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2.
Cardiol Ther ; 11(4): 611-623, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36319831

RESUMO

INTRODUCTION: The time course of reduction in the risk of venous thromboembolism (VTE) in patients who were diagnosed with cancer, treated with anticancer therapy, and in remission is unclear. We hypothesized that the risk of VTE will decrease over time after cancer remission. METHODS: We conducted a retrospective analysis using claims data for cancer remission in Japan. Background information of patients who developed VTE after cancer remission was collected, and the VTE incidence rate after cancer remission was analyzed. Subgroup analysis based on VTE history, cancer type, and the presence or absence of surgery during hospitalization was conducted. RESULTS: A total of 638,908 patients were eligible for the analysis. VTE occurred in 5533 of 638,908 cases, pulmonary embolism occurred in 779 cases, and deep vein thrombosis occurred in 5084 cases after cancer remission. The mean age of patients who developed VTE was 70.1 ± 12.5 years, and the proportion of men was 47.5%. All comorbidities and medications were higher in the VTE group (P < 0.001) than in the non-VTE group after cancer remission. The incidence of VTE was 2.4% per year in the first 30 days, 1.35% per year in 31-60 days, and gradually decreased to 0.48% per year in 181-360 days, becoming almost constant (annual rate 0.3%) 2 years after cancer remission. CONCLUSION: Risk of developing VTE decreased to the same level as that in patients without cancer 2 years after cancer remission. Although the guidelines do not specify the duration of anticoagulant prophylaxis for new onset or recurrent VTE after cancer remission and the appropriate duration of such prophylaxis may vary depending on VTE risk factors, determining the period of high risk of VTE for each patient and preventing VTE is considered important.

3.
Cardiol Ther ; 11(4): 589-609, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36318364

RESUMO

INTRODUCTION: Previous studies on anticoagulation treatment trends have mostly focused on hospitalized patients. This study aimed to clarify the treatment status of patients with venous thromboembolism (VTE) in Japan from 2011 to 2018, including outpatients, and to assess adherence with current guidelines. METHODS: Data of inpatients and outpatients who were treated for VTE were extracted from a nationwide claims database (Medical Data Vision Co., Ltd., Tokyo, Japan) and analyzed. RESULTS: The study included 79,330 patients with VTE; half were diagnosed during hospitalization for diseases other than VTE. The proportion of outpatient treatment increased significantly from 2015 to 2018 (Cochran-Armitage trend test, P < 0.0001), while 80% were anticoagulated in hospital after pulmonary embolism (PE) diagnosis. The proportion of patients with VTE treated as outpatients was no lower than the proportion of inpatients, even in the presence of active cancer, and there were no clear differences in anticoagulant choices. Treatment with direct oral anticoagulants (DOACs) did not always include the recommended initial intensification therapy. There was wide variation in the duration of DOAC treatment and the median duration of use was shorter than that recommended in VTE treatment guidelines. CONCLUSION: While the gradual increase in VTE outpatient treatment appears to be in line with guideline recommendations, PE outpatient treatment could be further facilitated. The large proportion of patients diagnosed with VTE during hospitalization for other conditions suggests the importance of further utilizing in-hospital manuals for thrombosis prevention. The presence or absence of cancer did not appear to affect the basic treatment strategy of anticoagulation for VTE. Future studies are expected to better define the characteristics of patients who can be safely and effectively treated in an outpatient setting, and to examine whether anticoagulation for a shorter treatment period than recommended by the guidelines or DOAC therapy without initial intensification would improve patient outcomes.

4.
Open Heart ; 7(1): e001232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341789

RESUMO

Objective: To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs. Methods: We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted. Results: A total of 73 989 patients were eligible for analysis. Notably, 52.8%-81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2-2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods. Conclusions: In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.


Assuntos
Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Dabigatrana/administração & dosagem , Registros Eletrônicos de Saúde , Feminino , Hemorragia/induzido quimicamente , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Tiazóis/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos
5.
Future Cardiol ; 16(1): 43-52, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31793345

RESUMO

Aim: Nonvalvular atrial fibrillation (NVAF) is associated with an increased risk of stroke however many patients are diagnosed after onset. This study assessed the potential of machine-learning algorithms to detect NVAF. Materials & methods: A retrospective database study using a Japanese claims database. Patients with and without NVAF were selected. 41 variables were included in different classification algorithms. Results: Machine learning algorithms identified NVAF with an area under the curve of >0.86; corresponding sensitivity/specificity was also high. The stacking model which combined multiple algorithms outperformed single-model approaches (area under the curve ≥0.90, sensitivity/specificity ≥0.80/0.82), although differences were small. Conclusion: Machine-learning based algorithms can detect atrial fibrillation with accuracy. Although additional validation is needed, this methodology could encourage a new approach to detect NVAF.


