28 results on '"Nagase I"'
Search Results
2. Recessed gate GaN-based MIS-HEMTs with Al2O3 gate dielectric deposited by mist-CVD method
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Ishiguro, M., primary, Urano, S., additional, Low, R. S., additional, Faris, M., additional, Nagase, I., additional, Baratov, A., additional, Asubar, J. T., additional, Motoyama, T., additional, Nakamura, Y., additional, Yatabe, Z., additional, and Kuzuhara, M., additional
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- 2021
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3. Electrical properties of GaN-based MIS-HEMTs with Al2O3 gate insulator deposited by ALD and mist-CVD techniques
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Urano, S., primary, Low, R. S., additional, Faris, M., additional, Ishiguro, M., additional, Nagase, I., additional, Baratov, A., additional, Asubar, J. T., additional, Motoyama, T., additional, Nakamura, Y., additional, Yatabe, Z., additional, and Kuzuhara, M., additional
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- 2021
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4. Fabrication and Characterization of ZrO2/AlGaN/GaN MIS-HEMTs with regrown AlGaN Layer
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Maeda, S., primary, Nagase, I., additional, Baratov, A., additional, Urano, S., additional, Asubar, J. T., additional, Yamamoto, A., additional, and Kuzuhara, M., additional
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- 2021
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5. A Complete Single-Chip GPS Receiver With 1.6-V 24-mW Radio in 0.18-<tex>$mu$</tex>m CMOS
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Kadoyama, T., primary, Suzuki, N., additional, Sasho, N., additional, Iizuka, H., additional, Nagase, I., additional, Usukubo, H., additional, and Katakura, M., additional
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- 2004
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6. TRANSIENT THERMAL MIXING PERFORMANCE AND FLOW PATTERN IN A ROOM WITH THROUGH-FLOW
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Inada, Shigeaki, primary, Kaneko, H., additional, and Nagase, I., additional
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- 2002
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7. A complete single-chip GPS receiver with 1.6-V 24-mW radio in 0.18-μm CMOS.
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Kadoyama, T., Suzuki, N., Sasho, N., Iizuka, H., Nagase, I., Usukubo, H., and Katakura, M.
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- 2003
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8. Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice
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Yoshida, T, primary, Sakane, N, additional, Umekawa, T, additional, Kogure, A, additional, Kondo, M, additional, Kumamoto, K, additional, Kawada, T, additional, Nagase, I, additional, and Saito, M, additional
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- 1999
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9. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist.
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Nagase, I, primary, Yoshida, T, additional, Kumamoto, K, additional, Umekawa, T, additional, Sakane, N, additional, Nikami, H, additional, Kawada, T, additional, and Saito, M, additional
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- 1996
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10. Rise and Fall of Blood Level of Tranexamic Acid in Horses
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NAKAMURA, KOICHI, primary, KADOYA, S., additional, NAGASE, I., additional, SANO, K., additional, and MOTOYOSHI, S., additional
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- 1976
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11. A complete single-chip GPS receiver with 1.6-V 24-mW radio in 0.18-μm CMOS
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Kadoyama, T., primary, Suzuki, N., additional, Sasho, N., additional, Iizuka, H., additional, Nagase, I., additional, Usukubo, H., additional, and Katakura, M., additional
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12. Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study.
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Ono A, Murakami H, Seto T, Shimizu T, Watanabe S, Takeshita S, Takeda K, Toyoshima J, Nagase I, Bahceci E, Morishita M, Morita S, Fukuoka M, and Nakagawa K
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- Administration, Oral, Adult, Aged, Anaplastic Lymphoma Kinase antagonists & inhibitors, Anaplastic Lymphoma Kinase genetics, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents pharmacokinetics, Appetite drug effects, Asian People, Dose-Response Relationship, Drug, Drug Administration Schedule, Fatigue chemically induced, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Myositis drug therapy, Myositis enzymology, Myositis genetics, Nausea chemically induced, Neoplasms enzymology, Neoplasms genetics, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors pharmacokinetics, Sarcoma, Ewing drug therapy, Sarcoma, Ewing enzymology, Sarcoma, Ewing genetics, Sulfones adverse effects, Sulfones blood, Sulfones pharmacokinetics, Treatment Outcome, Triazines adverse effects, Triazines blood, Triazines pharmacokinetics, Antineoplastic Agents administration & dosage, Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Sulfones administration & dosage, Triazines administration & dosage
- Abstract
Background and Objective: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required., Methods: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts., Results: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group)., Conclusion: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile., Clinical Trial Registration: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.
