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41.
42.
A Narimatsu K Nakao H Ikoma M Egawa Y Kitada S Yamazaki K Umezu M Miyake E Nishimura N Hashimoto 《Nihon yakurigaku zasshi. Folia pharmacologica Japonica》1986,87(2):223-251
MCI-2016 at 3 mg/kg, i.v., caused slight changes in systemic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and ECG but at 10 mg/kg, i.v., it caused a significant increase in RR, decrease in SBP, increase or decrease in HR and a moderate change in ECG. Biphasic changes in SBP, HR and blood flow were sometimes observed after high doses. MCI-2016 also decreased SBP at 30 mg/kg, i.p., in SHR. MCI-2016 (50 mg/kg, p.o./day) showed little influence on SBP, HR and ECG in conscious beagle dogs. In isolated hearts, MCI-2016 decreased HR and contractility at the concentrations above 10(-5) g/ml, and 30 micrograms, i.a. MCI-2016 prolonged the AVCT at 10 mg/kg, i.v. MCI-2016 (i.v. or i.a.) moderately increased cerebral and femoral artery blood flows. MCI-2016 did not change CMRO2, but decreased MVO2. Coronary and renal artery flows were moderately increased by 10 mg/kg, i.v., of MCI-2016. Renal function was suppressed after 10 mg/kg, i.v., or 300 mg/kg, p.o., of MCI-2016. MCI-2016 potentiated the action of NE (increase in SBP, contractions of nictitating membrane and vas deferens), but showed little anti-cholinergic action. In contrast, MCI-2016 moderately increased gastrointestinal motility and salivatory response. As for the influence on isolated smooth muscles, MCI-2016 antagonized the contraction of blood vessels by high K+ at 10(-6) g/ml, or more, and it depressed the contractions by ACh, 5-HT, histamine and BaCl2 and also depressed spontaneous movements of uterus and ileum at 10(-5) M or more, in a nonspecific manner. MCI-2016 had no influence on liver damage and bile secretion, but inhibited stress ulcer and gastric acid secretion on the one hand, and caused gastric damage (125 mg/kg p.o., or more) on the other hand. 相似文献
43.
K Watanabe M Arai S Narimatsu I Yamamoto H Yoshimura 《Biochemical pharmacology》1986,35(11):1861-1865
The effects of delta 8-tetrahydrocannabinol (delta 8-THC) and its major and active metabolite, 11-hydroxy-delta 8-tetrahydrocannabinol (11-OH-delta 8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-delta 8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with delta 8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-delta 8-THC increased the Vmax, but not the Km, values for both drug-metabolizing enzymes, whereas delta 8-THC decreases significantly the Km value (270 microM) for p-nitroanisole O-demethylase as compared with the control (398 microM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of delta 8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-delta 8-THC. In contrast, microsomal formation of 7 alpha-OH-delta 8-THC was decreased significantly by treatment with delta 8-THC. 11-OH-delta 8-THC, but not delta 8-THC, treatment increased the metabolism of 11-OH-delta 8-THC by hepatic microsomes. These findings indicate that delta 8-THC and 11-OH-delta 8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes. 相似文献
44.
Y Kitada M Kobayashi A Narimatsu Y Ohizumi 《The Journal of pharmacology and experimental therapeutics》1989,250(1):272-277
In the present study we have analyzed a likely biochemical mechanism underlying the Ca++-sensitizing action of MCI-154 (6-[4-(4'-pyridyl)aminophenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride), a novel cardiotonic agent, on the contractile protein system. MCI-154 (10(-7) to 10(-4) M) enhanced the tension development induced by -log molar-free Ca++ concentration (pCa) 5.8 in chemically skinned fiber from the canine right ventricular muscle in a concentration-dependent manner. At pCa 7.0, MCI-154 (10(-7) to 10(-4) M) markedly increased adenosine triphosphatase (ATPase) activities of canine myofibrils and reconstituted actomyosin. In myofibrils and reconstituted actomyosin, MCI-154 (10(-7) to 10(-4) M) caused a parallel shift of the pCa-ATPase activity relation curve to the left without affecting the maximum activity, suggesting an increase in Ca++ sensitivity. MCI-154 (10(-8) to 10(-4) M) had little effect on actin-activated, Mg++, Ca++ and (K+, EDTA)-ATPase activities of myosin. Ca++ binding to cardiac myofibrils or purified cardiac troponin was increased by 10(-4) M MCI-154. These results suggest that MCI-154 enhances Ca++ binding to cardiac troponin C to elevate the Ca++ sensitivity of myofilaments and thus may cause a positive inotropic action in cardiac muscle. MCI-154 may provide a valuable tool for studying the molecular mechanism by which Ca++ regulates the contractile system. 相似文献
45.
Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling 总被引:1,自引:0,他引:1 下载免费PDF全文
Nakaoka Y Nishida K Narimatsu M Kamiya A Minami T Sawa H Okawa K Fujio Y Koyama T Maeda M Sone M Yamasaki S Arai Y Koh GY Kodama T Hirota H Otsu K Hirano T Mochizuki N 《The Journal of clinical investigation》2007,117(7):1771-1781
Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1beta (NRG-1beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart. 相似文献
46.
