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Biomedical subjects

M Takemoto

Publications and source records attributed to M Takemoto.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cepharanthin enhances thermosensitivity without a resultant reduction in the thermotolerance of a murine mammary carcinoma.

Cepharanthin (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. The results of our previous in vitro study indicated that Ce reduces thermotolerance by enhancing thermosensitivity. In the present study, we investigated the in vitro and in vivo effects of Ce on thermosensitivity and thermotolerance using a murine mammary carcinoma, MCa, and C3H/HeN mice. Ce enhanced the thermosensitivity of MCa cells for heating at 44 degrees C not only in vitro but also in vivo. The in vivo enhancement ratio +/- SD of Ce at 100 mg/kg for heating at 44 degrees C was 1.3+/-0.3. The fractionated heat treatments at 44 degrees C for 30 and 60 min with an interval time of 0-6 days resulted in the development of remarkable thermotolerance and the expression of heat shock protein 70 in MCa tumors after the first heating. Ce at 100 mg/kg given immediately after the first heating increased the expression of heat shock protein 70 in MCa tumors, and did not reduce the development of thermotolerance. Ce given immediately before the first or second heating also did not inhibit the thermotolerance. The results of this study suggest that Ce enhances the thermosensitivity of MCa tumors as a thermosensitizer, but that this mild thermosensitizing property of Ce might be insufficient to conquer the remarkable thermotolerance in MCa tumors that develops after the first heating.

Alkaloids↗
PubMed1999

[Vascular remodeling and angiotensin II].

Numerous pharmacological approaches have failed to modify the high incidence of restenosis after balloon coronary angioplasty. This inability to alter the restenosis process was caused in part by our incomplete understanding of its pathology. Neointimal formation and geometric remodeling cause the restenosis after angioplasty. The development of restenosis involves vascular smooth muscle cells (VSMCs) migration and proliferation. Angiotensin II has been shown to stimulate the growth of VSMCs via an action on the angiotensin II AT1 receptor subtype. Angiotensin II AT1 receptor antagonists can block the angiotensin II-induced these actions. Angiotensin II AT1 receptor antagonists may block the restenosis after balloon coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1998

Fibronectin stimulates transcription of the platelet-derived growth factor beta-receptor in cultured rat aortic smooth muscle cells.

Fibronectin seems to play an important role in promoting the characteristic changes of vascular smooth muscle cells in diabetes mellitus including overexpression of the platelet-derived growth factor beta-receptor. To determine the regulatory mechanism of the beta-receptor by fibronectin, we have analyzed the effect of fibronectin on the expression of the beta-receptor in cultured rat aortic smooth muscle cells using the beta-receptor promoter/luciferase expression vector system. Fibronectin was found to stimulate the expression of the beta-receptor at the transcriptional level. Both a MEK1 inhibitor PD98059 and a tyrosine kinase inhibitor herbimycin A significantly inhibited the fibronectin-stimulated receptor transcription. Herbimycin A also completely inhibited the fibronectin-stimulated increase in tyrosine phosphorylation of focal adhesion kinase. These data suggest the involvement of the integrin-mediated mitogen-activated protein kinase pathway downstream of fibronectin stimulation in the activation process of the beta-receptor promoter.

Animals↗
PubMed1998

Comparison of contractions produced by carbachol, thapsigargin and cyclopiazonic acid in the guinea-pig tracheal muscle.

1. Thapsigargin (TPG, 3 microM) and cyclopiazonic acid (CPA, 10 microM) slowly increased muscle tone in the guinea-pig isolated tracheal muscle. A large sustained contraction was produced when 2.4 mM Ca2+ was readmitted after 10 min exposure to Ca2+-free solution following 30 min treatment with TPG or CPA. 2. The sustained contraction after Ca2+ readmission was partially inhibited by nifedipine (3 microM) and highly dependent on external Ca2+. The TPG- and CPA-induced sustained contractions were 75% and 67%, respectively, of the sustained contraction produced by carbachol (Cch, 1 microM, EC80) in the presence of nifedipine. 3. The contractions produced by Cch, TPG and CPA were all inhibited by isoprenaline (ISO) and sodium nitroprusside (SNP). In the presence of nifedipine, the IC50 of ISO was 11, 17, and 23 nM and that of SNP was 0.5, 1, 0.8 microM for Cch-, TPG-, and CPA-induced contractions, respectively. The contraction produced by 60 mM K+ was only weakly inhibited by ISO and SNP. As with ISO and SNP, the Cch-, TPG- and CPA-induced contractions were also similarly inhibited by SKF 96365 (100 microM) and cadmium (Cd2+, 100 microM). 4. It was concluded that TPG and CPA increased Ca2+ influx probably via a mechanism activated by Ca2+ depletion of the sarcoplasmic reticulum. The susceptibility of the contraction produced by TPG, CPA and Cch to inhibition by ISO and SNP and also by SKF-96365 and Cd2+ suggests that the contractions use common pathways for increasing intracellular Ca2+, and that the contractions produced by K+ involve a different mechanism.

