/kg lipopolysaccharide (LPS) separately and in combination. NO synthesis increased in a dose-dependent manner with LPS. NO generation at 5 hr after administration of LPS was greater than that at 24 hr. Enhancement of NO generation was demonstrated in mice administered GalN and LPS in combination. A nitrosyl-heme signal in 10,000 g supernatant of liver homogenate, due to cytochrome P450 (P450) combining with NO, NO-P450, was detected at more than ten hr and even more after administration of LPS by electron spin resonance (ESR) measurements at 77 degrees K. The strongest NO-P450 signal and most extreme elevation of aspartate oxoglutarate aminotransferase (AST), alanine oxoglutarate aminotransferase (ALT), and lactate dehydrogenase (LDH) in serum and of lysosomal enzyme activity in plasma were observed in the GalN + LPS group. Their potency was greater than in the 10 mg/kg LPS group, which was even greater than in the LPS 1 mg/kg group. The aniline hydroxylase activity was inversely proportional to NO-P450 signal intensity. It appears that NO might contribute to LPS-induced hepatic damage in GalN-sensitized mice through degeneration and inactivation of liver microsomal enzymes by binding P450 active sites.

Aniline Hydroxylase↗