Nishimura M Ejiri Y Kishimoto S Suzuki S Satoh T Horie T Narimatsu S Naito S 《Drug metabolism and pharmacokinetics》2011,26(2):137-144
We evaluated a novel three-dimensional primary culture system using micro-space plates to determine the expression levels of 61 target (drug-metabolizing enzymes, transporters, and nuclear receptors) mRNAs in human hepatocytes. We measured mRNA expression levels of many target genes in four lots of cryopreserved human hepatocyte primary cells after 120 h of culture and compared differences in mRNA expression levels between cultures using traditional plates and those using micro-space plates. In this study, we show that the mRNA levels of many experimental targets in human hepatocytes before inoculation resemble the levels inside the human liver. Furthermore, we show that the rate of change of expression levels of many target mRNAs relative to the value before inoculation of the hepatocytes into micro-space plates was relatively smaller than the rate of change in hepatocytes inoculated into traditional plates. Pharmacokinetics-related examinations using this system are possible within a time frame of 120 h. We report that this novel three-dimensional culture system reproduces mRNA expression levels that are nearer to those in the liver in vivo and is an excellent platform for maintaining mRNA expression levels of drug-metabolizing enzymes and transporters when compared to common monolayer cultures. 相似文献
47.
Moriwaki K Okudo K Haraguchi N Takeishi S Sawaki H Narimatsu H Tanemura M Ishii H Mori M Miyoshi E 《Cancer science》2011,102(6):1164-1170
Glycans exhibit characteristic changes in their structures during development and thus have been used as markers for stem/progenitor cells. However, the glycan structures unique to cancer stem cells (CSC) remain unknown. In the present study, we examined glycan structures in CD133+ CD13+ CSC, which were recently found to have a high CSC ability, by means of a lectin microarray. Seven sialylated glycan-recognizing lectins, MAL-I, SNA, SSA, TJA-I, ACG, ABA and MAH, showed higher affinity to CD133+ CD13+ CSC than CD133+ cells with a lower CSC ability. In addition, we demonstrated that CD133+ SSA+ cells isolated from Huh7 cells had a significantly higher ability to form tumors in non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice and spheres under serum-free conditions than CD133+ SSA- cells. These results suggest that hepatic CSC highly express sialylated glycans and that SSA lectin can be used as a tool for isolating CSC. This study is the first report to demonstrate the characteristic glycan structures in CSC and to indicate a new methodology involving lectins for isolating CSC. 相似文献
48.
Miyakoshi S Kami M Tanimoto T Yamaguchi T Narimatsu H Kusumi E Matsumura T Takagi S Kato D Kishi Y Murashige N Yuji K Uchida N Masuoka K Wake A Taniguchi S 《Transplantation》2007,84(3):316-322
BACKGROUND: Myeloablative cord blood transplantation (CBT) for adult patients offers a 90% chance of engraftment with a 50% rate of transplant-related mortality, mostly attributable to infection. We have demonstrated the feasibility of reduced-intensity CBT (RI-CBT) for adult patients, in which cyclosporine was used for acute graft-versus-host disease (GVHD) prophylaxis. Transplantation-related mortality (TRM) was 27% within 100 days. Therefore our objective was to evaluate the feasibility of RI-CBT with tacrolimus as GVHD prophylaxis for adult patients with hematologic malignancies. METHODS: Thirty-four patients with a median age of 56.5 years (range; 22-68) with hematologic diseases underwent RI-CBT at Toranomon Hospital between November 2003 and September 2004. Preparative regimen comprised fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. GVHD prophylaxis was continuous intravenous infusion of tacrolimus 0.03 mg/kg, starting on day -1. RESULTS: Thirty-one patients achieved neutrophil engraftment at a median of day 20. Median infused total cell dose was 2.4 x 10E7/kg (range; 1.6-4.8). Thirty-two patients achieved complete donor chimerism at day 60. Grade II-IV acute GVHD occurred in 45% of patients, with a median onset of day 26. Primary disease recurred in five patients, and TRM within 100 days was 12%. Estimated 1-year overall survival was 70%. CONCLUSION: This study demonstrated the possible improvement in transplant-related mortality by tacrolimus as GVHD prophylaxis in adult RI-CBT recipients. 相似文献
49.
Hanioka N Tsuneto Y Saito Y Sumada T Maekawa K Saito K Sawada J Narimatsu S 《Xenobiotica; the fate of foreign compounds in biological systems》2007,37(4):342-355
Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of a wide range of therapeutic drugs and exhibits genetic polymorphism with interindividual differences in metabolic activity. We have previously described two CYP2C19 allelic variants, namely CYP2C19*18 and CYP2C19*19 with Arg329His/Ile331Val and Ser51Gly/Ile331Val substitutions, respectively. In order to investigate precisely the effect of amino acid substitutions on CYP2C19 function, CYP2C19 proteins of the wild-type (CYP2C19.1B having Ile331Val) and variants (CYP2C19.18 and CYP2C19.19) were heterologously expressed in yeast cells, and their S-mephenytoin 4'-hydroxylation activities were determined. The K(m) value of CYP2C19.19 for S-mephenytoin 4'-hydroxylation was significantly higher (3.0-fold) than that of CYP2C19.1B. Although no significant differences in V(max) values on the basis of microsomal and functional CYP protein levels were observed between CYP2C19.1B and CYP2C19.19, the V(max)/K(m) values of CYP2C19.19 were significantly reduced to 29-47% of CYP2C19.1B. By contrast, the K(m), V(max) or V(max)/K(m) values of CYP2C19.18 were similar to those of CYP2C19.1B. These results suggest that Ser51Gly substitution in CYP2C19.19 decreases the affinity toward S-mephenytoin of CYP2C19 enzyme, and imply that the genetic polymorphism of CYP2C19*19 also causes variations in the clinical response to drugs metabolized by CYP2C19. 相似文献