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1.
PLoS One ; 18(9): e0290685, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37656760

RESUMO

ß3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the ß3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower ß3-AR densities than those of healthy individuals, and the ß3-AR density might be expected to affect agonist activity. This study assessed the ß3-AR selectivities of four ß3-AR agonists and examined the effects of ß-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human ß-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 µg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for ß1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for ß2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various ß3-AR densities. Vibegron has high ß3-AR selectivity and exhibits full agonist activity, regardless of the ß3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.


Assuntos
Receptores Adrenérgicos beta 3 , Animais , Cricetinae , Humanos , Células CHO , Cricetulus
2.
Neurourol Urodyn ; 41(6): 1336-1343, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35537073

RESUMO

AIMS: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. METHODS: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid. RESULTS: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. CONCLUSION: The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.


Assuntos
Bexiga Urinária Hiperativa , Bexiga Urinária , Ácido Acético/efeitos adversos , Trifosfato de Adenosina , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/etiologia , Micção/fisiologia
3.
Microbes Infect ; 22(9): 451-456, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32470393

RESUMO

With the introduction of the pneumococcal conjugate vaccine (PCV), the number of cases of non-vaccine type pneumococci and non-encapsulated Streptococcus pneumoniae (NESp) infection have increased. In order to clarify how pspK-harbouring NESp might have emerged, we characterised NESp and analysed the correlation between transformation and non-encapsulation. A total of 26 NESp strains were used in this study. The genetic backgrounds were compared using multilocus sequence typing (MLST). The ΔpspK::ermB strain, in which pspK was replaced by ermB in NESp, was constructed by homologous recombination. The genomic DNA of the ΔpspK::ermB strain was transformed into two types of encapsulated S. pneumoniae via transformation. The fitness of the parent and non-encapsulated transformants was compared using the growth curve. All NESp had pspK instead of capsular coding regions and were classified into 14 types by MLST, which indicated that NESp had several genetic backgrounds. Transformation of ΔpspK::ermB genomic DNA resulted in 10-4‒10-5 non-encapsulated transformants. Non-encapsulated transformants could grow faster than the encapsulated parent strain. The acquisition of pspK region via transformation contributed to the loss of encapsulation with high frequency. The present results suggest that non-encapsulation through pspK acquisition could be a potential mechanism to evade PCV.


Assuntos
Cápsulas Bacterianas , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Anticorpos Antibacterianos , Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , DNA Bacteriano/genética , Humanos , Tipagem de Sequências Multilocus , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas , Fatores de Virulência/genética
4.
J Pharmacol Exp Ther ; 373(2): 239-247, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32102918

RESUMO

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.


Assuntos
Vias Aferentes/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Infarto Cerebral/fisiopatologia , Feminino , Células HEK293 , Humanos , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPM/fisiologia , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/tratamento farmacológico , Micção/efeitos dos fármacos
5.
Bioorg Med Chem ; 21(3): 592-607, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23276448

RESUMO

Highly TRß selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRß) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRß selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRß specificity in a binding assay and exhibited full agonism in a reporter cell assay.


Assuntos
Desenho de Fármacos , Malonatos/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Relação Dose-Resposta a Droga , Humanos , Malonatos/síntese química , Malonatos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 20(11): 3622-34, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22542282

RESUMO

Thyromimetics that specifically target TRß have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRß) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRß selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.


Assuntos
Dislipidemias/metabolismo , Indanos/química , Fígado/metabolismo , Mimetismo Molecular , Receptores beta dos Hormônios Tireóideos/agonistas , Animais , Arginina/química , Colesterol/administração & dosagem , Colesterol/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/tratamento farmacológico , Humanos , Ligantes , Fígado/efeitos dos fármacos , Masculino , Malonatos/síntese química , Malonatos/química , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Receptores beta dos Hormônios Tireóideos/metabolismo
7.
Endocr Res ; 35(4): 174-82, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20722489

