RESUMO
INTRODUCTION AND OBJECTIVES: Liver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. MATERIAL AND METHODS: Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. RESULTS: In the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). CONCLUSION: Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway.
Assuntos
Circulação Colateral/efeitos dos fármacos , Ácido Fólico/farmacologia , Homocisteína/análogos & derivados , Cirrose Hepática/fisiopatologia , Neovascularização Patológica/induzido quimicamente , Sistema Porta/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Animais , Ducto Colédoco , Hemodinâmica/efeitos dos fármacos , Homocisteína/farmacologia , Ligadura , Cirrose Hepática/complicações , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Sistema Porta/patologia , Ratos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: Calpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia. METHODS: Yorkshire swine fed a high cholesterol diet for 4 weeks underwent surgical placement of an ameroid constrictor to their left circumflex coronary artery. Three weeks later, animals received no drug, high cholesterol control group (n = 8); low-dose calpain inhibition (0.12 mg/kg; n = 9); or high-dose calpain inhibition (0.25 mg/kg; n = 8). The heart was harvested after 5 weeks. RESULTS: Myocardial perfusion in ischemic myocardium significantly improved with high-dose calpain inhibition at rest and with demand pacing (P = .016 and .011). Endothelium-dependent microvessel relaxation was significantly improved with low-dose calpain inhibition (P = .001). There was a significant increase in capillary density, with low-dose calpain inhibition and high-dose calpain inhibition (P = .01 and .01), and arteriolar density with low-dose calpain inhibition (P = .001). Calpain inhibition significantly increased several proangiogenic proteins, including vascular endothelial growth factor (P = .02), vascular endothelial growth factor receptor 1 (P = .003), vascular endothelial growth factor receptor 2 (P = .003), and talin, a microvascular structural protein (P = .0002). There was a slight increase in proteins implicated in endothelial-dependent (nitric oxide mediated) relaxation, including extracellular signal-regulated kinase, phosphorylated extracellular signal-regulated kinase, and inducible nitric oxide synthase with calpain inhibition. CONCLUSIONS: In the setting of hypercholesterolemia, calpain inhibition improved perfusion, with a trend toward increased collateralization on angiography and increased capillary and arteriolar densities in ischemic myocardium. Calpain inhibition also improved endothelium-dependent microvessel relaxation and increased expression of proteins implicated in angiogenesis and vasodilatation.
Assuntos
Calpaína/antagonistas & inibidores , Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Hipercolesterolemia/complicações , Microvasos/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas Angiogênicas/metabolismo , Animais , Calpaína/metabolismo , Doença Crônica , Angiografia Coronária , Vasos Coronários/enzimologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Microcirculação/efeitos dos fármacos , Microvasos/enzimologia , Microvasos/fisiopatologia , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Neovascularização Fisiológica/efeitos dos fármacos , Fatores de Tempo , Vasodilatação/efeitos dos fármacosRESUMO
Portal hypertension is the main complication of cirrhosis and represents a leading cause of death in patients with chronic liver disease. Therapeutic agents to improve portal hypertension should ameliorate the underlying mechanisms of portal hypertension: the elevated hepatic resistance and the hyperdynamic circulation. In the present issue of Clinical Science, Hsu and co-workers show the beneficial effects of GTPs (green tea polyphenols) in improving portal hypertension. Long-term administration of GTPs inhibited the development of cirrhosis and portal hypertension by decreasing both hepatic resistance and splanchnic hyperdynamic circulation. The main underlying mechanism of the benefits of GTPs appears related to the down-regulation of splanchnic angiogenesis. The present study adds further evidence supporting the potential of natural compounds for an effective nutriceutical approach to the treatment of patients with cirrhosis of the liver.