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- 2021
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13. Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis.
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Soda M, Ito S, Matsumaru N, Nakamura S, Nagase I, Takahashi H, Ohno Y, Yasuda M, Yamamoto M, Tsukamoto K, Itoh Y, Deguchi T, and Kitaichi K
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- Adult, Anti-Bacterial Agents pharmacokinetics, Delayed-Action Preparations pharmacokinetics, Delayed-Action Preparations therapeutic use, Gonorrhea microbiology, Humans, Japan, Male, Microbial Sensitivity Tests, Middle Aged, Treatment Outcome, Urethritis microbiology, Young Adult, Anti-Bacterial Agents therapeutic use, Azithromycin pharmacokinetics, Azithromycin therapeutic use, Gonorrhea drug therapy, Neisseria gonorrhoeae drug effects, Urethritis drug therapy
- Abstract
The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain., (Copyright © 2017 American Society for Microbiology.)
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- 2017
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14. Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study.
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Kadokura T, Akiyama N, Kashiwagi A, Utsuno A, Kazuta K, Yoshida S, Nagase I, Smulders R, and Kageyama S
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- Adult, Aged, Area Under Curve, Asian People, Blood Glucose analysis, Diabetes Mellitus, Type 2 metabolism, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Tissue Distribution, Young Adult, Diabetes Mellitus, Type 2 drug therapy, Glucosides pharmacokinetics, Glucosides pharmacology, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents pharmacology, Thiophenes pharmacokinetics, Thiophenes pharmacology
- Abstract
Aims: Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM., Methods: In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days -1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0-3h (AUC0-3h) and 0-24h (AUC0-24h). Pharmacokinetic characteristics included AUC0-24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax)., Results: Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0-3h and AUC0-24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0-24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0-24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group., Conclusions: Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
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- 2014
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15. Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium-dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus.
- Author
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Kashiwagi A, Kazuta K, Yoshida S, and Nagase I
- Abstract
Aims/introduction: In the present dose-response study, we evaluated the efficacy and safety of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose cotransporter 2, in Japanese patients with type 2 diabetes mellitus., Materials and Methods: A total of 361 patients from 39 Japanese centers were randomized to receive either once-daily oral ipragliflozin (12.5, 25, 50 or 100 mg) or a placebo for 12 weeks., Results: All ipragliflozin-treated groups had clinically significant, dose-dependent decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose levels compared with placebo-treated groups. The adjusted mean difference in HbA1c change from baseline to the end of treatment between the placebo and 12.5, 25, 50, and 100 mg ipragliflozin groups were -0.61%, -0.97%, -1.29%, and -1.31%, respectively (P < 0.001). Reductions in HbA1c levels were similar between obese and non-obese patients, and were larger in patients with baseline HbA1c ≥8.4% than in those with HbA1c <8.4%. Furthermore, bodyweight significantly (P < 0.001) and dose-dependently decreased among ipragliflozin-treated groups compared with the placebo group. The incidence of adverse events was similar across all groups. However, mild increases in hematocrit and blood urea nitrogen were found in ipragliflozin treated groups., Conclusions: Once-daily administration of ipragliflozin was dose-dependently effective in glycemic control without major adverse effects. Ipragliflozin was equally effective between obese and non-obese patients, and led to weight loss in both groups. Ipragliflozin was safe and well-tolerated in Japanese patients with type 2 diabetes mellitus. This trial was registered with ClinicalTrials.gov (no. NCT00621868).
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- 2014
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16. Synthesis and evaluation of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety as selective β3-adrenergic receptor agonists.