Animals↗
PubMed1998

A new treatment for penile conservation in penile carcinoma: a preliminary study of combined laser hyperthermia, radiation and chemotherapy.

OBJECTIVE: To investigate the role of laser hyperthermia in penis-conserving therapy for penile carcinoma. PATIENTS, MATERIALS AND METHODS: Penile carcinoma KPK-1 cells were transplanted into nude mice to induce tumour; the effects of laser hyperthermia, the chemotherapeutic agent peplomycin, or their combination on the inhibition of KPK-1 tumour growth were assessed. In a clinical study, two patients with well-differentiated, stage T2 penile tumours with corporeal involvement were treated to conserve the penis using concurrent radiation, laser hyperthermia and peplomycin. They had no pathologically identified regional lymph node metastasis. Radiation was given for 5 days a week for 3 weeks at a total dose of 30 Gy. Nd:YAG laser hyperthermia was administered at 42-43 degrees C for 15 min twice a week for 3 weeks immediately after radiation. Peplomycin (10 mg per day) was administered intravenously over 24 h together with the laser hyperthermia. RESULTS: The combined treatment with laser hyperthermia and peplomycin completely inhibited KPK-1 tumour growth, but the treatment with either laser hyperthermia or peplomycin alone had little effect. The results were also corroborated by the histopathological findings; the necrotic area in mice treated with combined therapy was much larger than that in those treated with laser hyperthermia alone. Both patients given combined laser hyperthermia, radiation and peplomycin were treated successfully, with the penis and sexual function conserved, and both survived for > 7 years with no evidence of any local or regional recurrence. There were no major complications related to the combined treatment. CONCLUSIONS: This preliminary study showed that combined treatment with laser hyperthermia, radiation and peplomycin might be a promising therapy for conserving the penis in some patients with stage T2 penile tumours.

Animals↗
PubMed1998

Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats.

We previously reported that the chronic inhibition of nitric oxide (NO) synthesis increases cardiac tissue angiotensin-converting enzyme expression and causes cardiac fibrosis in rats. However, the mechanisms are not known. Transforming growth factor-beta (TGF-beta) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-beta in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-beta1 and extracellular matrix (ECM) proteins. TGF-beta immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type 1 receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-beta1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-beta did not affect the L-NAME-induced increase in TGF-beta1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-beta1 via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.

Administration, Oral↗
PubMed1998

Effects of excess K+ on carbachol-induced contractions in the guinea-pig tracheal muscle.

1. In smooth muscles isolated from the guinea-pig trachea, the effects of dihydropyridines, nifedipine and nicardipine on contractions produced by carbachol (Cch) were studied in normal (6 mM) and excess K+ concentration (60 mM). The tonic contraction produced by 1 microM Cch was highly dependent on the external Ca2+ concentration ([Ca2+]0) and was not significantly affected by cyclopiazonic acid or thapsigargin, Ca2+ uptake inhibitor. 2. [Ca2+]0-tension curves were steeper in the presence of 1 microM Cch (the Hill coefficient: 2.5) than in the presence of 60 mM K+ (Hill coefficient: 1.6) and their ED50 of Ca2+ was 0.16 and 0.39 mM, respectively. An increase of K+ to 60 mM in the presence of 1 microM Cch shifted the curve to the left roughly in parallel (ED50: 0.12 mM, Hill coefficient: 2.3). 3. [Ca2+]0-tension curve in the presence of 1 microM Cch was shifted to the right in parallel by nifedipine (1 microM). This was markedly potentiated by 60 mM K+ (the increase in ED50 of Ca2+ being 3 times at 6 mM and 15 times at 60 mM K+). No tension was evoked by Ca2+ up to 2.5 mM in 60 mM K+ solution containing 1 microM nifedipine but no Cch. 4. In the absence of nifedipine, Cch-induced contractions were potentiated by 60 mM K+, whereas in the presence of nifedipine, Cch-induced contractions were markedly inhibited by 60 mM K+. These mechanical changes were accompanied by an increase or a decrease in intracellular Ca2+. 5. A hypothesis is presented to explain the results which suggests that the kinetics of Ca2+ influx though a single type of pathway is modulated by membrane potential and receptor activation and that the susceptibility of the pathway to dihydropyridine blockade is closely related to the Ca2+ influx kinetics with receptor activation reducing and membrane depolarization increasing the susceptibility.