RESUMO

INTRODUCTION: The effect of beta3-adrenergic receptor agonists on beta cells in the islets of Langerhans is not yet clear. This study examined the beta3-adrenergic receptor agonist on beta cells in the islets of Langerhans. METHODS: Obese diabetic C57BL/KsJ-db/db mice were treated with KTO-7924, a newly-developed beta3-adrenergic receptor agonist for 28-day. We analyzed plasma parameters, insulin resistance, and insulin-positive areas among beta-cells in the islets of Langerhans. RESULTS AND CONCLUSION: After a 28-day oral administration period, plasma levels of hemoglobin (Hb) A1c, glucose, triglyceride (TG), and free fatty acid (FFA) were all significantly reduced in KTO-7924 treatment groups compared with controls. Plasma adiponectin levels decreased with age in the control group, but were significantly higher in a treatment group throughout the study period. Furthermore, sequential administration of KTO-7924 led to an improvement in insulin resistance in the OGTT (Oral glucose tolerance test (OGTT)), and an increase in the percentage of insulin-positive areas among beta-cells in the islets of Langerhans compared with controls. This is the first study to show islet histology after treatment of a beta3-adrenergic receptor agonist, and reveals that KTO-7924 reduces hyperglycemia, and protects beta-cells in the islets of Langerhans of db/db mice.


Assuntos
Agonistas Adrenérgicos/farmacologia , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Adiponectina/sangue , Adiponectina/genética , Animais , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Hiperglicemia/patologia , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , RNA/química , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/sangue
8.
Metabolism ; 54(8): 995-1001, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16092047

RESUMO

Obese (fa/fa) Zucker rat is a spontaneous genetic obesity model and, by comparison with lean Zucker rat, exhibits hyperphagia, hyperinsulinemia, and hyperlipidemia. The aim of this study was to examine the physiological difference concerning adiponectin between obese (fa/fa) Zucker rats and control lean Zucker rats. We therefore measured plasma adiponectin level and analyzed adiponectin and adiponectin receptor 1 mRNA expression in retroperitoneal white adipose tissue (RT WAT), brown adipose tissue (BAT), liver, and soleus muscle. We also examined the tissue mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR delta, and PPAR gamma, which regulate adiponectin expression sensitivity to a PPAR gamma agonist shown by brown adipocytes from obese (fa/fa) Zucker rats and lean Zucker rats, by measuring adiponectin release from these cells. Plasma adiponectin levels of obese (fa/fa) Zucker rats were significantly higher than those of lean Zucker rats. Adiponectin mRNA expression levels in RT WAT were lower in obese (fa/fa) Zucker rats than in lean Zucker rats, but those in BAT were higher. Adiponectin receptor 1 expression levels in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats were lower than in lean Zucker rats. The expression level of PPAR alpha, PPAR delta, and PPAR gamma in BAT was lower in obese (fa/fa) Zucker rats than in lean Zucker rats. Moreover, the PPAR gamma agonist increased adiponectin release only from the brown adipocytes isolated from lean Zucker rats. It is the conclusive difference between obese (fa/fa) Zucker rats and lean Zucker rats that plasma adiponectin levels of obese (fa/fa) Zucker rats are significantly higher than those of lean Zucker rats. Moreover, we clarified that mRNA expression level of adiponectin receptor 1 in RT WAT, BAT, and liver of obese (fa/fa) Zucker rats is low despite high plasma adiponectin level, and low expression of PPARs in BAT leads to less sensibility of adiponectin release from brown adipocytes to a PPAR gamma agonist in obese (fa/fa) Zucker rats.