Assuntos
Inibidores da Angiogênese/farmacologia , Camellia sinensis , Circulação Colateral/efeitos dos fármacos , Hipertensão Portal/prevenção & controle , Circulação Hepática/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Neovascularização Patológica , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Animais , MasculinoRESUMO
Abnormal angiogenesis in liver cirrhosis often leads to severe complications such as variceal haemorrhage and encephalopathy. Furthermore, splanchnic angiogenesis elevates portal pressure, in which angiogenic factors play pivotal roles. GTP (green tea polyphenol) extracted from Camellia sinensis has anti-angiogenic properties, but the effects on the parameters described above in cirrhosis have not been investigated. The aim of the present study was to determine the effects of GTP in cirrhosis and to investigate the underlying mechanism. Liver cirrhosis was induced in Spraque-Dawley rats by common BDL (bile duct ligation). They randomly received GTP or DW (distilled water, vehicle) for 28 days, then haemodynamic parameters, portosystemic shunting, mesenteric window vascular density, intrahepatic angiogenesis, liver fibrosis, plasma VEGF (vascular endothelial growth factor) concentration, mesenteric angiogenic factor and receptor protein expression, and serum and mesenteric oxidative stress parameters were assessed. Compared with the DW group, GTP significantly decreased portosystemic shunting, liver fibrosis, intrahepatic angiogenesis, mesenteric window vascular density, VEGF concentration and down-regulated the mesenteric HIF (hypoxia-inducible factor)-1α, VEGF and phospho-Akt expression. In conclusion, GTP ameliorates the severity of portosystemic shunting and mesenteric angiogenesis via the suppression of HIF-1α, Akt activation and VEGF. GTP appears to be an appropriate agent in controlling portal hypertension-related complications via anti-angiogenesis.
Assuntos
Inibidores da Angiogênese/farmacologia , Camellia sinensis , Circulação Colateral/efeitos dos fármacos , Hipertensão Portal/prevenção & controle , Circulação Hepática/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Neovascularização Patológica , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Animais , Biomarcadores/sangue , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/fisiopatologia , Masculino , Artérias Mesentéricas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Fitoterapia , Plantas Medicinais , Pressão na Veia Porta/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVE: The purpose of the present study was to evaluate the effect of atorvastatin on oxidative stress and angiogenesis in ischemic myocardium in a clinically relevant porcine model of the metabolic syndrome. METHODS: Sixteen Ossabaw pigs were fed either a high-fat diet alone or a high-fat diet supplemented with atorvastatin (1.5 mg/kg daily) for 14 weeks. Chronic myocardial ischemia was induced by ameroid constrictor placement around the circumflex artery. After 6 months of the diet, myocardial perfusion was measured at rest and with demand pacing. The heart was harvested for analysis of perfusion, microvessel relaxation, protein expression, and oxidative stress. RESULTS: Both groups had similar endothelium-dependent microvessel relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside. Myocardial perfusion in the ischemic territory was also not significantly different either at rest or with demand pacing. Atorvastatin treatment increased total myocardial protein oxidation and serum lipid peroxidation. However, the expression of markers of oxidative stress, including NOX2, RAC1, myeloperoxidase, and superoxide dismutase 1, 2, and 3, were not statistically different. The expression of proangiogenic proteins endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase (Ser 1177), phosphorylated adenosine monophosphate kinase (Thr 172), phosphorylated extracellular signal-regulated kinase (T202, Y204), and vascular endothelial growth factor were all upregulated in the atorvastatin group. CONCLUSIONS: Atorvastatin increased the capillary and arteriolar density and upregulated the proangiogenic proteins endothelial nitric oxide synthase and phosphorylated endothelial nitric oxide synthase, phosphorylated adenosine monophosphate kinase, phosphorylated extracellular signal-regulated kinase, and vascular endothelial growth factor in a swine model of the metabolic syndrome. However, it failed to increase myocardial perfusion. Atorvastatin treatment was associated with increased myocardial and serum oxidative stress, which might contribute to the lack of collateral-dependent perfusion in the setting of angiogenesis.
Assuntos
Indutores da Angiogênese/farmacologia , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Síndrome Metabólica/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pirróis/farmacologia , Proteínas Angiogênicas/metabolismo , Animais , Atorvastatina , Biomarcadores/sangue , Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiopatologia , Isquemia Miocárdica/sangue , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco Miniatura , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.
