Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37
Filtrar
1.
Acta Physiol (Oxf) ; 240(1): e14067, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38093597
2.
PLoS One ; 13(8): e0201597, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30118486

RESUMO

BACKGROUND: In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats. METHODS: Coronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA). RESULTS: After 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect. CONCLUSION: Intermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.


Assuntos
Oclusão Coronária/tratamento farmacológico , Dinitrato de Isossorbida/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Nitroglicerina/administração & dosagem , Animais , Aorta Torácica , Aspirina/efeitos adversos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Modelos Animais de Doenças , Humanos , Dinitrato de Isossorbida/farmacologia , Masculino , Nitroglicerina/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Projetos de Pesquisa
3.
Atherosclerosis ; 272: 87-93, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29579672

RESUMO

BACKGROUND AND AIMS: Arteriogenesis, the positive outward remodeling and growth of pre-existent collateral vessels, holds potential as a novel treatment for ischemic vascular disease. An extracranial arteriogenesis model in a pig will allow us to study molecular changes in a complex arteriolar network in a more clinically relevant large-animal model. To increase fluid shear stress in the brain, an experimental carotid arteriovenous fistula (AVF model) in minipigs was established, providing high flow through the extracranial rete mirabile. The aim of the study was to examine whether creation of a carotid AVF can induce extracranial arteriogenesis in the pig. METHODS: Angiography was performed to demonstrate blood flow diversion. Animals were sacrificed after 0, 3 and 14 days post-surgery and both retia mirabilia were removed. Immunohistochemical analysis was performed to analyze cell proliferation and accumulation of mononuclear cells in the vessel wall. RESULTS: After 3 days of high-flow conditions, increases in vascular cell proliferation (approximately 1.5-fold; p = 0.143) and monocyte invasion (approximately 6-fold; p = 0.057) were observed when compared to animals sacrificed immediately after AVF formation. Quantitative PCR (RT-qPCR) analysis from rete mirabile tissue samples 3 days post-surgery revealed that monocyte chemoattractant protein (MCP)-1 and tissue inhibitor of metalloproteinases (TIMP)-1 were highly upregulated. Expression of the pro-arteriogenic marker, CD44, reached maximum expression level 14 days post-surgery. CONCLUSIONS: In response to high levels of shear stress produced in the pig AVF model, the onset of the arteriogenic process can be induced. This was demonstrated by enhanced cell proliferation, monocyte invasion and vascular remodeling.


Assuntos
Artérias/fisiologia , Fístula Arteriovenosa/fisiopatologia , Modelos Animais de Doenças , Neovascularização Patológica , Angiografia , Animais , Fístula Arteriovenosa/complicações , Proliferação de Células , Quimiocina CCL2/metabolismo , Circulação Colateral , Feminino , Regulação da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica , Inflamação , Leucócitos Mononucleares/citologia , Macrófagos/citologia , Masculino , Monócitos/citologia , Neovascularização Fisiológica , Suínos , Porco Miniatura , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Regulação para Cima
4.
Open Heart ; 5(2): e000889, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613411

