RESUMEN
Stenosis of the internal carotid arteries is one of the leading causes of ischemic stroke. With increasing age of the general population, both physicians and patients have to increasingly face that problem, which is often found accidentally for example in the context of a routine checkup examination. In patients over seventy years, the incidence of carotid artery stenosis is about 15%. Principally, there are three options for the treatment of carotid artery stenosis: 1) best medical treatment, 2) operative revision by endarterectomy and 3) interventional therapy via stent implantation. Based on technical development and new scientific data, there has been tremendous progress of all three treatment strategies in the last few years. Therefore, the results of prior trials must not necessarily be considered when choosing a treatment option for the patient. The choice of therapy for the individual patient must take into account a number of criteria, such as grade of stenosis, symptoms, patient age, concomitant disease, anatomical conditions and patients' preference. Recently, a number of clinical trials have been performed to compare operative versus interventional treatment. The results of these studies led to some answers, but there are questions remaining which need to be clarified. The present article gives a brief overview and comment on the current status of treatment strategies of internal carotid artery stenosis based on the recent literature.
Asunto(s)
Arteria Carótida Interna , Estenosis Carotídea/terapia , Stents , Anciano , Estenosis Carotídea/diagnóstico , Estenosis Carotídea/epidemiología , Revascularización Cerebral , Ensayos Clínicos como Asunto , Estudios Transversales , Alemania , Humanos , Guías de Práctica Clínica como Asunto , Factores de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
BACKGROUND: Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD. METHODS: In a single centre, single-blinded, prospective study, 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months. Primary endpoint was the improvement of the absolute treadmill WD. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and disease-related quality of life (DRQL) were examined as well. RESULTS: After 12 months, maximum WD increased by 26% in the telmisartan group (P < 0.001). However, in the placebo group it was comparable to baseline. FMD rose by 40% in the telmisartan group while it deteriorated in the placebo group (P < 0.001). IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months. In non-diabetic patients (72.2%), the ABI did not change in the placebo group, whereas it increased by 11% in the telmisartan group (P < 0.001). While the DRQL remained stable in the telmisartan group, placebo treatment was associated with a marked deterioration (P < 0.01). CONCLUSION: Telmisartan improves WD and endothelial function, the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bencimidazoles/uso terapéutico , Benzoatos/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Índice Tobillo Braquial , Bencimidazoles/farmacología , Benzoatos/farmacología , Endotelio Vascular/patología , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/fisiopatología , Estudios Prospectivos , Calidad de Vida , Método Simple Ciego , Telmisartán , Resultado del Tratamiento , Vasodilatación/efectos de los fármacos , CaminataRESUMEN
With increasing age of the population and improvement of diagnostic tools, the incidence of abdominal aortic aneurysms (AAA) has been rising steadily. Despite an improvement in operative and interventional treatment options, AAA is the cause of death in 1-3% of men over 65 years of age in industrial countries, mostly due to rupture [1]. Therefore, routine screening for AAA by ultrasonography has been postulated in the past: a 60 year old man with an abdominal aortic diameter of less than 3 cm has a life-time risk of developing AAA close to zero. However, routine screening has not been found to be cost effective. Despite of the results of two well-designed studies, the limits of AAA qualifying the patient for surgery or intervention in contrast to conservative treatment is still a matter of debate. The present review article summarizes the current knowledge of the pathology, incidence, risks, natural course as well as symptoms and current treatment strategies of AAA on the basis of the recent literature.