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Maruyama T, Onda K, Suzuki T, Hayakawa M, Takahashi T, Matsui T, Takasu T, Nagase I, and Ohta M
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- Administration, Oral, Adrenergic beta-3 Receptor Agonists chemistry, Adrenergic beta-3 Receptor Agonists therapeutic use, Animals, Diabetes Mellitus, Type 2 drug therapy, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Hypoglycemic Agents chemistry, Hypoglycemic Agents therapeutic use, Male, Mice, Obesity drug therapy, Receptors, Adrenergic, beta-1 chemistry, Receptors, Adrenergic, beta-1 metabolism, Receptors, Adrenergic, beta-2 chemistry, Receptors, Adrenergic, beta-2 metabolism, Receptors, Adrenergic, beta-3 metabolism, Acetamides chemistry, Adrenergic beta-3 Receptor Agonists chemical synthesis, Hypoglycemic Agents chemical synthesis, Phenoxypropanolamines chemistry, Receptors, Adrenergic, beta-3 chemistry
- Abstract
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with functional selectivity over the β1- and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.
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- 2012
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17. Synthesis and evaluation of novel phenylethanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
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Maruyama T, Onda K, Hayakawa M, Suzuki T, Kimizuka T, Matsui T, Takasu T, Nagase I, Hamada N, and Ohta M
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- Adrenergic Agonists chemical synthesis, Adrenergic Agonists pharmacology, Animals, Blood Glucose drug effects, Humans, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents pharmacology, Male, Mice, Models, Molecular, Molecular Conformation, Phenethylamines chemical synthesis, Phenethylamines pharmacology, Receptors, Adrenergic, beta-1 metabolism, Receptors, Adrenergic, beta-2 metabolism, Receptors, Adrenergic, beta-3 metabolism, Adrenergic Agonists chemistry, Adrenergic Agonists therapeutic use, Adrenergic beta-3 Receptor Agonists, Hypoglycemic Agents chemistry, Hypoglycemic Agents therapeutic use, Phenethylamines chemistry, Phenethylamines therapeutic use
- Abstract
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human beta3-, beta2-, and beta1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.
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- 2010
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18. Effects of the dipeptidyl peptidase-IV inhibitor ASP8497 on glucose tolerance in animal models of secondary failure.
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Someya Y, Nakano R, Tahara A, Takasu T, Takeuchi A, Nagase I, Matsuyama-Yokono A, Hayakawa M, Sasamata M, Miyata K, and Uchiyama Y
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- Animals, Diabetes Mellitus blood, Diabetes Mellitus pathology, Diabetes Mellitus therapy, Disease Models, Animal, Drug Administration Schedule, Glucose Tolerance Test, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells pathology, Male, Mice, Piperidines administration & dosage, Pyrrolidines administration & dosage, Rats, Sulfonylurea Compounds therapeutic use, Treatment Failure, Blood Glucose metabolism, Dipeptidyl-Peptidase IV Inhibitors administration & dosage, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Piperidines pharmacology, Pyrrolidines pharmacology
- Abstract
Unlabelled: Sulfonylureas promote insulin secretion and potently lower blood glucose levels, however, they induce hypoglycemia and undergo a reduction in efficacy when administered long-term (secondary failure). The dipeptidyl peptidase (DPP)-IV inhibitor ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, inhibits the degradation of glucagon-like peptide-1 (GLP-1), an incretin hormone, and promotes insulin secretion in a glucose-dependent manner. ASP8497 is therefore less likely to induce hypoglycemia and less likely to show reduced efficacy even after repeated administration. Here, to determine whether or not ASP8497 improves glucose tolerance in Zucker fatty rats, we examined the effects of ASP8497 and gliclazide, a sulfonylurea, on glucose tolerance after repeated administration. We also developed an animal model of secondary failure using streptozotocin-nicotinamide-induced diabetic mice., Results: ASP8497 (3mg/kg) improved glucose intolerance in Zucker fatty rat without any attenuation (blood glucose AUC: P=0.034 vs. vehicle) while gliclazide (10mg/kg) did not (P=0.916 vs. vehicle). Furthermore, ASP8497 (3, 10mg/kg) was found to effect glucose tolerance dose-dependently (3mg/kg: P=0.230, 10mg/kg: P=0.003 vs. glibenclamide (10mg/kg)) by enhancing insulin secretion in mice inadequately controlled with glibenclamide. Our results suggest that ASP8497 may be effective even in patients with secondary failure who are unable to maintain satisfactory glycemic control using sulfonylureas.