RESUMO

Objective: We investigated the impact of cardioprotective drugs on ST-elevation, arrhythmias and infarct size in a rat model of repetitive coronary artery occlusion. Methods: Seventy Sprague-Dawley rats were randomised to two control and five treatment groups. Placebo was either implantation of a pneumatic occluder onto the left anterior descending coronary artery (LAD) without starting repetitive occlusion (SHAM) or subsequent RO of the LAD over 10 days without medication (ROP). Treatment groups underwent RO and additionally received nitroglycerin (NTG), metoprolol, verapamil (VER), ranolazine (RAN) or candesartan (CAN). Two weeks after the intervention, rats underwent a single, sustained LAD occlusion followed by reperfusion. To evaluate differences in cardiac resistance against myocardial ischaemia and reperfusion injury, cardiac surrogate parameters including maximal ST-elevation, arrhythmias and infarct size were assessed. Results: Compared with sham, RO alone and RO plus nitroglycerin were associated with significantly lower maximal ST-elevation and percentage of infarcted myocardium (SHAM 0.12 mV, ROP 0.06 mV (p=0.004), NTG 0.05 mV (p=0.005); SHAM 16.2%, ROP 6.6% (p=0.008), NTG 5.9% (p=0.006). Compared with RO alone, RO plus RAN was accompanied by increased ST-elevation (0.13 mV, p=0.018) and RO plusVER or CAN by more infarcted myocardium (14.2%, p=0.004% and 15.5%, p=0.003, respectively). Rats treated with VER, RAN or CAN tended to severe arrhythmias more frequently than those of the control groups. Conclusions: RO led to an increased myocardial resistance against ischaemia and reperfusion injury. Concomitant administration of nitroglycerin did not affect the efficacy of RO. Cardiovascular channel or receptor blockers reduced the efficacy of RO.

5.
Coron Artery Dis ; 29(2): 127-137, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29084040

RESUMO

BACKGROUND: For patients with severe ischemic heart disease, complete revascularization by a percutaneous coronary intervention or coronary artery bypass grafting is often not achieved and may still cause residual angina. In case of progressive coronary artery occlusions, therapeutic arteriogenesis constitutes a promising strategy for increasing blood supply to the ischemic myocardium. Whether the formation of collaterals in the hypofused myocardium is angiogenetic in nature or based on preformed coronary artery anastomoses remains debatable. The objectives of this research were (i) the development of an appropriate research methodology to study a humanoid animal semiacute infarction model with low mortality and (ii) to answer the question of whether collateral revascularization follows a pre-existing 'blueprint'. MATERIALS AND METHODS: A porcine model was chosen in which a step-wise vessel occlusion was performed by implantation of a copper stent into the distal left anterior descending artery. Vessel occlusion and collateral development were confirmed in vivo every 14 days up to day 56 by repeated coronary angiography and myocardial perfusion measurement using cardiac MRI. After the completion of the in-vivo imaging studies, animals were euthanized and collateral growth was evaluated using microcomputer tomography. RESULTS: Our porcine model of semiacute noninvasive coronary artery occlusion confirmed the existence of preformed coronary anastomoses and the proliferation of functional vessels in hypoperfused myocardium. Repetitive intra-animal MRIs showed the functional impact of these growing collaterals. CONCLUSION: The confirmation of preformed coronary anastomoses during the process of collateralization (natural bypasses) offers a preclinical avenue to carry out arteriogenetic pharmaceutical research in patients with ischemic heart disease.


Assuntos
Circulação Colateral , Circulação Coronária , Oclusão Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Animais , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/cirurgia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/cirurgia , Imagem de Perfusão do Miocárdio/métodos , Neovascularização Fisiológica , Intervenção Coronária Percutânea/instrumentação , Stents , Sus scrofa , Fatores de Tempo , Microtomografia por Raio-X
6.
Heart Vessels ; 32(11): 1400-1409, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28776069

RESUMO

Bridging collaterals (BC) develop in several chronic total artery occlusion diseases, and can prevent extensive myocardial necrosis. Yet, their origin, growth process, and histo-morphology are still unclear. Since vasa vasorum (VV) may take part in collateralization, we hypothesized that VV are the basis for BCs. To comprehensively investigate this arteriogenesis process, we used high-resolution imaging, including corrosion casts, post-mortem angiography with stereoscopy, micro-CT, and immunohistology, in combination with a novel semi-acute vessel occlusion model. This porcine model was produced by implanting a copper stent minimally invasively into the left anterior descending coronary artery. To define the kinetics of arteriogenesis, pigs (n = 11) were assigned to one of the five euthanasia timepoints: day 0.5 (D0.5, n = 2), D3 (n = 2), D5 (n = 1), D7 (n = 3), or D12 (n = 3) after stent implantation. We found that (1) BCs originate from longitudinally running type 1 VV, mainly VV interna, partially also from VV externa; (2) the growth of VV to BC is rapid, occurring within 7 days; and (3) porcine BCs are likely functionally relevant, considering an observed 102% increase in the number of smooth muscle cell layers in their vascular wall. High-resolution imaging in a minimally invasive non-acute vessel occlusion model is an innovative technique that allowed us to provide direct evidence that porcine BCs develop from the VV. These data may be crucial for further studies on the treatment of angina pectoris and thromboangiitis obliterans through therapeutic stimulation of BC development.