Asunto(s)
Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Aneurisma de la Aorta Abdominal/diagnóstico , Aneurisma de la Aorta Abdominal/epidemiología , Aneurisma de la Aorta Abdominal/fisiopatología , Quimioterapia Combinada , Alemania/epidemiología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Incidencia , Tamizaje Masivo , Prevalencia , Inhibidores de Proteasas/uso terapéutico , Factores de Riesgo , Análisis de Supervivencia , Tetraciclinas/uso terapéutico , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/métodosRESUMEN
Enzymes involved in the metabolism nitric oxide (NO) and reactive oxygen species (ROS) may play a role for the decreased availability of NO in atherosclerosis. We, therefore, hypothesized that the pattern of gene expression of these enzymes is altered in atherosclerosis. Myocardial tissue from patients with coronary heart disease (CHD) or without CHD (control group) was investigated. The level of enzymes related to NO/ROS metabolism was determined both at mRNA level and protein level by rt-PCR, real-time PCR, and western blot. The expression of NOS1-3 (synthesis of NO), arginase1 (reduction of L-arginine), p22phox (active subunit of NADPH oxidase), GTPCH (rate limiting enzyme for tetrahydrobiopterin), SOD1-3 (scavengers of superoxide anions), PRTMT1-3, and DDAH2 (involved in the metabolism of ADMA) was determined. All enzymes were found to be expressed in human myocardium. NOS isoforms were decreased in CHD in protein level, but only the downregulation of NOS3 expression reached statistical significance. The expression of PRMT1 and PRMT3 was increased. In addition, the expression of DDAH2 was reduced, both theoretically leading to an increase of ADMA concentration. SOD3 was downregulated in tissue from patients with CHD. Taken together, in myocardial tissue from patients with atherosclerosis, the expression of genes increasing ADMA levels is enhanced in contrast to a reduced expression of genes promoting NO synthesis. These results may contribute to the explanation of increased oxidative stress in atherosclerosis on the level of gene expression.
Asunto(s)
Enfermedad Coronaria/enzimología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Anciano , Amidohidrolasas/metabolismo , Arginasa/metabolismo , Femenino , GTP Ciclohidrolasa/metabolismo , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismoRESUMEN
OBJECTIVE: To disclose possible influences of alcoholic beverages on restenosis rate in men with coronary artery disease treated with percutaneous transluminal coronary angioplasty (PTCA) and stent implantation. DESIGN: Retrospective cohort study. PATIENTS: 225 consecutive male patients underwent PTCA and stent implantation. All patients had a control angiography and were contacted for a questionnaire regarding their drinking habits. MAIN OUTCOME MEASURES: Mean late loss of luminal diameter, rate of coronary restenosis of 50% or more within the stented segment, and rate of repeat angioplasty. RESULTS: 53 patients (with 80 stents) consumed < 50 g of alcohol a week and 172 (with 266 stents) consumed more (50-700 g a week). Baseline characteristics were similar in both groups except for a higher prevalence of reduced cardiac function and multivessel disease and a lower high density lipoprotein cholesterol concentration among patients who consumed little or no alcohol. Patients who consumed > or = 50 g alcohol a week had a lower mean late loss of the luminal diameter (1.1 (0.79) mm v 1.45 (0.82) mm, p = 0.002), a lower rate of coronary restenosis within the stented segment (33.7% v 48.8%, p = 0.001), and a lower rate of repeat angioplasty (23.3% v 42.5%, p = 0.002). In multivariate analysis, only alcohol consumption and diabetes were independent and significant discriminators for late loss of luminal diameter (p = 0.005 and p = 0.01, respectively), restenosis (odds ratio 0.54 and 2.08, respectively), and repeat angioplasty (odds ratio 0.39 and 2.18, respectively). CONCLUSION: Alcohol intake is associated with reduced restenosis after PTCA and stent implantation.
Asunto(s)
Consumo de Bebidas Alcohólicas , Reestenosis Coronaria/etiología , Anciano , Angioplastia Coronaria con Balón , HDL-Colesterol/sangre , Angiografía Coronaria , Reestenosis Coronaria/sangre , Reestenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/sangre , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/terapia , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Estudios Retrospectivos , StentsRESUMEN
Statins have a variety of cardioprotective properties following chronic treatment. In contrast, little is known about the acute effects. Reperfusion acutely injures the heart by activation of neutrophils as well as endothelial cells. Because statins are known to influence the processes pathogenetically involved, we hypothesized that acute application of statins attenuates the sequelae of cardiac reperfusion. In rats, myocardial infarction (MI) was induced by ligature of the left coronary artery followed by reperfusion. Myocardial blood flow (MBF) was determined by H2 clearance and regional myocardial function (fractional thickening, FT) by pulsed Doppler. MI size was measured by triphenyltetrazolium chloride (TTC) staining, neutrophil extravasation by determination of myeloperoxidase (MPO) activity, and nitric oxide generation via measurement of cGMP. Treatment with fluvastatin, administered intravenously 20 min before the onset of ischemia, significantly attenuated the decline of FT and MBF at the end of the reperfusion period and significantly reduced MI size. Furthermore, fluvastatin induced a significant reduction of MPO activity and an increase of cGMP level compared with the control group. The effect of fluvastatin was completely abolished following pretreatment of NG-nitro-l-arginine methyl ester (l-NAME). These findings suggest that acute application of fluvastatin reduces MI size and attenuates reperfusion injury. We propose that the underlying mechanism is at least partially an inhibition of inflammation and endothelial dysfunction by preventing the activation and extravasation of neutrophils.