Assuntos
Isquemia Encefálica/complicações , Circulação Cerebrovascular/fisiologia , Circulação Colateral/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tocotrienóis/uso terapêutico , Animais , Isquemia Encefálica/enzimologia , Isquemia Encefálica/fisiopatologia , Angiografia Cerebral , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Fluoroscopia , Imageamento por Ressonância Magnética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Tocotrienóis/administração & dosagem , Tocotrienóis/farmacologiaRESUMO
OBJECTIVE: To investigate the effects and mechanisms of panaxoside Rg1 on the new vessel formation in acute myocardial infarction (AMI) rats. METHODS: The AMI model of male Sprague-Dawley (SD) rats was established, and rats were randomly divided into the AMI model group, the treatment group of panaxoside Rg1, the placebo group and the treatment group of panaxoside Rg1 plus rapamycin. Cardiac creatases were determined with 1 mL blood drawn from vena caudalis of the rats 48 h after the model was successfully made. After 4 weeks, Evans blue was injected into the aorta roots of the rats, and then, red tetrazoline was dyed again and the myocardial infarction area was evaluated. The microvessel density (MVD) of infarction area was determined by the immunohistochemistry of CD31; enzyme-linked immunosorbent assay (ELISA) was used to detect the protein content of CD31 and hypoxia inducible factor-1alpha (HIF-1alpha) of the infarction area. RESULTS: The MVD in the infarction area and the contents of CD31 and HIF-1alpha in the Rg1 treatment group were higher than those in the AMI model group significantly (P<0.05). The cardiac creatase and infarction area were lower in the Rg1 treatment group than those in the AMI model group significantly (P<0.05). The above effects, however, disappeared when rapamycin, the antagonist of mammalian target of rapamycin (mTOR), was administered simultaneously. CONCLUSIONS: Panaxoside Rg1 could increase the expression of HIF-1alpha and CD31 of myocardium and stimulate the angiogenesis. The above mentioned role of panaxoside Rg1 might be related to the excitation of mTOR receptor.
Assuntos
Ginsenosídeos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Contagem de Células , Circulação Colateral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ginsenosídeos/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Masculino , Microvasos/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Placebos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Serina-Treonina Quinases TORRESUMO
The mechanisms for decreased tolerance to ischemia in the aging hearts have not been fully explored but they appear to be multifactorial. The elderly patients most often meet classification of "no-option" patients who suffer from symptoms of chronic recurrent myocardial ischemia without good options for intervention. As such these patients are in greatest need of alternative therapies for revascularization such as angiogenesis. Not only does aging and their co-morbid conditions such as hypercholesterolemia and diabetes impair the endogenous angiogenesis response but there may be decreased responsiveness to exogenous angiogenic therapies. Enhancing the effectiveness of angiogenic therapy in this ever increasing subgroup of cardiovascular patients is as yet unmet. One such promising avenue involves sirtuins. Herein, we review the effect of aging on the processes of angiogenesis and explore the implications for successful clinical treatment of myocardial ischemia with angiogenesis therapy, with particular focus on modification of sirtuins and their targets by resveratrol along with some recent patents.
Assuntos
Envelhecimento/fisiologia , Indutores da Angiogênese/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Sirtuínas/agonistas , Indutores da Angiogênese/farmacologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Circulação Colateral/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Humanos , Isquemia Miocárdica/fisiopatologia , Resveratrol , Estilbenos/farmacologia , Estilbenos/uso terapêuticoRESUMO
UNLABELLED: Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. CONCLUSION: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.
Assuntos
Benzenossulfonatos/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Circulação Esplâncnica/efeitos dos fármacos , Animais , Benzenossulfonatos/farmacologia , Circulação Colateral/efeitos dos fármacos , Enterite/tratamento farmacológico , Enterite/etiologia , Heme Oxigenase-1/metabolismo , Hepatite/tratamento farmacológico , Hepatite/etiologia , Hipertensão Portal/etiologia , Fígado/metabolismo , Cirrose Hepática/complicações , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Niacinamida/análogos & derivados , Óxido Nítrico Sintase Tipo III/metabolismo , Compostos de Fenilureia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , SorafenibeRESUMO
OBJECTIVE: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine. METHODS: Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated. RESULTS: Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% +/- 3% vs 70% +/- 7%, ATOR vs NORM at 10(-10) mol/L, P = .05) and fibroblast growth factor-2 (35% +/- 3% vs 57% +/- 5%, ATOR vs NORM at 10(-10) mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (-0.29 +/- 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% +/- 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% +/- 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups. CONCLUSIONS: Atorvastatin supplementation is associated with impaired growth factor-mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.