Assuntos
Algoritmos , Fibrilação Atrial/diagnóstico , Aprendizado de Máquina , Acidente Vascular Cerebral/prevenção & controle , Idoso , Fibrilação Atrial/complicações , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologia
6.
BMJ Open ; 9(10): e029913, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575535

RESUMO

OBJECTIVES: The purpose of this study was to investigate the effects of smoking on prognosis after elective surgeries. Incidence of 30-day postoperative complications was compared between propensity score-matched 'ever-smoker' and 'never-smoker' cohorts. Thirty-day mortality and medical costs during the hospital stay were also compared. DESIGN AND SETTING: A large-scale retrospective study using deidentified administrative claims data obtained from 372 acute care hospitals across Japan using the Diagnosis Procedure Combination system (ie, a flat-fee payment system). PARTICIPANTS: Inpatients who were hospitalised to undergo elective surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint of this study was incidence of 30-day postoperative complications. Secondary endpoints were 30-day mortality and total medical costs during hospitalisation. Comparison between ever-smokers and never-smokers was conducted using matched cohorts created by 1:1 propensity score matching. RESULTS: Using 561 598 eligible patients, matched ever-smoker and never-smoker cohorts (n=1 55 593 each) were created. Ever-smokers were defined as patients with Brinkman Index ≥1. The percentage of patients who were male was 76.7%, and mean ages for ever-smokers and never-smokers were 65.1±13.8 years old and 66.4±15.3 years old, respectively. The Brinkman Index of the ever-smoker cohort was 677.6±553.4. Smoking was significantly associated with higher risk of 30-day postoperative complications compared with not smoking (OR 1.15, 95% CI 1.13 to 1.17, p<0.001). Similarly, smoking was significantly associated with postoperative 30-day mortality, with OR of 1.22 (95% CI 1.08 to 1.39, p=0.002). CONCLUSIONS: Our results suggest that smoking could be associated with risk of poor postoperative outcomes. In particular, a history of smoking may increase the risk of 30-day postoperative complications as well as that of 30-day mortality. The results suggest that smoking might have a harmful effect on postoperative outcomes irrespective of types of surgery.


Assuntos
Procedimentos Cirúrgicos Eletivos , Complicações Pós-Operatórias/etiologia , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Procedimentos Cirúrgicos Eletivos/economia , Feminino , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Humanos , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/epidemiologia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Fumar/economia
7.
Curr Med Res Opin ; 34(9): 1627-1634, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29772946

RESUMO

OBJECTIVE: To investigate the risk of bleeding events and stroke/systemic embolism (SE) among Japanese patients with nonvalvular atrial fibrillation (NVAF), focusing on the initial dosage of apixaban and patient age. METHODS: This retrospective cohort study used de-identified electronic health records based claims data from 314 acute-care hospitals in Japan. NVAF patients newly initiated on warfarin or apixaban, with no prescription during the 180-day blanking period, were eligible. Patients were allocated to receive warfarin or 5 or 2.5 mg twice daily (BID) apixaban. One-to-one propensity-score matching was used to balance patient characteristics between apixaban and warfarin. RESULTS: Among 31,006 eligible patients, 11,972 matched pairs were identified for apixaban versus warfarin. Mean age ± standard deviation was 77.7 ± 10.0 and 77.6 ± 10.0 years and CHADS2 score was 2.2 ± 1.4 and 2.2 ± 1.4 for warfarin and apixaban, respectively. In the apixaban cohort, 39.4% of patients received the standard dose (5 mg BID) and 60.6% received the reduced dose (2.5 mg BID). Incidence rates (events per 100 person-years) of major bleeding, any bleeding and stroke/SE were 3.7, 23.1 and 3.1, and 2.5, 18.6 and 2.0 for warfarin and apixaban cohorts, respectively. Apixaban was associated with a significantly lower risk of any bleeding (hazard ratio [HR] 0.809, 95% confidence interval [CI] 0.731-0.895; p < .001), major bleeding (HR 0.655, 95% CI 0.505-0.849; p = .001) and stroke/SE (HR 0.637, 95% CI 0.478-0.850; p = .002). CONCLUSIONS: Our observational data from clinical practice broadly confirms the safety and efficacy results of pivotal randomized controlled trials of apixaban for stroke prevention among NVAF patients.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Hemorragia , Pirazóis , Piridonas , Acidente Vascular Cerebral/prevenção & controle , Varfarina , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Feminino , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Japão/epidemiologia , Masculino , Pontuação de Propensão , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Varfarina/administração & dosagem , Varfarina/efeitos adversos
8.
Curr Med Res Opin ; 33(11): 1955-1963, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28857611