Assuntos
Peso Corporal , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Adipócitos/fisiologia , Adiponectina , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/fisiologia , Animais , Fígado/fisiologia , Masculino , Músculo Esquelético/fisiologia , PPAR alfa/genética , PPAR delta/genética , PPAR gama/genética , RNA Mensageiro/análise , Ratos , Ratos Zucker , Receptores de Adiponectina , Receptores de Superfície Celular/genética
9.
Pharmacol Res ; 52(5): 395-400, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16027000

RESUMO

We aimed to examine the effects of KTO-7924 (beta3-adrenoceptor agonist) on lipid metabolism and mRNA expressions in retroperitoneal white adipose tissue (RP WAT) in obese (fa/fa) Zucker rats using DNA microarray. Oral KTO-7924 for 28 days significantly decreased RP WAT weight, plasma triglyceride, free fatty acid, and insulin, and improved insulin resistance in oral glucose tolerance tests. In RP WAT of KTO-7924-treated rats, DNA microarray analysis revealed specifically enhanced mRNA expressions of uncoupling protein 1 (UCP1) and cytochrome c oxidase subunit VIII-H (COX8H), which are reportedly highly expressed in brown adipose tissue (BAT). Since these mRNA expression levels in RP WAT were significantly lower in obese (fa/fa) Zucker rats than in lean Zucker rats, these genes may be important in lipid metabolism. Our results imply that in obese (fa/fa) Zucker rats, continuous stimulation of beta3-adrenoceptors by KTO-7924 causes BAT-like adipocytes to appear in RP WAT, and improves lipid metabolism.


Assuntos
Tecido Adiposo/metabolismo , Agonistas Adrenérgicos/farmacologia , Agonistas de Receptores Adrenérgicos beta 3 , Obesidade/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Tecido Adiposo Marrom/metabolismo , Animais , Perfilação da Expressão Gênica , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Zucker
10.
Eur J Pharmacol ; 518(1): 71-6, 2005 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-15979609

RESUMO

Our aim was to determine the effect of a beta3-adrenoceptor agonist on plasma adiponectin levels and on the level of expression of mRNA for adiponectin, adiponectin receptor 1, and adiponectin receptor 2 in db/db mice. Two weeks' oral administration of CL-316,243 led to decreased plasma levels of hemoglobin A1c, glucose, insulin, triglyceride and free fatty acid, and to an increased plasma adiponectin levels. It also improved insulin resistance in the oral glucose tolerance test. Adiponectin mRNA expression was significantly higher in the CL-316,243-treatment group than in the control group in epididymal white adipose tissue but not in brown adipose tissue, soleus muscle or liver. Adiponectin receptor 2 mRNA expression was significantly lower only in the liver of the CL-316,243-treatment group (versus the control group). These results suggest that the increased plasma adiponectin levels seen in db/db mice treated with this beta3-adrenoceptor agonist induce a down-regulation of adiponectin receptor 2 mRNA expression specifically in the liver.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Diabetes Mellitus Tipo 2/genética , Dioxóis/farmacologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Receptores de Superfície Celular/genética , Adiponectina , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Agonistas de Receptores Adrenérgicos beta 3 , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/sangue , Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adiponectina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
11.
J Atheroscler Thromb ; 11(4): 224-31, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15356383

RESUMO

The effect of short-term bezafibrate (BF) administration over time on the expression of UCP mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into a high-dose (100 mg/kg) BF group (n = 15), a low-dose (10 mg/kg) BF group (n = 15) and a control group (n = 15), and followed for 14 days. Feed intake by the high-dose BF group increased significantly between days 10 and 14 of administration. Triglyceride, free fatty acid, and T(4) levels decreased significantly in a dose-dependent manner in the high-dose BF group. Leptin and insulin levels significantly decreased on days 3 and 7. Throughout the study period, liver UCP2 mRNA increased in the high-dose BF group. On day 3 of BF administration, the levels of UCP2 mRNA expression in the skeletal muscles as well as UCP3 mRNA expression in the WAT were significantly increased in the high-dose BF group. PPAR-alpha mRNA significantly increased in the liver on day 3 of BF administration. We thus conclude that the PPAR-alpha-mediated effects of BF on the expression of liver UCP2 may be one of the factors that helped to decrease insulin levels.