Assuntos
Oclusão Coronária/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Neovascularização Patológica/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Vasa Vasorum/diagnóstico por imagem , Microtomografia por Raio-X/métodos , Doença Aguda , Animais , Angiografia Coronária , Modelos Animais de Doenças , Suínos
7.
Drug Des Devel Ther ; 9: 4793-805, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26316714

RESUMO

Nitroglycerin is the oldest and most commonly prescribed short-acting anti-anginal agent; however, despite its long history of therapeutic usage, patient and health care provider education regarding the clinical benefits of the short-acting formulations in patients with angina remains under-appreciated. Nitrates predominantly induce vasodilation in large capacitance blood vessels, increase epicardial coronary arterial diameter and coronary collateral blood flow, and impair platelet aggregation. The potential for the prophylactic effect of short-acting nitrates remains an under-appreciated part of optimal medical therapy to reduce angina and decrease myocardial ischemia, thereby enhancing the quality of life. Short-acting nitroglycerin, administered either as a sublingual tablet or spray, can complement anti-anginal therapy as part of optimal medical therapy in patients with refractory and recurrent angina either with or without myocardial revascularization, and is most commonly used to provide rapid therapeutic relief of acute recurrent angina attacks. When administered prophylactically, both formulations increase angina-free walking time on treadmill testing, abolish or delay ST segment depression, and increase exercise tolerance. The sublingual spray formulation provides several clinical advantages compared to tablet formulations, including a lower incidence of headache and superiority to the sublingual tablet in terms of therapeutic action and time to onset, while the magnitude and duration of vasodilatory action appears to be comparable. Furthermore, the sublingual spray formulation may be advantageous to tablet preparations in patients with dry mouth. This review discusses the efficacy and utility of short-acting nitroglycerin (sublingual spray and tablet) therapy for both preventing and aborting an acute angina attack, thereby leading to an improved quality of life.


Assuntos
Circulação Coronária/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Nitroglicerina/uso terapêutico , Vasodilatação/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Administração Sublingual , Aerossóis , Animais , Química Farmacêutica , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/fisiopatologia , Nitroglicerina/administração & dosagem , Nitroglicerina/efeitos adversos , Guias de Prática Clínica como Assunto , Comprimidos , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos
8.
Methods Mol Biol ; 1135: 121-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24510860

RESUMO

Unilateral common carotid artery occlusion (CCAO) is a standardized method to initiate collateral artery growth (arteriogenesis) in mouse brain. After CCAO is induced, blood circulation in the circle of Willis is changed and increases shear stress, which triggers increased arterial diameter and improvements in cerebrovascular reserve capacity. Functional improvement can be quantified after experimentally induced stroke by external middle cerebral artery occlusion (MCAO). Stroke volume is evaluated by standard tetrazolium chloride (TTC) staining. Here, we describe in vivo methods of CCAO and MCAO in detail and also the evaluation of stroke volume by TTC staining.