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- 2009
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19. Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
- Author
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Maruyama T, Onda K, Hayakawa M, Seki N, Takahashi T, Moritomo H, Suzuki T, Matsui T, Takasu T, Nagase I, and Ohta M
- Subjects
- Acetanilides chemistry, Adrenergic beta-1 Receptor Agonists, Adrenergic beta-2 Receptor Agonists, Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental drug therapy, Dose-Response Relationship, Drug, Drug Design, Humans, Male, Mice, Models, Molecular, Molecular Conformation, Phenoxypropanolamines chemistry, Rats, Structure-Activity Relationship, Acetanilides chemical synthesis, Acetanilides pharmacology, Adrenergic beta-3 Receptor Agonists, Phenoxypropanolamines chemical synthesis, Phenoxypropanolamines pharmacology
- Abstract
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
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- 2009
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20. ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity.
- Author
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Matsuyama-Yokono A, Tahara A, Nakano R, Someya Y, Nagase I, Hayakawa M, and Shibasaki M
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- Animals, Blood Glucose analysis, Glucose Tolerance Test, Insulin blood, Mice, Streptozocin, Diabetes Mellitus, Experimental enzymology, Dipeptidyl-Peptidase IV Inhibitors, Hypoglycemic Agents pharmacology, Piperidines pharmacology, Protease Inhibitors pharmacology, Pyrrolidines pharmacology
- Abstract
Dipeptidyl peptidase (DPP)-IV inhibitors are expected to become a useful new class of antidiabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, which is a novel DPP-IV inhibitor. ASP8497 inhibited DPP-IV in plasma from mice, rats, dogs and humans with IC(50) values of 3.86, 2.36, 5.53 and 5.30 nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC(50)>200 nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 (3 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30 mg/kg) did not cause hypoglycemia in fasted normal mice. Furthermore, administration of exogenous GLP-1 induced significant inhibition of gastric emptying and small intestinal transit rates, but ASP8497 (30 mg/kg) had no significant effects in normal mice. These present preclinical studies indicate that ASP8497 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.
- Published
- 2008
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21. Pharmacological profile of ASP8497, a novel, selective, and competitive dipeptidyl peptidase-IV inhibitor, in vitro and in vivo.
- Author
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Someya Y, Tahara A, Nakano R, Matsuyama-Yokono A, Nagase I, Fukunaga Y, Takasu T, Hayakawa M, and Shibasaki M
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- Animals, Blood Glucose drug effects, Diabetes Mellitus, Type 2 physiopathology, Dipeptidases drug effects, Dipeptidyl Peptidase 4 metabolism, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases drug effects, Dogs, Dose-Response Relationship, Drug, Glucagon-Like Peptide 1 blood, Glucagon-Like Peptide 1 drug effects, Glucose Tolerance Test, Humans, Hypoglycemic Agents administration & dosage, Inhibitory Concentration 50, Insulin blood, Male, Mice, Mice, Inbred ICR, Piperidines administration & dosage, Protease Inhibitors administration & dosage, Protease Inhibitors pharmacology, Pyrrolidines administration & dosage, Rats, Rats, Sprague-Dawley, Rats, Zucker, Diabetes Mellitus, Type 2 drug therapy, Dipeptidyl Peptidase 4 drug effects, Hypoglycemic Agents pharmacology, Piperidines pharmacology, Pyrrolidines pharmacology
- Abstract
Dipeptidyl peptidase (DPP)-IV is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibitors are expected to become a useful new class of antidiabetic agent. This report describes the pharmacological profile of the novel DPP-IV inhibitor, ASP8497 [(2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate], both in vitro and in vivo. ASP8497 inhibited DPP-IV in plasma from mice, dogs, and humans with median inhibition concentration (IC(50)) values of 2.6 nM, 7.3 nM, and 6.2 nM, respectively. In contrast, ASP8497 did not potently inhibit human DPP8 or DPP9 activity (IC(50)=1,700 nM and 100 nM, respectively) and exhibited selectivity against several proteases, including proline-specific proteases (IC(50)>10 microM). Kinetic analysis indicated that ASP8497 is a competitive DPP-IV inhibitor. In normal mice, ASP8497 inhibited plasma DPP-IV activity even 12 h after administration. ASP8497 significantly inhibited increases in the blood glucose level during the oral glucose tolerance test (OGTT) conducted 0.5 h after administration. This was accompanied by increases in the plasma active GLP-1 and insulin levels. In addition, ASP8497 significantly inhibited increases in the blood glucose level during the OGTT conducted 8 h after administration. Furthermore, in Zucker fatty rats, ASP8497 dose dependently improved glucose tolerance with significance at doses of 1 mg/kg or higher. In contrast, ASP8497 did not cause hypoglycemia in fasted normal mice. These results indicate that ASP8497 is a potent, competitive, and selective DPP-IV inhibitor with antihyperglycemic activity.