Assuntos
Circulação Coronária/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Pirróis/farmacologia , Animais , Atorvastatina , Colesterol/sangue , Circulação Colateral/efeitos dos fármacos , Feminino , Técnicas In Vitro , Masculino , Microcirculação/efeitos dos fármacos , SuínosRESUMO
PURPOSE: To observe and evaluate the effects of long-term use of the heat-clearing, diuresis-promoting and collateral-mediating Chinese drugs on changes of proteinuria in patients with chronic nephritis, to analyze the influence of renal function, blood pressure, proteinuria and TCM syndrome types on therapeutic effects of the therapy, and to analyze the indications and effects of the heat-clearing, diuresis-promoting and collateral-mediating Chinese drugs when added with small dosage of Lei Gong Teng ([Chinese characters: see text] Radix et Rhizoma Tripterygii). METHOD: 43 cases of chronic nephritis were treated for one year with the heat-clearing, diuresis-promoting and collateral-mediating Chinese drugs. RESULT: A one-year treatment showed obvious reduction of proteinuria in patients with chronic nephritis. CONCLUSIONS: (1) The heat-clearing, diuresis-promoting and collateral-mediating Chinese drugs are effective for a long-term treatment of proteinuria in patients with chronic nephritis. (2) Additional use of Lei Gong Teng can help control proteinuria. (3) Damp-heat deeply accumulated in the kidney is one of the pathologic characteristics for chronic nephritis with the damp-heat syndrome.
Assuntos
Circulação Colateral/efeitos dos fármacos , Diurese/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Febre/tratamento farmacológico , Nefrite/complicações , Proteinúria/tratamento farmacológico , Adulto , Doença Crônica/tratamento farmacológico , Feminino , Febre/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Various growth factors promote collateral vessel development and are regarded as promising for the treatment of vascular occlusive diseases. However, an efficacious delivery system for them has yet to be established. We devised a strategy to augment functional collateral vessels by using acidic gelatin hydrogel microspheres (AGHMs) incorporating basic fibroblast growth factor (bFGF). The aim of the present study was to investigate the hypothesis that by intra-arterial (IA) administration of bFGF-impregnated AGHMs, bFGF could be delivered from AGHMs trapped in distal small-diameter vessels and thereby induce functional collateral vessels with an assured blood supply through the process of arteriogenesis. METHODS AND RESULTS: Various sizes of AGHMs (3 mg) incorporating 125I-labeled bFGF were injected into the left internal iliac artery of a rabbit model of hindlimb ischemia. Less than 50% of radioactivity accumulated in the ischemic hindlimb after injection of AGHMs that were 10 mum in diameter, whereas approximately 80% of radioactivity was counted in the ischemic limb after administration of 29- or 59-microm-diameter AGHMs. Calf blood pressure ratio and the ratio of regional blood flow of the bilateral hindlimbs immediately before and after IA administration of 29-microm-diameter AGHMs showed no significant change. Then we evaluated the function of the developed collateral vessels 28 days after IA administration of bFGF-impregnated, 29-microm-diameter AGHMs. IA administration of bFGF-impregnated AGHMs induced marked collateral vessel improvement compared with IA administration of phosphate buffered saline-treated AGHMs and intramuscular administration of bFGF-impregnated AGHMs. CONCLUSIONS: IA administration of bFGF-impregnated, 29-microm-diameter AGHMs strongly induced functional collateral vessels without worsening ischemia, indicating the possible therapeutic usefulness of this approach.