Asunto(s)
Ácidos Grasos Monoinsaturados/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Indoles/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Animales , Presión Sanguínea/fisiología , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/fisiología , GMP Cíclico/metabolismo , Ecocardiografía Doppler de Pulso , Inhibidores Enzimáticos/farmacología , Femenino , Fluvastatina , Frecuencia Cardíaca/fisiología , Hidrógeno/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/patología , NG-Nitroarginina Metil Éster/farmacología , Infiltración Neutrófila/efectos de los fármacos , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Peroxidasa/metabolismo , Ratas , Ratas Endogámicas WF , Función Ventricular Izquierda/fisiologíaRESUMEN
Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or (99m)Tc have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (99m)TcO(BAT-NI), a new (99m)Tc complex comprising the nitroimidazole ligand, 2,10-dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(99m)TcO(BAT-I)], (b) the 2-nitroimidazole functionality was replaced by a Br atom [(99m)TcO(BAT-Br)] and (c) the (99m)TcO(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((125)IP-NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (99m)TcO(BAT-NI), (99m)TcO(BAT-I) and (99m)TcO(BAT-Br), respectively. In contrast, (125)IP-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (99m)TcO(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (99m)TcO(BAT-NI) in ischaemic tissue and an I/N of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (99m)TcO(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (99m)TcO(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (99m)TcO(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo.
Asunto(s)
Imidazoles/farmacocinética , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/metabolismo , Compuestos de Organotecnecio/farmacocinética , Animales , Autorradiografía , Estudios de Factibilidad , Femenino , Especificidad de Órganos , Cintigrafía , Radiofármacos/farmacocinética , Ratas , Ratas Endogámicas WF , Distribución TisularRESUMEN
OBJECTIVE: GTP cyclohydrolase I (GTPCH I) catalyzes the de novo biosynthesis of tetrahydrobiopterin (BH(4)), an essential cofactor of NO-synthase. The enzyme underlies negative feedback regulation by the end product BH(4). This feedback inhibition is mediated through complex formation with the GTP cyclohydrolase I feedback regulatory protein (GFRP). To further classify the mechanism involved in the regulation of BH(4) synthesis, we measured expression of GTPCH I and GFRP in different human tissues. Furthermore, we looked for the influence of phenylalanine that is known to reverse BH(4)-mediated feedback inhibition of GTPCH I, and of immunostimulation with interferon gamma on the expression of GTPCH I and GFRP. METHODS AND RESULTS: Using RT-PCR and northern blot technique, coexpression of GFRP and GTPCH I could be demonstrated in a number of different tissues such as endothelial cells and peripheral blood cells. Following stimulation of human umbilical vein endothelial cells (HUVEC) with phenylalanine (1 mM), there was no change of GFRP mRNA. In contrast, the mRNA level of GTPCH I was significantly upregulated with a maximum after 6 hours (p = 0.04). Incubation of HUVEC with interferon-gamma (100 U/ml) showed an increase of GTPCH I mRNA and a significant downregulation of GFRP mRNA after 24 hours (p = 0.03). CONCLUSION: This study shows for the first time the expression of GFRP in different human tissues. The biosynthesis of BH(4) is not only regulated on the substrate level but also through transcription of the interacting proteins. Phenylalanine stimulates the biosynthesis of BH(4) not only by reversing the negative feedback inhibition of GTPCH I but also by increasing the mRNA level of GTPCH I. Immunostimulation alters protein expression of GTPCH I and GFRP in a way that favors BH(4) synthesis.