Assuntos
Isquemia Encefálica/fisiopatologia , Artérias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/fisiopatologia , Neovascularização Fisiológica , Animais , Camundongos
9.
Cerebrovasc Dis ; 33(5): 419-29, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22456527

RESUMO

BACKGROUND AND PURPOSE: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. METHODS: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 µg/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. RESULTS: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 µg/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 µg/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 ± 2 to 12 ± 6%) and rats (3 ± 4 to 19 ± 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 ± 7-271 ± 57 µm; contralateral: 208 ± 11-252 ± 28 µm) and in mice the diameter of anterior cerebral arteries (185 ± 15-222 ± 12 µm) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 ± 2%) was diminished following CCAO (7 ± 4%) and G-CSF treatment (4 ± 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. CONCLUSION: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Círculo Arterial do Cérebro/crescimento & desenvolvimento , Circulação Colateral/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Animais , Arteriopatias Oclusivas/patologia , Estenose das Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Transtornos Cerebrovasculares/patologia , Círculo Arterial do Cérebro/efeitos dos fármacos , Interpretação Estatística de Dados , Hemodinâmica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/uso terapêutico , Recuperação de Função Fisiológica
10.
Int J Cardiol ; 161(2): 88-92, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21601932

RESUMO

BACKGROUND: Since their introduction, genetically modified mice have become more and more important to examine molecular mechanisms involved in vascular growth. Today the gold standard for measuring vessel conductivity is to directly assess in vivo perfusion. However, this usually becomes more complicated the smaller the animal, especially due to the need for extensive instrumentation and requirement of maximal vasodilation. METHODS: We developed an automated system that allows pressure-controlled in vivo perfusion of small animals with differently labeled fluorescent microspheres. RESULTS: Besides precise operation of the system (mean pressures divergence 0.08%), automation of small animal microsphere perfusion is reliable and highly accurate in mice with and without femoral artery occlusion. In sham-operated control mice, which did not undergo femoral occlusion, highly reproducible measurements of hind limb perfusion (right vs. left=1.03 ± 0.037) could be assessed. In mice after unilateral femoral artery occlusion, mean perfusion ratios of the automated method (ratio occluded vs. non-occluded hind limb=0.598 ± 0.046) were comparable to the manual approach (0.561 ± 0.062). However, inter-individual variances were significantly smaller with the automated system. CONCLUSION: We describe here a novel and innovative technical approach for pressure-controlled fluid handling specifically designed for microsphere perfusion measurements in small animals.


Assuntos
Artérias/crescimento & desenvolvimento , Microesferas , Neovascularização Fisiológica , Animais , Fluorescência , Camundongos , Camundongos Endogâmicos C57BL , Perfusão/métodos
11.
J Cereb Blood Flow Metab ; 32(1): 105-14, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21829214

RESUMO

This study investigated the effects of acetylsalicylic acid (ASA) and clopidogrel, standardly used in the secondary prevention of vascular occlusions, on cerebral arteriogenesis in vivo and in vitro. Cerebral hypoperfusion was induced by three-vessel occlusion (3-VO) in rats, which subsequently received vehicle, ASA (6.34 mg/kg), or clopidogrel (10 mg/kg). Granulocyte colony-stimulating factor (G-CSF), which enhanced monocyte migration in an additional cell culture model, augmented cerebrovascular arteriogenesis in subgroups (40 µg/kg). Cerebrovascular reactivity and vessel diameters were assessed at 7 and 21 days. Cerebrovascular reserve capacity was completely abolished after 3-VO and remained severely compromised after 7 (-14±14%) and 21 (-5±11%) days in the ASA groups in comparison with controls (4±5% and 10±10%) and clopidogrel (4±13% and 10±8%). It was still significantly decreased when ASA was combined with G-CSF (1±4%) compared with G-CSF alone (20±8%). Posterior cerebral artery diameters confirmed these data. Monocyte migration into the vessel wall, improved by G-CSF, was significantly reduced by ASA. Acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis.