- Published
- 2008
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22. Wogonin prevents glucocorticoid-induced thymocyte apoptosis without diminishing its anti-inflammatory action.
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Enomoto R, Sugahara C, Suzuki C, Nagase I, Takamura Y, Yoshikawa A, Hosoda A, Hirano H, Yokoi T, and Lee E
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- Animals, Anti-Inflammatory Agents administration & dosage, Biological Transport, DNA Fragmentation drug effects, Dexamethasone pharmacology, Dose-Response Relationship, Drug, Drugs, Chinese Herbal administration & dosage, Edema chemically induced, Edema drug therapy, Etoposide pharmacology, Flavanones administration & dosage, Glucocorticoids pharmacology, Immunosuppression Therapy, In Vitro Techniques, Inflammation drug therapy, Male, Phosphatidylserines metabolism, Rats, Rats, Sprague-Dawley, Scutellaria baicalensis chemistry, Thymus Gland cytology, Anti-Inflammatory Agents pharmacology, Apoptosis drug effects, Drugs, Chinese Herbal pharmacology, Flavanones pharmacology
- Abstract
The effect of wogonin, a flavone highly purified from the roots of Scutellaria baicalensis, on apoptotic cell death was re-evaluated in rat thymocytes. This flavone inhibited glucocorticoid-induced apoptotic changes such as DNA fragmentation, phosphatidylserine translocation, and nuclear condensation in rat thymocytes. Similar inhibition was also observed in apoptosis induced by other inducers such as etoposide. No significant changes of these apoptotic features were observed in rat thymocytes treated with wogonin alone, suggesting that this flavone protects against glucocorticoid-mediated immunosuppression caused by thymocyte apoptosis. Wogonin was reported to possess anti-inflammatory action in some previous studies, but this flavone had no effect on carrageenan-induced paw edema in this study. The simultaneous treatment of wogonin and glucocorticoid neither enhanced nor reduced the anti-inflammatory effect of glucocorticoid. These results indicate that wogonin is likely to prevent the immunosuppression of glucocorticoid without diminishing its drug efficacy as an anti-inflammatory agent.
- Published
- 2007
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23. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function.
- Author
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Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, and Yamaguchi O
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- Animals, CHO Cells, Carbachol pharmacology, Cricetinae, Cricetulus, Cyclic AMP metabolism, Humans, Isoproterenol pharmacology, Muscle Contraction drug effects, Propanolamines pharmacology, Urinary Bladder physiology, Acetanilides pharmacology, Adrenergic beta-3 Receptor Agonists, Adrenergic beta-Agonists pharmacology, Thiazoles pharmacology, Urinary Bladder drug effects
- Abstract
We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta3-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta1- and beta2-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta3-ARs, 0.1 for human beta1-ARs, and 0.1 for human beta2-ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (beta3-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 microM, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 microM, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.