Asunto(s)
Biopterinas/análogos & derivados , Biopterinas/metabolismo , Endotelio Vascular/metabolismo , GTP Ciclohidrolasa/metabolismo , Proteínas/metabolismo , Antivirales/farmacología , Northern Blotting , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , GTP Ciclohidrolasa/efectos de los fármacos , Regulación de la Expresión Génica , Humanos , Interferón gamma/farmacología , Péptidos y Proteínas de Señalización Intracelular , Fenilalanina/farmacología , Proteínas/efectos de los fármacos , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Venas Umbilicales/citologíaRESUMEN
Before it gets to the development of manifest atherosclerotic lesions, all known risk factors primarily induce functional alterations in the vascular wall, namely in endothelial cells. Being termed endothelial dysfunction or endothelial activation, this condition is characterized by an altered availability of nitric oxide (NO). Under physiological conditions, NO is of unequivocal importance for the regulation of vascular homeostasis. Endothelium-derived NO released abluminally increases soluble guanylat cyclase activity in smooth muscle cells, thereby inducing relaxation and consequently vasodilatation. Intraluminally, NO inhibits the expression of adhesion molecules both on endothielial cells and neutrophils, thus preventing the adherence of cellular elements to the vascular wall. Furthermore, NO has antithrombotic effcts by inhibiting platelet aggregation and directly infuencing the synthesis of different factors involved in the coagulation cascade. Finally, in the long term, NO has been shown to exert antiproliferative properties. NO is generated intracellularly from L-arginine via NO-synthase with the help of several cofactors, including tetrahydobiopterin. Interestingly, it has recently become evident that under certain conditions, when there is a lack of tetrahydrobiopterin, NO-synthase produces reactive oxygen species instead of NO. Reactive oxygen species counteract the effects of NO and also scavenge NO resulting in the formation of peroxynitrite (ONOO). Peroxynitrite has been shown to have deleterious effects with respect to vascular function. The aim of the current review is to elucidate recent progress regarding the pathophysiological understanding of endothelial dysfunction. Furthermore, the significance of this condition for the evaluation and prognosis of patients is discussed. Finally, current therapeutical strategies in the treatment and improvement of endothelial dysfunction are highlighted.
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Endotelio Vascular/fisiopatología , Óxido Nítrico/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Arginina/uso terapéutico , Ensayos Clínicos como Asunto , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Homocisteína/antagonistas & inhibidores , Homocisteína/sangre , Terapia de Reemplazo de Hormonas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Óxido Nítrico/biosíntesis , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/fisiopatologíaAsunto(s)
Biopterinas/análogos & derivados , Biopterinas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Endotelio Vascular/metabolismo , Óxido Nítrico Sintasa/metabolismo , Pterinas , Animales , Arginina/administración & dosificación , Biopterinas/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/fisiopatología , Ensayos Clínicos como Asunto , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Perros , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/administración & dosificación , Histamina/farmacología , Humanos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Técnicas In Vitro , Infusiones Intraarteriales , Ionóforos/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Pteridinas/metabolismo , Pteridinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Especificidad de la Especie , Sustancia P/farmacología , Porcinos , Vasoconstrictores/administración & dosificación , Vasodilatadores/uso terapéutico , omega-N-Metilarginina/administración & dosificaciónRESUMEN
BACKGROUND: Tetrahydrobiopterin (BH4), an essential cofactor for the synthesis of NO, improves endothelial dysfunction after ischemia/reperfusion. Therefore, we hypothesized that reduction of BH4 is involved in the attenuation of endothelium-dependent vasodilation in atherosclerosis, and we investigated the effect of alterations of the BH4 level on the vasodilatory potential of coronary resistance vessels from humans and pigs with atherosclerosis. METHODS AND RESULTS: Coronary arterioles were obtained from patients undergoing CABG (atherosclerosis group) or valve replacement (control group) and from pigs fed either a standard diet (control group) or atherogenic diet (atherosclerosis group). After isolation, vessels were cannulated, pressurized, and placed on the stage of an inverted microscope. Dose-response curves were investigated in response to the endothelium-dependent agonists histamine, serotonin, and acetylcholine (for pigs, substance P) and to the endothelium-independent agonist sodium nitroprusside (SNP) under control conditions and before and after incubation of the vessels with sepiapterin (substrate for BH4 synthesis). In vessels from patients and from animals with atherosclerosis, compared with vessels from the control groups, there was a significant (P:<0.05) reduction of vasodilation to all tested endothelium-dependent agonists but not to SNP. After application of sepiapterin, the responses to the endothelium-dependent agonists but not to SNP were significantly improved in vessels from the atherosclerosis groups. Sepiapterin did not influence vascular reactivity in the control groups. CONCLUSIONS: Atherosclerosis severely compromises endothelial function of coronary resistance arteries. Administration of sepiapterin leads to a significant improvement of endothelium-dependent vasodilatation to different agonists in vessels from humans and pigs with atherosclerosis. Therefore, we conclude that a reduced availability of BH4 is involved in the development of endothelial dysfunction in atherosclerosis.