Assuntos
Aspirina/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Ticlopidina/análogos & derivados , Animais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Angiografia Cerebral , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Clopidogrel , Modelos Animais de Doenças , Humanos , Masculino , Monócitos/citologia , Monócitos/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Ratos , Ratos Sprague-Dawley , Ticlopidina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
12.
Front Mol Neurosci ; 4: 14, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21904523

RESUMO

Vascular growth forms the first functional organ system during development, and continues into adult life, wherein it is often associated with disease states. Genetically determined vasculogenesis produces a primary vascular plexus during ontogenesis. Angiogenesis, occurring, e.g., in response to metabolic stress within hypoxic tissues, enhances tissue capillarization. Arteriogenesis denotes the adaptive outgrowth of pre-existent collateral arteries to bypass arterial stenoses in response to hemodynamic changes. It has been debated whether vasculogenesis occurs in the adult, and whether or not circulating progenitor cells structurally contribute to vessel regeneration. Secondly, the major determinants of vascular growth - genetic predisposition, metabolic factors (hypoxia), and hemodynamics - cannot be assigned in a mutually exclusive fashion to vasculogenesis, angiogenesis, and arteriogenesis, respectively; rather, mechanisms overlap. Lastly, all three mechanisms of vessel growth seem to contribute to physiological embryogenesis as well as adult adaptive vascularization as occurs in tumors or to circumvent arterial stenosis. Thus, much conceptual and terminological confusion has been created, while therapies targeting neovascularization have yielded promising results in the lab, but failed randomized studies when taken to the bedside. Therefore, this review article aims at providing an exact definition of the mechanisms of vascular growth and their contribution to embryonic development as well as adult adaptive revascularization. We have been looking for potential reasons for why clinical trials have failed, how vitally the application of appropriate methods of measuring and assessment influences study outcomes, and how relevant, e.g., results gained in models of vascular occlusive disease may be for antineoplastic strategies, advocating a reverse bedside-to-bench approach, which may hopefully yield successful approaches to therapeutically targeting vascular growth.

13.
J Cereb Blood Flow Metab ; 31(4): 1085-92, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20978518

RESUMO

The adipocytokine leptin has distinct functions regulating vascular tone, inflammation, and collateral artery growth. Arteriogenesis is an inflammatory process and provides a mechanism to overcome the effects of vascular obstruction. We, therefore, tested the effects of leptin in hypoperfused rat brain (three-vessel occlusion). Systemic leptin administration for 1 week after occlusion surgery increased cerebral hemodynamic reserve similar to granulocyte-macrophage colony-stimulating factor (GM-CSF), as indicated by improved CO(2) reactivity (vehicle 0.53%±0.26% versus leptin 1.05%±0.6% per mm Hg arterial pCO(2), P<0.05). Infusion of microspheres under maximal vasodilation failed to show a positive effect of leptin on cerebral perfusion (vehicle 64.9%±4.5% versus leptin 66.3%±7.0%, occluded/nonoccluded hemisphere). Acute treatment with GM-CSF led to a significant increased CO(2) reactivity and cerebral perfusion (79.2%±8.1% versus 64.9%±4.5%, P<0.05). Vasoconstrictive response of isolated rat carotid artery rings, after phenylephrine was attenuated at 24 hours following preincubation with leptin, was unaffected by removal of endothelium but abrogated by coculture with N-(omega)-nitro-L-arginine methylester, pointing toward an inducible nitric oxide synthase-mediated mechanism. In chronic cerebral hypoperfusion, acute leptin treatment restored the hemodynamic reserve of the cerebral vasculature through its effects on vascular tone, while leaving vascular outward remodeling unaffected. Our results, for the first time, reveal a protective role of leptin on vascular function in hemodynamically compromised brain tissue.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/fisiopatologia , Leptina/farmacologia , Tono Muscular/efeitos dos fármacos , Animais , Artéria Cerebral Anterior/fisiologia , Peso Corporal/fisiologia , Dióxido de Carbono/metabolismo , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Proliferação de Células/efeitos dos fármacos , Transtornos Cerebrovasculares/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Consumo de Oxigênio/efeitos dos fármacos , Fenilefrina/farmacologia , Artéria Cerebral Posterior/fisiologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia
14.
Int J Cardiol ; 145(3): 432-7, 2010 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19539385