Assuntos
Circulação Colateral/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Membro Posterior/irrigação sanguínea , Isquemia/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Artéria Femoral/lesões , Fator 2 de Crescimento de Fibroblastos/farmacologia , Gelatina , Hidrogel de Polietilenoglicol-Dimetacrilato , Concentração de Íons de Hidrogênio , Injeções Intra-Arteriais , Isquemia/fisiopatologia , Masculino , Microesferas , Tamanho da Partícula , Coelhos , Distribuição TecidualRESUMO
AIM: To evaluate the results of surgical treatment of patients with ischemic heart disease in combination with intraoperative intramyocardial introduction of the human gene VEGF165 (angiostimulin). MATERIAL AND METHODS: Twenty four patients enrolled in the study were examined using 12-lead ECG, echocardiography, treadmill exercise test, single-photon emission computed tomography of the myocardium with Tc-99m-tetrophosmine, fluorodesoxyglucose (FDG) positron-emission tomography of the myocardium, selective coronarography. Out of 24 patients, 10 patients have been reexamined so far. The effect of the treatment was assessed by the data obtained at the treadmill test, transthoracic echocardiography, myocardial scintigraphy and FDG. RESULTS: All the patients demonstrated a clinical response. The class of effort angina improved, the dose of the prescribed nitric drugs was decreased, exercise tolerance and total stress time rose, quality of life improved. Myocardial scintigraphy registered reduction of the total area and better accumulation of the radiopharmaceutical under load and at rest 3 and 6 months after the operation including myocardial areas which had not been revacularised at coronary artery bypass grafting but had been treated with the preparation of the human gene VEGF165. CONCLUSION: The results of the study suggest that therapeutic angiogenesis may be an alternative impact on those myocardial areas which are supplied by the affected but ineligible for bypass grafting coronary arteries.
Assuntos
Circulação Colateral/efeitos dos fármacos , Isquemia Miocárdica/terapia , Revascularização Miocárdica , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Terapia Combinada , Angiografia Coronária , Ecocardiografia , Eletrocardiografia , Teste de Esforço , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/cirurgia , Compostos Organofosforados , Compostos de Organotecnécio , Qualidade de Vida , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/administração & dosagemRESUMO
PURPOSE: To evaluate the therapeutic efficacy and safety of supplemental transcatheter arterial chemoembolization (TACE) through the extrahepatic collateral omental artery (OA) for the treatment of hepatocellular carcinoma (HCC). METHODS: We studied 21 patients with extrahepatic collaterals of the OA, among 1,512 patients with HCC who had undergone angiography. HCCs supplied by collateral OAs were located at: segment IV in seven, segment V in five, segment III in three, segment VI in three and segment VIII in three patients (Couinaud classification of segments). On preoperative CT scans, every HCC was abutting the liver surface. Adjacent omental infiltration or engorgement was noted in 11 patients. Celiac and hepatic arteriograms showed hypertrophy of the feeding OA in all patients. TACE of the OA was performed in 19 patients with an emulsion of iodized oil and doxorubicin hydrochloride. Embolization with gelatin sponge particles was added in five patients. RESULTS: Collaterals of the OA to the HCC were found on the first to seventeenth sessions of TACE. On follow-up CT scans, five patients showed complete uptake of iodized oil in the tumor. Partial uptake of iodized oil was noted in 13 patients and no uptake in one patient. There was no serious complication that related to the omental embolization, such as omental or bowel ischemia. The cumulative survival rates from the time of the TACE of the OA were 81% at 6 months and 68% at 12 months. CONCLUSION: TACE of the OA is safe and has a potential therapeutic effect in the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Omento/irrigação sanguínea , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Cateteres de Demora , Circulação Colateral/efeitos dos fármacos , Meios de Contraste/administração & dosagem , Meios de Contraste/metabolismo , Progressão da Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Artéria Gastroepiploica/cirurgia , Artéria Hepática/diagnóstico por imagem , Artéria Hepática/cirurgia , Humanos , Óleo Iodado/administração & dosagem , Óleo Iodado/metabolismo , Coreia (Geográfico) , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Omento/diagnóstico por imagem , Omento/patologia , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , alfa-Fetoproteínas/administração & dosagemRESUMO
Angiogenesis is a novel approach for the therapy of various ischemia-related pathophysiologic conditions. Proangiogenic growth factors have shown promising results in preclinical studies using protein- and gene-based therapies. However, their success in clinical trials is hindered by the lack of an optimal delivery strategy that would provide sustained and localized levels of the growth factors in the diseased tissue. Targeted delivery of proangiogenic agents is expected to demonstrate therapeutic efficacy of growth factors at relatively lower doses, without the risk of systemic toxicity in terms of unwanted angiogenesis. To achieve the above objectives, various drug delivery systems are under investigation. This review describes the basic mechanism of action of growth factors, their current status in preclinical and clinical studies, and the issue of drug delivery.