RESUMO

OBJECTIVES: There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. METHODS: A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. RESULTS: Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421-0.815), dabigatran (HR 0.617; 0.425-0.895) and rivaroxaban (HR 0.693; 0.514-0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682-0.896), but not for dabigatran (HR 0.988; 0.860-1.135) or rivaroxaban (HR 0.938; 0.832-1.057) when comparing to warfarin. CONCLUSIONS: Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real-world practice needs to be assessed further.


Assuntos
Dabigatrana/efeitos adversos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Rivaroxabana/efeitos adversos , Varfarina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Estudos de Coortes , Dabigatrana/administração & dosagem , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Risco , Rivaroxabana/uso terapêutico , Varfarina/uso terapêutico
9.
Anal Sci ; 25(9): 1069-75, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19745532

RESUMO

A weak laser irradiation (523-785 nm, 5-60 mW) onto an Au electrode surface of a 27-MHz quartz crystal microbalance (QCM) caused a frequency increase (a mass decrease) in the air phase. These frequency changes depended on the wavelength of the irradiated laser in the order of 523 nm > 636 nm > 785 nm, which corresponds to the light absorbance of the Au electrode of the QCM. The laser response increased linearly with increasing laser power (5-60 mW). In addition, the laser response showed a maximum at the incidence angle of 72 degrees when the P-polarized 636 nm laser was irradiated on the Au surface, due to the evanescent effect. These laser responses were also observed in the humid air of H2O, D2O, and in the vapors of various alcohols. Based on these findings, the observed frequency increase (mass decrease) can be explained by the photo-induced reversible desorption of water molecules from the Au electrode surface of the QCM due to the interfacial property changes.


Assuntos
Ar , Lasers , Luz , Quartzo , Álcoois/química , Óxido de Deutério/química , Eletrodos , Ouro/química , Umidade , Propriedades de Superfície , Volatilização
10.
Circulation ; 111(17): 2157-64, 2005 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15851599

RESUMO

BACKGROUND: The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)-dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II-independent remodeling is unclear. METHODS AND RESULTS: Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor-knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. CONCLUSIONS: Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II-independent mechanisms.


Assuntos
Aldosterona/biossíntese , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Aldosterona/fisiologia , Animais , Citocromo P-450 CYP11B2/biossíntese , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Infarto do Miocárdio/complicações , Receptor Tipo 1 de Angiotensina/deficiência , Receptor Tipo 1 de Angiotensina/genética , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Remodelação Ventricular
11.
J Pharmacol Exp Ther ; 313(1): 286-92, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15576468

RESUMO

Postoperative peritoneal adhesion represents a major complication of surgery, but the molecular mechanism underlying pathogenesis of adhesion is not fully understood. The present study investigated the roles of cyclooxygenase (COX)-1 and COX-2 in peritoneal adhesion induced by scraping the surface of the cecum and abdominal wall in mice. Slight, but macroscopically observable, peritoneal adhesion was induced even on day 1, and the extent of adhesion reached a maximum on day 7 and beyond. COX-1 mRNA was constitutively expressed in the intact cecum, and its expression level was not altered after the mechanical stimulus. In contrast, expression of the COX-2 gene was markedly increased after the stimulus, and maximum expression was observed on days 3 to 7. Mofezolac, a specific COX-1 inhibitor, had no effect on peritoneal adhesion at 30 mg/kg and had only marginal effects on prostaglandin (PG)E2 levels in the cecum or peritoneal fluid. On the other hand, two highly selective inhibitors for COX-2, NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide) and CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], dose-dependently inhibited both adhesion formation and the increase in PGE2 levels (3-30 mg/kg). The effects of NS-398 were eliminated when PGE2 or (R)-butaprost was administered exogenously. A COX-2 antisense oligonucleotide also attenuated adhesion formation. Activation of p38 mitogen-activated protein (MAP) kinase was observed in the traumatized cecum, and an MAP kinase inhibitor, SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole], inhibited adhesion formation (54% inhibition at 15 microM) and also reduced the COX-2 mRNA level and PGE2 levels. In conclusion, COX-2, but not COX-1, plays a significant role in mechanical stimulus-induced peritoneal formation in the mouse cecum.