Asunto(s)
Arteriosclerosis/fisiopatología , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Vasos Coronarios/fisiopatología , Endotelio Vascular/efectos de los fármacos , Pterinas , Resistencia Vascular/efectos de los fármacos , Acetilcolina/farmacología , Animales , Arteriosclerosis/sangre , Apéndice Atrial , Biopterinas/farmacología , Colesterol/sangre , Vasos Coronarios/efectos de los fármacos , Dieta Aterogénica , Relación Dosis-Respuesta a Droga , Endotelio Vascular/fisiopatología , Histamina/farmacología , Humanos , Técnicas In Vitro , Nitroprusiato/farmacología , Pteridinas/administración & dosificación , Pteridinas/metabolismo , Serotonina/farmacología , Sustancia P/farmacología , Porcinos Enanos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: Alpha-adrenergic activation in vivo causes constriction of coronary arterioles, but, paradoxically, in vitro these microvessels do not contract to this stimulus. We hypothesized that cardiac myocytes have a requisite role in alpha1-adrenergic coronary arteriolar constriction through the release of myocyte-derived contractile factor(s). METHODS AND RESULTS: Administration of the alpha1-adrenergic agonist phenylephrine did not constrict isolated coronary arterioles, but constriction was observed to supernatant obtained from phenylephrine-treated cardiac myocytes. Constriction to the supernatant was blocked by administration of an endothelin-A antagonist to the microvessel preparation or an alpha-adrenergic antagonist to the myocytes and was augmented after administration of an adenosine antagonist. Administration of phenylephrine to the myocytes increased endothelin-1 levels in the supernatant, but only to subthreshold concentrations. CONCLUSIONS: Cardiac myocytes have a requisite role in constriction of coronary resistance vessels to alpha1-adrenergic stimuli, which may be mediated by endothelin-1 and other unidentified myocyte-derived vasoconstrictors.
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Agonistas alfa-Adrenérgicos/farmacología , Vasos Coronarios/fisiología , Miocardio/citología , Fenilefrina/farmacología , Adenosina/antagonistas & inhibidores , Antagonistas Adrenérgicos alfa/farmacología , Animales , Arteriolas/fisiología , Perros , Endotelina-1/análisis , Técnicas In Vitro , Vasoconstricción/fisiologíaRESUMEN
Apart from local heterogeneities of myocardial blood flow, the regulation of vascular tone is equally complex. Changes in vascular tone are essential for the adaptation of coronary blood flow to varying metabolic demands. The majority of coronary vascular resistance is found in the microcirculation, that is, in vessels with less than 150-200 microns in diameter; therefore, understanding the regulatory mechanisms that exercise control of the tone of these vessels is paramount to our understanding the control of myocardial perfusion. Recently, it became evident that different regulatory systems such as metabolic, neurohumoral, myogenic, and flow-mediated mechanisms have preferential effects on particular microvascular segments. However, the significance of specific vasoactive mediators is still under investigation. Growth factors, which are synthesized in cells in the surrounding of vessels such as mast cells and cardiac myocytes, have recently been suggested to play a role in the coordination of endothelium-dependent and endothelium-independent vasoactive mechanisms. The aim of this review is, first, to focus on the heterogeneity of the regulation of coronary vascular resistance in general and, second, to discuss recent studies showing a possible role of growth factors, especially fibroblast growth factor (FGF), heparin, and endothelin, as modulators of microvascular tone.