- Published
- 2007
- Full Text
- View/download PDF
24. Up-regulation of uncoupling proteins by beta-adrenergic stimulation in L6 myotubes.
- Author
-
Nagase I, Yoshida T, and Saito M
- Subjects
- Adrenergic beta-Antagonists pharmacology, Albuterol pharmacology, Alitretinoin, Animals, Cell Line, Cyclic AMP metabolism, Energy Metabolism, Epinephrine pharmacology, Epoprostenol analogs & derivatives, Epoprostenol pharmacology, Ion Channels, Isoproterenol pharmacology, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Propanolamines pharmacology, Propranolol pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Receptors, Adrenergic, beta genetics, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Retinoic Acid metabolism, Retinoid X Receptors, Time Factors, Transcription Factors metabolism, Tretinoin pharmacology, Uncoupling Protein 2, Uncoupling Protein 3, Adrenergic beta-Agonists pharmacology, Carrier Proteins genetics, Membrane Transport Proteins, Mitochondrial Proteins, Muscle, Skeletal drug effects, Proteins genetics, Receptors, Adrenergic, beta metabolism, Up-Regulation drug effects
- Abstract
Catecholamine-induced and beta-adrenergic receptor (beta-AR)-mediated thermogenesis in skeletal muscle is a significant component of whole-body energy expenditure. Skeletal muscle expresses uncoupling protein (UCP) 2 and UCP3, which can dissipate the transmitochondrial electrochemical gradient and thereby may be involved in regulation of energy metabolism. We investigated the effects of beta-AR stimulation on UCP2 and UCP3 expression in L6 myotubes. Stimulation of the cells with epinephrine increased the UCP3 mRNA level transiently at 6 h, and also the UCP2 mRNA level at 6-24 h. The stimulatory effects of epinephrine were also observed in the presence of carbacyclin and 9-cis retinoic acid, and mimicked by isoproterenol and salbutamol (beta2-AR agonists), but abolished by propranolol and ICI-118,551 (beta2-AR antagonists). Pharmacological and mRNA analyses revealed the existence of beta2-AR, but not beta1- and beta3-ARs, in L6 myotubes. These results suggested that catecholamines up-regulate UCP2 and UCP3 expression through direct action on the beta2-AR in skeletal muscle.
- Published
- 2001
- Full Text
- View/download PDF
25. Beta 3-adrenergic agonist up-regulates uncoupling proteins 2 and 3 in skeletal muscle of the mouse.
- Author
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Nakamura Y, Nagase I, Asano A, Sasaki N, Yoshida T, Umekawa T, Sakane N, and Saito M
- Subjects
- Adipose Tissue, Brown drug effects, Adipose Tissue, Brown metabolism, Adipose Tissue, Brown physiology, Animals, Blood Glucose metabolism, Blotting, Northern, Carrier Proteins genetics, Disease Models, Animal, Fatty Acids blood, Female, Ion Channels, Mice, Mice, Inbred C57BL, Mice, Obese, Muscle, Skeletal metabolism, Muscle, Skeletal physiology, Proteins genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Messenger metabolism, Uncoupling Protein 2, Uncoupling Protein 3, Up-Regulation drug effects, Adrenergic beta-3 Receptor Agonists, Adrenergic beta-Agonists pharmacology, Carrier Proteins biosynthesis, Dioxoles pharmacology, Membrane Transport Proteins, Mitochondrial Proteins, Muscle, Skeletal drug effects, Protein Biosynthesis
- Abstract
Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective beta3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8-4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the beta3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of beta3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.
- Published
- 2001
- Full Text
- View/download PDF
26. Up-regulation of uncoupling protein 3 by thyroid hormone, peroxisome proliferator-activated receptor ligands and 9-cis retinoic acid in L6 myotubes.
- Author
-
Nagase I, Yoshida S, Canas X, Irie Y, Kimura K, Yoshida T, and Saito M
- Subjects
- Alitretinoin, Animals, Carrier Proteins genetics, Cells, Cultured, Chromans pharmacology, Dimerization, Drug Synergism, Epoprostenol analogs & derivatives, Epoprostenol pharmacology, Ion Channels, Mitochondrial Proteins, Muscle, Skeletal cytology, Oleic Acid pharmacology, Palmitates pharmacology, Protein Isoforms biosynthesis, Protein Isoforms genetics, RNA, Messenger biosynthesis, Rats, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Retinoic Acid chemistry, Receptors, Retinoic Acid drug effects, Retinoid X Receptors, Thiazoles pharmacology, Transcription Factors chemistry, Troglitazone, Uncoupling Protein 3, Carrier Proteins biosynthesis, Gene Expression Regulation drug effects, Muscle, Skeletal drug effects, Receptors, Cytoplasmic and Nuclear drug effects, Thiazolidinediones, Transcription Factors drug effects, Tretinoin pharmacology, Triiodothyronine pharmacology
- Abstract
Uncoupling protein 3 (UCP3), expressed abundantly in the skeletal muscle, is one of the carrier proteins dissipating the transmitochondrial electrochemical gradient as heat, and thereby has been implicated in the regulation of energy metabolism. We have investigated UCP3 mRNA expression in the widely used L6 myocyte cell line by Northern blot analysis. UCP3 mRNA was not detected in L6 myoblasts, but appeared after their differentiation to myotubes. The UCP3 mRNA level was increased when L6 myotubes were treated with increasing concentrations of triiodothyronine (T3), oleic acid, alpha-bromopalmitate and carbacyclin, a non-selective ligand of peroxisome proliferator-activated receptors (PPARs), whereas it was not influenced when treated with selective ligands of PPARalpha (WY 14¿ omitted¿643) and PPARgamma (troglitazone). A ligand of retinoid X receptor (RXR), 9-cis retinoic acid, was also effective by itself and in combination with carbacyclin in stimulating UCP3 mRNA expression. The mRNA analysis of individual PPAR isoforms revealed that L6 cell expressed a significant level of PPARdelta but undetectable levels of PPARalpha and PPARgamma. These results suggest that UCP3 expression in myocytes is differentiation-dependent and regulated by the T3 receptor, RXR and PPARdelta.