Assuntos
Bezafibrato/farmacologia , Hipolipemiantes/farmacologia , Obesidade/genética , Desacopladores , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Colesterol/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Canais Iônicos , Leptina/metabolismo , Masculino , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/genética , Obesidade/tratamento farmacológico , Obesidade/etiologia , PPAR alfa/efeitos dos fármacos , PPAR alfa/genética , PPAR delta/efeitos dos fármacos , PPAR delta/genética , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Hormônios Tireóideos/metabolismo , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3 , Vísceras/efeitos dos fármacos
12.
Endocrine ; 25(3): 247-51, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15758252

RESUMO

The effect of short-term bezafibrate (BF) administration over time on the expression of adiponectin mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into the high-dose (100 mg/kg) BF group (n=15), the low-dose (10 mg/kg) BF group (n=15), or the control group (n=15) and followed up for 14 d. Tri-glyceride and free fatty acid levels significantly decreased in a dose-dependent manner in the high-dose BF group. The insulin levels increased with time, although they were significantly lower in the high-dose BF group on d 3 and 7 than the control group. Adiponectin levels significantly increased in the high-dose BF group. On d 14 of BF administration, the levels of VLDL and chy-lomicron were significantly lower in BF groups, and adiponectin mRNA expression in the white adipose tissue was significantly higher in the high-dose BF group. Findings from this study suggest that in type 2 diabetes with insulin resistance, hypertriglyceridemia is closely linked to adiponectin.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Bezafibrato/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Hipolipemiantes/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/genética , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Adiponectina , Tecido Adiposo/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , VLDL-Colesterol/sangue , VLDL-Colesterol/efeitos dos fármacos , Quilomícrons/sangue , Quilomícrons/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Obesidade/complicações , Ratos , Ratos Endogâmicos OLETF
13.
J Urol ; 170(2 Pt 1): 654-8, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12853850

RESUMO

PURPOSE: We compared the effect of a beta 3-adrenoceptor (AR) agonist with that of beta 1 and beta 2-AR agonists on the urethra and bladder in the dog and rat. MATERIALS AND METHODS: In an in vitro experiment we studied the relaxant effect of subtype selective beta-AR agonists in canine and rat urethral and bladder smooth muscle using an organ bath method. In addition, in urethane anesthetized rats we measured urethral pressure and bladder pressure simultaneously in the presence of the beta 3-agonist CL316243 and the beta 2-agonist procaterol in 4 or 5 animals. RESULTS: In the dog the relaxing effects of isoprenaline in the distal urethra were about half those seen in the detrusor and trigone. The rank order of relaxing potency was CL316243 > dobutamine (beta 1-agonist) = procaterol in detrusor and trigone but procaterol > dobutamine = CL316243 in the prostatic and distal urethra. In rat urethral smooth muscle in vitro the corresponding order was procaterol > CL316243 > dobutamine and the maximal relaxation to each agonist was about half that seen in the bladder. In the anesthetized rat procaterol clearly decreased urethral pressure but CL316243 produced only a slight decrease at its maximal dose, although each agonists clearly reduced bladder pressure. The beta 2-antagonist ICI-118551 counteracted the decrease in urethral and bladder pressure induced by procaterol. CONCLUSIONS: In rats and dogs a selective beta 3-AR agonist can decrease bladder pressure without affecting urethral pressure.


Assuntos
Receptores Adrenérgicos beta/fisiologia , Uretra/fisiologia , Bexiga Urinária/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Dioxóis/farmacologia , Dobutamina/farmacologia , Cães , Feminino , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Procaterol/farmacologia , Propanolaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Uretra/metabolismo , Bexiga Urinária/metabolismo
14.
J Toxicol Sci ; 28(1): 25-34, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12696182

RESUMO

This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa , Piperidinas/farmacologia , Serina Endopeptidases/metabolismo , Animais , Anticoagulantes/química , Arginina/análogos & derivados , Cães , Haplorrinos , Humanos , Masculino , Camundongos , Modelos Animais , Ácidos Pipecólicos/farmacologia , Piperidinas/química , Coelhos , Ratos , Ratos Wistar , Sulfonamidas
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