Asunto(s)
Vasos Coronarios/fisiología , Resistencia Vascular , Animales , Vasos Coronarios/efectos de los fármacos , Endotelinas/fisiología , Factores de Crecimiento de Fibroblastos/farmacología , Heparina/farmacología , Humanos , Óxido Nítrico/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
OBJECTIVE: The strong angiogenic and mitogenic agents acidic and basic fibroblast growth factors (aFGF and bFGF, respectively) share signalling pathways with known vasodilatory agonists. Therefore, we hypothesized the FGF's produce vasoactive responses. We also proposed that heparin would exert a similar action to FGF, because this proteoglycan not only binds to the FGF receptor, but also facilitates the release of FGF from the cardiac extracellular matrix and promotes its binding to a high-affinity receptor. To test these hypotheses, we examined the vasodilatory reactions of coronary arterioles to aFGF, bFGF, and heparin, and the effects of antagonists to nitric oxide synthase (L-NMMA), prostaglandins (indomethacin), ATP-sensitive potassium (K[ATP]) channels (glibenclamide), FGF and FGF receptors on the vasoactive responses. METHODS: Arterioles (70-110 microns, internal diameter) were dissected from pig hearts and cannulated with micropipettes. Diameter was determined with videomicroscopy in response to bFGF and aFGF in concentrations of 1-100 ng/ml and to heparin (5-200 U/ml). RESULTS: Basic FGF, but not aFGF, caused dose-dependent vasodilation with a maximum of 61 +/- 4%. Relaxation of bFGF was antagonized by pretreatment with L-NMMA, but was not affected by pretreatment with indomethacin or glibenclamide. Heparin caused dose-dependent vasodilation with a maximum of 100 +/- 3% which was partially blocked by either L-NMMA or glibenclamide, but not by indomethacin. Furthermore, the effect of bFGF could be significantly blocked by pretreatment with an FGF receptor antibody as well as with a monoclonal antibody against FGF. Pretreatment with both antibodies significantly inhibited also the effect of heparin. CONCLUSIONS: These results indicate that bFGF and heparin cause vasodilation of coronary arterioles via an increase in NO production and heparin additionally by other mechanisms such as by activating K[ATP] channels. Furthermore, the effect of heparin is partially mediated via FGF and FGF receptors. We therefore speculate that both substances may be involved in the regulation of coronary microvascular tone acting partially through the same signalling mechanisms.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Heparina/farmacología , Vasodilatación/efectos de los fármacos , Animales , Anticuerpos Monoclonales/farmacología , Relación Dosis-Respuesta a Droga , Factor 1 de Crecimiento de Fibroblastos/farmacología , Factor 2 de Crecimiento de Fibroblastos/inmunología , Gliburida/farmacología , Técnicas In Vitro , Indometacina/farmacología , Microscopía por Video , Óxido Nítrico Sintasa/antagonistas & inhibidores , Canales de Potasio/efectos de los fármacos , Receptores de Factores de Crecimiento de Fibroblastos/inmunología , Porcinos , omega-N-Metilarginina/farmacologíaRESUMEN
We investigated the potential of inhibition of elastase, a granulocyte-derived proteolytic enzyme, in ameliorating the effects of myocardial stunning caused by repetitive ischaemia (RI) and myocardial infarction (MI) for the first time in an in situ, perfused, rat heart model. The effects of the elastase-inhibitors Elafin (EL, 10 mg/kg/h) and ICI 200,880 (ICI,5 mg/kg/h) on myocardial blood flow (MBF, H2 clearance), regional myocardial function (FT, pulsed doppler) and neutrophil extravasation (myocardial myeloperoxidase activity, MPO) were investigated in RI (5x10 min ligature of the anterior descending ramus (LAD), 5x20 min reperfusion) and MI (50 min LAD ligature, 60 min reperfusion). Under control conditions, MBF and FT were significantly reduced and MPO was significantly increased after RI (n=8) and MI (n=8) in the ischaemic area compared with baseline. Pretreatment with EL (n=7) or ICI (n=7) did not improve MBF significantly and did not influence the successive attenuation of peak values of reactive hyperaemia. However, both EL and ICI significantly improved FT and significantly reduced MPO after RI and MI compared with control conditions. Additionally, both the area at risk and MI size were reduced significantly by both inhibitors. These results demonstrate that elastase inhibitors significantly improve the reduction of FT both in myocardial stunning and in myocardial infarction in the rat without significant improvement of MBF. It is concluded that elastase inhibitors exert a cardioprotective effect against reperfusion injury, probably by inhibition of leukocyte extravasation as indicated by the decrease in MPO activity.