- Published
- 1999
- Full Text
- View/download PDF
27. beta 3-Adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers.
- Author
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Yoshida T, Umekawa T, Kumamoto K, Sakane N, Kogure A, Kondo M, Wakabayashi Y, Kawada T, Nagase I, and Saito M
- Subjects
- Adipose Tissue metabolism, Animals, Carrier Proteins genetics, Female, Food Additives pharmacology, Guanosine Diphosphate metabolism, Ion Channels, Membrane Proteins genetics, Mice, Mice, Obese, Microscopy, Immunoelectron, Mitochondria, Muscle drug effects, Mitochondria, Muscle metabolism, Mitochondrial Proteins, Muscle Fibers, Slow-Twitch metabolism, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, Obesity metabolism, RNA, Messenger metabolism, Receptors, Adrenergic, beta drug effects, Receptors, Adrenergic, beta-3, Sodium Glutamate pharmacology, Uncoupling Protein 1, Adipose Tissue drug effects, Adrenergic beta-Agonists pharmacology, Carrier Proteins biosynthesis, Dioxoles pharmacology, Membrane Proteins biosynthesis, Muscle Fibers, Slow-Twitch drug effects, Receptors, Adrenergic, beta metabolism
- Abstract
The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the beta 3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodium L-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5'-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the beta 3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.
- Published
- 1998
- Full Text
- View/download PDF
28. Hyperplasia of brown adipose tissue after chronic stimulation of beta 3-adrenergic receptor in rats.
- Author
-
Nagase I, Sasaki N, Tsukazaki K, Yoshida T, Morimatsu M, and Saito M
- Subjects
- Adipose Tissue, Brown drug effects, Adipose Tissue, Brown innervation, Animals, Cold Temperature adverse effects, Female, Hyperplasia chemically induced, Rats, Rats, Wistar, Receptors, Adrenergic, beta classification, Time Factors, Adipose Tissue, Brown physiology, Adrenergic beta-Agonists pharmacology
- Abstract
When mammals are exposed to a cold environment for a long time, the capacity of nonshivering thermogenesis by brown adipose tissue (BAT) increases in association with the increased expression of some specific proteins and tissue hyperplasia, which are totally dependent on sympathetic innervation to this tissue. To clarify roles of the beta-adrenergic mechanism in BAT hyperplasia, the effects of chronic administration of various beta-adrenergic agonists on BAT were examined in rats, especially focusing on some agonists to the beta 3-adrenoceptor which is present specifically in adipocytes. Chronic administration of noradrenaline or isoproterenol for 7-10 days produced a marked increase in the tissue contents of DNA, total protein, mitochondrial uncoupling protein, and insulin-regulatable glucose transporter protein. The trophic effects of noradrenaline and isoproterenol were mimicked by chronic administration of beta 3-adrenergic agonists, such as CL316,243, BRL 26830A, and ICI D7114. These results suggest that the beta 3-adrenoceptor plays important roles for hyperplasia of BAT, and thereby increasing in the capacity of thermogenesis.
- Published
- 1994
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