Animals↗
PubMed1998

Progression to moderate or severe mitral regurgitation after percutaneous transvenous mitral commissurotomy using stepwise inflation technique.

Progression to moderate or severe mitral regurgitation (MR) was studied after Inoue balloon percutaneous transvenous mitral commissurotomy (PTMC) using the stepwise inflation technique, performed at increments of 1 mm of balloon diameter, in 49 consecutive patients with rheumatic mitral stenosis (aged from 32-73 years; 8 males, 41 females). The patients were classified on the basis of the degree of MR after PTMC, compared with that before PTMC, into either Group A, development of moderate or more severe (> or = grade 2) MR (n = 8) or Group B, no increase in MR or development of mild (grade 1) MR (n = 41). Progression to moderate or severe MR was significantly associated only with advanced age (60 +/- 8 vs 52 +/- 10 years, p < 0.05) and narrower mitral valve area (0.87 +/- 0.35 vs 1.11 +/- 0.29 cm2, p < 0.05), but other characteristics before PTMC were similar in both groups. There was no difference between the two groups in the total number and degree of balloon inflation. Immediately before the final inflation, the left atrial mean pressure and v wave pressure were decreased in smaller degrees in Group A compared with Group B (-2 +/- 2 vs -5 +/- 4 mmHg, p < 0.05; -2 +/- 2 vs -6 +/- 6 mmHg, p < 0.05, respectively). Thus, the stepwise inflations require careful monitoring of changes in the left atrial pressure and waveform to recognize the aggravation of MR, especially in older patients with severe stenosis. Patients who do not have a significant drop in left atrial mean pressure and v wave pressure during stepwise inflations of the balloon might be at risk of development of moderate or severe MR after further dilations.

Adult↗
PubMed1997

Sphingosine induces apoptosis in androgen-independent human prostatic carcinoma DU-145 cells by suppression of bcl-X(L) gene expression.

Our recent studies have suggested that sphingosine, an endogenous protein kinase C (PKC) inhibitor, may mediate apoptosis induced by a phorbol ester (PMA) in human promyelocytic leukemia HL-60 cells [Ohta et al. Cancer Res. 1995;55:691-697], and that the apoptotic induction by both PMA and sphingosine is accompanied by down-regulation of bcl-2, a gene which acts to prevent apoptotic cell death [Sakakura et al. FEBS Lett. 1996;397:177-180]. In this study, we examined the sphingosine-induced apoptosis of the androgen-independent human prostatic carcinoma cell line DU-145, which expresses bcl-X(L) and Bax but not bcl-2, and found that treatment of DU-145 cells with sphingosine suppressed bcl-X(L) in both mRNA and protein levels but did not change bax expression at all. In contrast, in apoptotic cells treated with a PKC inhibitor, staurosporine, no effect on bcl-X(L) or bax expression was observed. The initial metabolites of sphingosine in the cells, ceramide and sphingosine 1-phosphate, failed to induce apoptosis. These results indicate that, in DU-145 cells, sphingosine, but not its metabolites, induces apoptosis through down-regulation of bcl-X(L), independently of PKC inhibition. Our present results, together with previous observations, strongly suggest that apoptosis regulatory genes differ according to cell type and apoptosis induction through sphingosine is accompanied by inhibition of either bcl-2 or bcl-X(L) activity in these cells.

Androgens↗
PubMed1997

Metanestin, a glycoprotein with metastasis-associated expression in transitional cell carcinoma of the urinary bladder.