Asunto(s)
Elastasa de Leucocito/antagonistas & inhibidores , Infarto del Miocardio/metabolismo , Miocardio/enzimología , Animales , Circulación Coronaria , Femenino , Neutrófilos/metabolismo , Oligopéptidos/farmacología , Peroxidasa/metabolismo , Proteínas Inhibidoras de Proteinasas Secretoras , Proteínas/farmacología , Ratas , Ratas Wistar , Inhibidores de Serina Proteinasa/farmacologíaRESUMEN
OBJECTIVE: To investigate the role of endothelial vasodilating factors in adaptation of myocardial blood flow to increased metabolic demands. DESIGN: Alterations in the effects of endothelium dependent (acetylcholine) and independent (sodium nitroprusside) vasodilators and the beta 1 receptor agonist dobutamine were studied after inhibition of endothelium derived relaxing factor (EDRF) with L-NG-nitro-arginine methyl ester (L-NAME), prostanoid synthesis with indomethacin, and ATP sensitive potassium channels with glibenclamide. EXPERIMENTAL ANIMALS: Female Wistar rats, in situ perfused heart. MAIN OUTCOME MEASURES: Myocardial blood flow (H2 clearance); systolic fractional thickening (pulsed Doppler); mean arterial blood pressure. RESULTS: L-NAME reduced myocardial blood flow by 58 (12)% (mean (SD), P < 0.001) and systolic thickening fraction (FT) by 36 (9)% (P < 0.05). These effects were significantly reversed by administration of L-arginine but not D-arginine. Pretreatment with L-NAME inhibited the increase in myocardial blood flow caused by acetylcholine (control: +42 (9)%; L-NAME: -29 (7)%, P < 0.001) but did not affect the increase in myocardial blood flow caused by sodium nitroprusside (control: +44 (5)%; L-NAME: +34 (10)%, NS). Pretreatment with L-NAME did not change the effect of dobutamine on myocardial blood flow (+61 (3)%) and FT (+32 (8)%) compared with baseline values (P < 0.001). Neither pretreatment with indomethacin nor with glibenclamide reduced the dobutamine induced increase in myocardial blood flow. CONCLUSIONS: Inhibition of EDRF, prostanoid synthesis, and ATP sensitive potassium channels did not reduce the vasodilator reserve during increased metabolic demands induced by beta 1 adrenergic stimulation. Therefore, adaptation of myocardial blood flow to increased metabolic demands is independent of endothelial relaxing factors in the rat heart.
Asunto(s)
Adaptación Fisiológica , Agonistas de Receptores Adrenérgicos beta 1 , Circulación Coronaria/efectos de los fármacos , Dobutamina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Vasodilatadores/farmacología , Acetilcolina/farmacología , Animales , Inhibidores de la Ciclooxigenasa/farmacología , Femenino , Gliburida/farmacología , Indometacina/farmacología , Nitroprusiato/farmacología , Perfusión , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
An increased release of the potent vasoconstrictor endothelin (ET) may play a role in the development of myocardial stunning. We, therefore, hypothesized that blockade of ET with either monoclonal antibodies against ET-1 and ET-3 (a-ET1/3-ab) or with the ET(A) receptor antagonist BQ123 would improve the reduction in myocardial blood flow (MBF; H2 clearance) and fractional wall thickening (FT; pulsed Doppler) after repetitive ischemia/reperfusion in an in situ perfused rat model. Under baseline conditions, ET-1 dose dependently decreased MBF and increased mean arterial blood pressure. FT and heart rate were unaltered. Pretreatment with both a-ET1/3-ab or BQ123 effectively blocked the effects of ET. Following repetitive ischemia, MBF was significantly reduced from 3.5 +/- 0.4 to 2.1 +/- 0.3 ml x min-1 x g-1 (p < 0.05) and FT from 16.2 +/- 1.7 to 9.4 +/- 1.1% in the control group (p < 0.05). Pretreatment with either antibodies did not significantly improve the attenuation in MBF and FT at the end of the ischemic protocol. These results indicate that inhibition of ET-1 by monoclonal antibodies or by ET(A) receptor blockade does not influence the decrease in MBF and FT in repetitive ischemia/reperfusion. We, therefore, propose that ET is not a major determinant in the development of myocardial stunning.