RESUMO

BACKGROUND: Stimulation of collateral artery growth is a promising therapeutic option for patients with coronary artery disease. External counterpulsation is a non-invasive technique suggested to promote the growth of myocardial collateral arteries via increase of shear stress. The Art.Net.2 Trial tests invasively and functionally for the first time the hypothesis whether a treatment course with external counterpulsation (over 7 weeks) can induce the growth of myocardial collateral arteries. METHODS: This study is designed as a prospective, controlled, proof-of-concept study. Inclusion criteria are (1) age 40 to 80 years, (2) stable coronary disease, (3) a residual significant stenosis of at least one epicardial artery and (4) a positive ischemic stress-test for the region of interest. As primary endpoint serves the pressure-derived collateral flow index (CFIp), the invasive gold-standard to assess myocardial collateral pathways. CFIp is determined by simultaneous measurement of mean aortic pressure (Pa, mm Hg), distal coronary occlusive (wedge) pressure (Pw, mm Hg) and central venous pressure (Pv, mm Hg). The index is calculated as CFIp=(Pw-Pv)/(Pa-Pv). The pressure derived fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) are assessed as secondary invasive endpoints to investigate the effect of ECP on the myocardial vasculature. The non-invasive secondary endpoints include symptoms (CCS and NYHA classification), treadmill-testing and analysis of shear-stress related soluble proteins. CONCLUSIONS: The Art.Net.-2 Trial will report within the next months whether direct evidence can be brought that ECP promotes coronary collateral growth in patients with stable angina pectoris.


Assuntos
Circulação Colateral/fisiologia , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Circulação Coronária/fisiologia , Contrapulsação , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Venosa Central/fisiologia , Vasos Coronários/fisiologia , Teste de Esforço , Humanos , Pessoa de Meia-Idade , Pletismografia , Estudos Prospectivos , Resistência Vascular/fisiologia
15.
J Cereb Blood Flow Metab ; 28(11): 1811-23, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18594555

RESUMO

Cerebral arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischaemia; however, transcriptional profiles important for therapeutic target identification have not yet been investigated. This study aims at a comprehensive characterization of transcriptional and morphologic activation during early-phase collateral vessel growth in a rat model of adaptive cerebral arteriogenesis. Arteriogenesis was induced using a three-vessel occlusion (3-VO) rat model of nonischaemic cerebral hypoperfusion. Collateral tissue from growing posterior cerebral artery (PCA) and posterior communicating artery (Pcom) was selectively isolated avoiding contamination with adjacent tissue. We detected differential gene expression 24 h after 3-VO with 164 genes significantly deregulated. Expression patterns contained gene transcripts predominantly involved in proliferation, inflammation, and migration. By using scanning electron microscopy, morphologic activation of the PCA endothelium was detected. Furthermore, the PCA showed induced proliferation (PCNA staining) and CD68+ macrophage staining 24 h after 3-VO, resulting in a significant increase in diameter within 7 days after 3-VO, confirming the arteriogenic phenotype. Analysis of molecular annotations and networks associated with differentially expressed genes revealed that early-phase cerebral arteriogenesis is characterised by the expression of protease inhibitors. These results were confirmed by quantitative real-time reverse transcription-PCR, and in situ hybridisation localised the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and kininogen to collateral arteries, showing that TIMP-1 and kininogen might be molecular markers for early-phase cerebral arteriogenesis.