Assuntos
Arteriosclerose/tratamento farmacológico , Circulação Colateral/efeitos dos fármacos , Substâncias de Crescimento/uso terapêutico , Angiopoietina-1 , Animais , Embrião de Galinha , Ensaios Clínicos como Assunto , Doença da Artéria Coronariana/tratamento farmacológico , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fatores de Crescimento Endotelial/farmacologia , Fatores de Crescimento Endotelial/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Previsões , Terapia Genética , Substâncias de Crescimento/administração & dosagem , Substâncias de Crescimento/efeitos adversos , Membro Posterior/irrigação sanguínea , Humanos , Hipotensão/induzido quimicamente , Isquemia/tratamento farmacológico , Linfocinas/farmacologia , Linfocinas/uso terapêutico , Glicoproteínas de Membrana/farmacologia , Glicoproteínas de Membrana/uso terapêutico , Camundongos , Neovascularização Patológica/induzido quimicamente , Neovascularização Fisiológica/fisiologia , Coelhos , Ratos , Receptores de Fatores de Crescimento/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Endothelium-derived nitric oxide (EDNO) plays an important role in the regulation of angiogenesis, whereas hypercholesterolemia (HC) impairs EDNO release. We examined the hypothesis that HC may inhibit ischemia-induced angiogenesis by inhibition of EDNO in a rat model of unilateral hindlimb ischemia and that oral L-arginine supplementation, a substrate for NO synthase, may prevent HC-related impairment of angiogenesis. METHODS AND RESULTS: Male Sprague-Dawley rats were fed (A) standard diet (control), (B) 2% high-cholesterol diet (HC group), or (C) high-cholesterol diet with oral L-arginine (2.25% in drinking water) (HC+L-arg group). At 2 weeks of the dietary intervention, unilateral limb ischemia was surgically induced in all animals. Dietary HC groups (B and C) revealed elevated total and LDL cholesterol levels compared with control animals. Laser Doppler blood flow analyses showed significant decreases in the ischemic/normal limb blood flow ratio in the HC group compared with controls (P:<0.05) when followed up until 4 weeks after surgery. Selective angiography and immunohistochemical analyses in the ischemic limb at postoperative day 14 revealed significantly lower angiographic scores (P:<0.01) and capillary densities (P:<0.01) in the HC group than controls, which were associated with decreased tissue contents of NO(x) and cGMP. Oral L-arginine supplementation (HC+L-arg) significantly improved all parameters of the laser Doppler blood perfusion ratio, angiographic scores, and capillary densities (P:<0.01 versus HC group), which were accompanied by significant elevations in serum L-arginine levels and tissue NO(x) and cGMP contents. CONCLUSIONS: Collateral vessel formation and angiogenesis in response to hindlimb ischemia were significantly attenuated in rats with dietary HC. The mechanism may be related to the reduced NO bioactivity in the ischemic tissues. Augmentation of the tissue NO activity by oral L-arginine supplementation restored the impaired angiogenesis in HC.
Assuntos
Arginina/análogos & derivados , Membro Posterior/irrigação sanguínea , Hipercolesterolemia/complicações , Isquemia/complicações , Isquemia/metabolismo , Neovascularização Fisiológica , Óxido Nítrico/metabolismo , Administração Oral , Animais , Arginina/administração & dosagem , Arginina/sangue , Arginina/metabolismo , Peso Corporal , Colesterol na Dieta/farmacologia , Circulação Colateral/efeitos dos fármacos , GMP Cíclico/metabolismo , Endotélio Vascular/metabolismo , Hipercolesterolemia/fisiopatologia , Imuno-Histoquímica , Fluxometria por Laser-Doppler , Lipídeos/sangue , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Nitratos/metabolismo , Óxido Nítrico/farmacologia , Nitritos/metabolismo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
To evaluate the effect of Salvia Miltiorrhiza on coronary collateral circulation in dogs with experimental acute myocardial infarction, 12 dogs were randomly divided into Salvia Miltiorrhiza group (group D) and control group (group C). Acute myocardial infarction model was established in all dogs, Salvia Miltiorrhiza or saline was administered to the 2 groups respectively for 21 days. Coronary angiography was performed before and after ligation of coronary artery. The capillaries and distribution vessel density in tissue sections of myocardia were assessed. Angiography 2 h and 22 days after ligation of coronary artery revealed significant augmentation of collateral vessels, and capillaries and distribution vessel density in ischemic zone on day 22 showed statistically significant augmentation in group D as compared with that of controls (P < 0.05 and P < 0.01). It is concluded that Salvia Miltiorrhiza might improve the opening and formation of coronary collateral circulation of ischemic myocardia in dogs and thereby protecting myocardia from ischemia.