Assuntos
Prostaglandina-Endoperóxido Sintases/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Western Blotting , Ceco/lesões , Ceco/metabolismo , Adesão Celular/fisiologia , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Imunoprecipitação , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Oligonucleotídeos Antissenso/farmacologia , Cavidade Peritoneal/citologia , Estimulação Física , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/genética , Piridinas/farmacologia , Receptores de Prostaglandina/biossíntese , Receptores de Prostaglandina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
12.
Drug Metab Pharmacokinet ; 18(1): 48-70, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-15618719

RESUMO

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

13.
J Pharmacol Exp Ther ; 302(3): 949-56, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12183651

RESUMO

Chymase is a serine protease responsible for local production of angiotensin (Ang) II from its precursor Ang I in several species, including humans, dogs, and hamsters. We have previously reported that chymase facilitates angiogenesis in sponge granulation tissues via local production of Ang II. Herein, we report the significance of vascular endothelial growth factor (VEGF) up-regulation mediated by Ang II during angiogenesis in hamster sponge granulomas. Treatment of granulation tissues with an anti-VEGF neutralizing antibody or antisense oligomers against VEGF mRNA significantly reduced Ang II-induced angiogenesis, supporting a significant role for VEGF during angiogenesis. In cultured fibroblasts prepared from granulation tissues, VEGF mRNA was up-regulated in response to Ang II within 2 h and this enhanced expression was abolished in the presence of an Ang II type 1 receptor-selective antagonist, an inhibitor of nuclear factor-kappaB activation, or an activator protein-1 inhibitor. To study the significance of local production of Ang II by chymase, we examined the effects of chymostatin on in vivo angiogenesis. We found that chymostatin markedly inhibited both up-regulation of VEGF mRNA and angiogenesis in granulation tissues treated by compound 48/80 or basic fibroblast growth factor. Our results suggest that Ang II directly acts on fibroblasts in granulation tissue to up-regulate VEGF mRNA and thereby induce angiogenesis. Furthermore, a chymase-Ang II-VEGF pathway may operate in granulation tissue as the primary mediator of angiogenesis.


Assuntos
Angiotensina II/fisiologia , Fatores de Crescimento Endotelial/biossíntese , Linfocinas/biossíntese , Neovascularização Patológica/patologia , Serina Endopeptidases/fisiologia , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia , Animais , Células Cultivadas , Quimases , Cricetinae , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibroblastos , Granuloma/patologia , Hemoglobinas/metabolismo , Oligonucleotídeos Antissenso/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , p-Metoxi-N-metilfenetilamina/farmacologia
14.
Br J Pharmacol ; 136(4): 484-91, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12055126

RESUMO

Physiological roles of angiotensin II type 2 receptor (AT(2)) are not well defined. This study was designed to investigate the mechanisms of AT(2)-dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments. Perfusion of angiotensin II in the presence of AT(1) antagonist elicited vascular relaxation, which was completely dependent on AT(2) receptors on endothelium. FR173657 (>1 microM), a bradykinin (BK) B(2)-specific antagonist, significantly suppressed AT(2)-dependent vasodilation (maximum inhibition: 68.5% at 10 microM). Kininogen-deficient Brown Norway Katholiek rats showed a significant reduction in AT(2)-mediated vasodilatory response compared with normal wild-type Brown Norway rats. Indomethacin (>1 microM), aprotinin (10 microM) and soybean trypsin inhibitor (10 microM) also reduced AT(2)-dependent vasodilation. Our results demonstrated that stimulation of AT(2) receptors caused a significant vasodilation through local production of BK in resistant arteries of rat mesentery in a flow-dependent manner. Such vasodilation counterbalances AT(1)-dependent vasoconstriction to regulate the vascular tone.


Assuntos
Angiotensina II/metabolismo , Bradicinina/biossíntese , Receptores de Angiotensina/fisiologia , Vasodilatação/fisiologia , Angiotensina II/farmacologia , Animais , Antagonistas dos Receptores da Bradicinina , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Técnicas In Vitro , Indometacina/farmacologia , Calicreínas/antagonistas & inibidores , Cininogênios/deficiência , Cininogênios/genética , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Perfusão , Pressão , Ratos , Ratos Endogâmicos BN , Receptor Tipo 2 de Angiotensina , Receptor B2 da Bradicinina , Resistência Vascular , Vasodilatadores/farmacologia
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