Asunto(s)
Circulación Coronaria/fisiología , Endotelinas/fisiología , Corazón/fisiopatología , Isquemia Miocárdica/fisiopatología , Animales , Anticuerpos Monoclonales/farmacología , Presión Sanguínea/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Antagonistas de los Receptores de Endotelina , Endotelina-1/farmacología , Endotelinas/antagonistas & inhibidores , Femenino , Péptidos Cíclicos/farmacología , Ratas , Ratas Endogámicas WF , Receptor de Endotelina A , RecurrenciaRESUMEN
BACKGROUND: A deficit in the endothelial production of nitric oxide (NO) is associated with the sequelae of reperfusion injury. Because endothelial NO synthesis depends on the cofactor tetra-hydrobiopterin (BH4), we hypothesized that depletion of this cofactor underlies the reduction of endothelium-dependent dilation in reperfusion injury. METHODS AND RESULTS: After occlusion of the left anterior descending coronary artery of a pig for 60 minutes followed by 90 minutes of reperfusion (ischemia/reperfusion), hearts were removed and the arterioles were isolated, cannulated, pressurized, and placed on an inverted microscope stage. Dose responses to the endothelium-independent dilator sodium nitroprusside and the endothelium-dependent dilators serotonin, A23187, and substance P were obtained under control conditions, after incubation with sepiapterin (intracellularly converted to BH4) or synthetic BH4 6-methyltetrahydropterin (MH4), and again after their washout. After ischemia/reperfusion, sodium nitroprusside maximally dilated arterioles (99 +/- 3%), whereas relaxation to serotonin, A23187, and substance P was significantly reduced (19 +/- 9%, 44 +/- 9%, and 54 +/- 8%, respectively). During incubation with sepiapterin (1 mumol/L) or MH4 (10 mumol/L), endothelium-dependent dilation was significantly enhanced (P < .05), whereas the response to sodium nitroprusside was unaltered. After washout, the vasodilatory responses were not significantly different from the initial ischemia/reperfusion responses. Sepiapterin and MH4 did not affect vasodilatory responses in vessels obtained from nonischemic control hearts. As after ischemia/reperfusion, incubation of control vessels with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, decreased endothelium-dependent vasodilation, which was restored in the presence of sepiapterin or MH4. CONCLUSIONS: These data indicate that exogenous administration of sepiapterin or MH4 restores the response to endothelium-dependent vasodilators in pig coronary arterioles after ischemia/ reperfusion. We therefore conclude that ischemia/reperfusion alters the availability or production of BH4, which contributes to blunted endothelial nitroxidergic vasodilation.
Asunto(s)
Biopterinas/análogos & derivados , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Vasodilatación/efectos de los fármacos , Animales , Biopterinas/farmacología , Inhibidores Enzimáticos/farmacología , Hemodinámica , Hipoxantinas/farmacología , Técnicas In Vitro , Pteridinas/farmacología , Pterinas/farmacología , Valores de Referencia , PorcinosRESUMEN
BACKGROUND: Endothelin is an oligopeptide of endothelial origin with potent vasoconstrictive and mitogenic properties, implicated in the pathogenesis of cyclosporine-induced hypertension, graft vasculopathy, and renal failure. Experimental animal data suggest a role for endothelin in allograft rejection also. METHODS: To determine the role of endothelin in acute graft rejection after heart transplantation, we determined endothelin plasma levels in 165 blood samples from 79 cardiac allograft recipients (2 to 81 months after the operation) with normal graft function and correlated our findings with the histologic severity of acute graft rejection according to International Society for Heart and Lung Transplantation grading. For comparison endothelin levels were determined in 30 healthy controls and in 22 early postoperative transplant recipients (< 2 months after the operation). RESULTS: Endothelin plasma levels were significantly higher in transplant recipients than in controls (early postoperative: 7.97 = 7.53 pg/ml; late postoperative: 3.68 +/- 1.72 pg/ml; controls: 1.55 +/- 0.89 pg/ml). Endothelin plasma levels were not significantly different between groups of rejection grades 0 to 4. In the comparison of two groups of no rejection or lower (International Society for Heart and Lung Transplantation grade 0 and 1, n = 134) and higher (International Society for Heart and Lung Transplantation grade > or = 2, n = 31) rejection severity or comparing patients requiring rejection therapy (n = 20) with those not requiring therapy (n = 145), endothelin levels did not differ significantly between the groups. In 22 patients with three to six available consecutive biopsy scores and endothelin levels, intraindividual longitudinal analysis did also not show any significant correlation. The only positive correlation of endothelin levels with other laboratory parameters was found with serum creatinine concentrations (p < 0.001). In the early postoperative recipients, no correlation of endothelin plasma levels with rejection severity was seen; furthermore the only significant association was found with time after operation. CONCLUSIONS: In this study endothelin plasma levels were not influenced by acute allograft rejection after heart transplantation. Therefore endothelin levels do not appear to be a useful marker for noninvasive rejection diagnosis. Furthermore, a relevant pathogenetic role of endothelin in the rejection process cannot be derived from these data.