Assuntos
Circulação Colateral/efeitos dos fármacos , Circulação Coronária , Medicamentos de Ervas Chinesas/farmacologia , Infarto do Miocárdio/fisiopatologia , Salvia miltiorrhiza/química , Animais , Angiografia Coronária , Cães , Feminino , Masculino , Distribuição AleatóriaRESUMO
OBJECTIVE: To evaluate the effect and mechanism of puerarin on coronary collateral circulation in dogs with experimental acute myocardial infarction. METHOD: Twelve dogs were randomly divided into puerarin (Gegen su, G) group and control(C) group, the acute myocardial infarction model was built in all dogs. Puerarin or saline was administered for 21 days. Coronary angiography was performed before and after ligating coronary artery. The capillaries and distribution vessel density in tissue sections of myocardium were assessed. RESULT: Angiography on hour 2 and day 22 after ligating coronary artery revealed significant augmentation of collateral vessels in G group versus controls. Capillaries and distribution vessel density in ischemic and infarctive zone on day 22 revealed statistically significant augmentation in G group versus controls (P < 0.05 and P < 0.01). CONCLUSION: Puerarin might improve the opening and forming of coronary collateral circulation to ischemic myocardium in dogs and protect ischemic myocardium.
Assuntos
Circulação Colateral/efeitos dos fármacos , Isoflavonas/farmacologia , Infarto do Miocárdio/fisiopatologia , Vasodilatadores/farmacologia , Animais , Circulação Coronária/efeitos dos fármacos , Cães , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Isoflavonas/isolamento & purificação , Masculino , Plantas Medicinais/química , Pueraria/química , Vasodilatadores/isolamento & purificaçãoAssuntos
Indutores da Angiogênese/uso terapêutico , Circulação Colateral/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Projetos de PesquisaRESUMO
BACKGROUND: N-methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase of glycogen-debranching enzyme in the liver, in addition to possessing an antihyperglycemic action by blocking alpha-1,4-glucosidase in the intestine. Because the reduction of the glycogenolytic rate may be one of the mechanisms of myocardial protection in ischemic preconditioning, the compounds inhibiting myocardial alpha-1,6-glucosidase may be protective against ischemic damage. Thus, we investigated whether MOR-14 could inhibit alpha-1,6-glucosidase and reduce the infarct size in rabbit hearts without collateral circulation. METHODS AND RESULTS: MOR-14 dose-dependently decreased the alpha-1,6-glucosidase activity in rabbit heart extract. A tracer study demonstrated the myocardial uptake of a considerable amount of MOR-14 sufficient to fully inhibit alpha-1,6-glucosidase. To assess the infarct size-reducing effect of MOR-14, 54 rabbits were subjected to 30-minute coronary occlusion followed by 48-hour reperfusion. Preischemic treatment with 25, 50, and 100 mg/kg of MOR-14 dose-dependently reduced the infarct size (to 26+/-4%, 19+/-3%, and 14+/-2% of the area at risk, respectively), compared with the saline control (45+/-5%) without altering the blood pressure or heart rate. Another 40 rabbits given 100 mg of MOR-14 or saline 10 minutes before ischemia were euthanized at 10 or 30 minutes of ischemia for biochemical analysis. MOR-14 decreased the alpha-1,6-glucosidase activity to approximately 20% in vivo, reduced the glycogen breakdown, and attenuated the lactate accumulation at both 10 and 30 minutes of ischemia. CONCLUSIONS: Preischemic treatment with MOR-14 preserved glycogen, attenuated the accumulation of lactate, and reduced the myocardial infarct size by 69%. This cardioprotective effect was independent of changes of blood pressure and heart rate or regional blood flow. It may be associated with alpha-1,6-glucosidase inhibition, because MOR-14 markedly decreased the alpha-1,6-glucosidase activity in the heart.