A 60-kDa glycoprotein named metanestin was identified by molecular cloning. The glycoprotein had a twice-repeated motif of Pro-Gly-Pro-Gly and carried metastasis-associated carbohydrate epitopes. The antibody to the protein portion of metanestin strongly reacted with lymph-node metastasis of transitional-cell carcinoma of the urinary bladder, but the reactivity to the primary tumor was generally weaker and the normal urothelium was scarcely reactive. Thus both metanestin and the carbohydrate on it showed metastasis-associated expression. In addition, we identified a 100-kDa glycoprotein with a 4-times-repeated motif of Pro-Ala-Pro-Ala. The antibody to the 100-kDa glycoprotein showed reactivity similar to that to metanestin.

Amino Acid Sequence↗
PubMed1997

Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats.

The long-term administration of N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, produces coronary vascular remodeling and myocardial hypertrophy in animals. This study used a rat model to investigate the role of angiotensin I converting enzyme (ACE) in the pathogenesis of such changes. We studied the following groups, all of which received drug treatment in their drinking water: untreated controls, and those administered L-NAME, L-NAME, and an ACE inhibitor (ACEI), and L-NAME and hydralazine. Cardiovascular structural changes and tissue ACE activities were evaluated after the first, fourth, and eighth week of treatment. In rats treated with L-NAME alone, vascular remodeling was evident at the fourth and eighth week, and myocardial hypertrophy was present at the eighth week of treatment. The vascular and myocardial remodeling were characterized by increased tissue ACE activities and immunodetectable ACE in those tissues. These changes were markedly reduced by ACEI, but not by hydralazine treatment. Increased local ACE expression may thus be important in the pathogenesis of cardiovascular remodeling in this model.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists.

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.

Angiotensin Receptor Antagonists↗
PubMed1997

Effect of oral adsorbent AST-120 on cyclosporin absorption in rats.

The oral adsorbent AST-120 is used to inhibit the progression of renal failure by adsorbing uraemic toxins in the gastrointestinal tract. When AST-120 is administered to patients receiving immunosuppressive medicines, it is important to study the effect of AST-120 on the amount of these and other drugs absorbed. We have, therefore, studied the in-vitro adsorption of cyclosporin by AST-120 and investigated the effect of oral administration of AST-120 on the absorption of cyclosporin in rats. The in-vitro adsorption ratios of AST-120 for cyclosporin were more than 80%. When pure cyclosporin powder was administered with AST-120, blood cyclosporin concentrations were significantly higher than when cyclosporin was administered alone. When cyclosporin dissolved in medium-chain triglyceride was administered to rats by intramuscular injection there was no significant difference in the blood cyclosporin concentration of rats given combined AST-120 and cyclosporin and those given cyclosporin alone. There was no significant difference between the serum concentration of total bile acids, in rats receiving combined oral AST-120 and cyclosporin dissolved in olive oil, and those receiving orally solely a solution of cyclosporin dissolved in olive oil. These results suggest that oral administration of AST-120 accelerates the absorption of orally administered cyclosporin from the gastrointestinal tract and does not affect the metabolism of cyclosporin. When a solution of cyclosporin in olive oil is administered orally, however, oral administration of AST-120 has no influence on cyclosporin absorption and does not affect the enterohepatic circulation of bile acids.

Absorption↗
PubMed1997

Chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade: effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis.

We have shown previously that angiotensin-converting enzyme (ACE) inhibitors prevent coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and hypertrophy) in rats induced by long-term inhibition of nitric oxide (NO) synthesis with oral administration of N omega-nitro-L-arginine methyl ester (L-NAME). ACE inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin. In this study, we aimed to determine the relative contribution of the latter two mechanisms to the beneficial effects of an ACE inhibitor on structural remodeling. First, we examined the effects of the ACE inhibitor temocapril and the angiotensin II AT1 subtype receptor antagonist CS-866 on the structural remodeling induced by administering L-NAME for 8 weeks. Temocapril and CS-866 were equally effective in preventing remodeling. Second, we examined whether the effect of temocapril on the remodeling induced by L-NAME was reduced by the bradykinin receptor antagonist HOE140. The latter drug did not alter the beneficial effect of temocapril on remodeling. In conclusion, although species differences must be considered to apply our conclusion to clinical conditions, the present results suggest that the inhibition of angiotensin II activity, mediated via the AT1 receptors, is responsible for the beneficial effects of an ACE inhibitor in our animal model of coronary vascular and myocardial remodeling induced by the long-term inhibition of NO synthesis.

Angiotensin Receptor Antagonists↗