Assuntos
Arteriopatias Oclusivas/fisiopatologia , Arteriopatias Oclusivas/terapia , Isquemia Encefálica/fisiopatologia , Artérias Cerebrais/fisiologia , Circulação Cerebrovascular/fisiologia , Circulação Colateral/fisiologia , Proteínas do Tecido Nervoso/genética , Inibidores de Proteases/metabolismo , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Artérias Cerebrais/crescimento & desenvolvimento , Modelos Animais de Doenças , Hibridização In Situ , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Amiloide A Sérica/genética , Transcrição Gênica
19.
Orv Hetil ; 148(14): 633-42, 2007 Apr 08.
Artigo em Húngaro | MEDLINE | ID: mdl-17403636

RESUMO

The term arteriogenesis became clarified only some years ago. This endogenous process is a natural compensation mechanism against stenosis or arterial occlusion-induced tissue hypoperfusion via improvement of blood distribution in the pre-existent collateral arteries. The main chronic artery disorders like coronary heart disease, peripheral artery disease and cerebrovascular disease were extensively studied for angiogenesis and arteriogenesis during the last decade. The in vivo animal experiments and the ex vivo analysis of the cellular and molecular mechanisms behind collateral artery development revealed the crucial role of circulating monocytes, endothelial and smooth muscle cells in the remodelling of collateral blood vessels. The adaptive arteriogenesis in the heart, brain and periphery can be stimulated by different chemokines and growth factors. The therapeutic application of these substances resulted in promising data in pre-clinical animal models, i.e. improved collateral conductance, extended neo-vascularization in the collateral dependent tissue regions, decreased infarct area after hemodynamic stroke and better functional parameters in myocardial ischemia. The questions that have to be addressed during the design of human investigations are the optimal delivery approach, the appropriate dosage, timing and the durability of the follow up. The present review tries to give an overview about the main points of the mechanism and the most important experimental data concerning spontaneous and stimulated collateral artery growth, this new and promising therapeutic approach for chronic artery diseases.


Assuntos
Indutores da Angiogênese/farmacologia , Arteriopatias Oclusivas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Quimiocinas/farmacologia , Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Indutores da Angiogênese/uso terapêutico , Animais , Arteriopatias Oclusivas/fisiopatologia , Transtornos Cerebrovasculares/tratamento farmacológico , Quimiocinas/uso terapêutico , Doença Crônica , Doença da Artéria Coronariana/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Monócitos/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Doenças Vasculares Periféricas/tratamento farmacológico
20.
Int J Cardiol ; 115(2): e83-5, 2007 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-17084920

RESUMO

We report about a 41-year old male patient who presented to the emergency room with acute chest pain, exertion dyspnoea, muscle stiffness, myalgia and adynamia. There was no history of coronary artery disease but known arterial hypertension and insulin dependent diabetes mellitus. Four weeks before submission the patient had been thyroidectomized after he had been diagnosed with papillary thyroid carcinoma and was now awaiting further radioiodine therapy. The thyroid-stimulating hormone level was markedly elevated to 67 mU/l (normal range 0.27-4.20 mU/l) and fT4 significantly reduced to 0.19 ng/ml (normal range 0.9-1.9 ng/ml). CK was elevated to 328 U/l, cardiac Troponin I (Stratus CS) above the threshold with 0.13 microg/l and Elecsys third generation troponin T above the threshold with 0.04 microg/l. The electrocardiogram showed a normal sinus rhythm and did not reveal any signs of ST-elevation or -depression. During follow-up a cardiac MRI was performed, showing normal dimensions and function but a very small area of diffuse myocardial damage, atypical of ischemic injury. In coronary angiography normal coronary arteries were found. We conclude that cardiac troponins I and T may be elevated in severe hypothyroidism without coronary artery disease due to diffuse myocardial injury which can be imaged by MRI.


Assuntos
Dor no Peito/sangue , Dor no Peito/complicações , Hipotireoidismo/complicações , Hipotireoidismo/etiologia , Tireoidectomia/efeitos adversos , Troponina I/sangue , Troponina T/sangue , Adulto , Doença da Artéria Coronariana , Humanos , Doença Iatrogênica , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...