Vasodilatación dependiente de endotelio en la arteria braquial: uso en neurología clínica y experimental / Brachial arterial flow mediated dilation: utility in clinical and experimental practice

La cuantificación del grado de vasodilatación mediada por hiperaflujo (VMH) de la arteria braquial constituye una técnica ultrasonográfica no invasiva, barata, sencilla, reproducible, fácilmente disponible y validada, que nos permite conocer el estado de salud y funcionamiento del endotelio vascular. Es una respuesta dependiente del óxido nítrico endotelial y, cuando está disminuida, traduce una alteración del normal funcionamiento del endotelio (disfunción endotelial). La VMH está reducida en pacientes con factores de riesgo vascular, patología vascular cerebral, coronaria o periférica, y constituye un predictor independiente de eventos vasculares y recurrencia vascular. Nos permite, además, poder detectar y cuantificar el grado de disfunción endotelial de forma precoz, adelantándonos a la aparición de la placa de ateroma, y mejora con diversos fármacos, como antihipertensivos, antidiabéticos, antiagregantes o estatinas. Es útil en el ictus isquémico, ya que podría ayudar a filiar la etiología y presenta valor pronóstico, pero también lo podría ser en otras patologías, como la hemorragia cerebral, la migraña o el síncope. En el presente trabajo, revisamos lo más relevante en cuanto a la VMH y su posible aplicación no sólo en patología vascular, sino también en otras enfermedades (AU)

Brachial artery flow mediated dilation (FMD) is a validated, noninvasive physiological measure widely used as a research tool to quantify endothelial function. FMD is diminished in patients with several coronary risk factors, coronary artery disease, peripheral arterial disease, stroke, and is an independent predictor of cardiovascular events. FMD represents a useful method for identify asymptomatic atherosclerotic subjects with raised risk of developing atherothrombotic complications and improves with risk-reduction therapy such as antihypertensive or antidiabetic drugs, antiplatelet agents and statins. FMD could be a great usefulness in ischemic stroke such as stroke subtypes classification, prognostic significance in acute phase, and independent predictor for new-onset vascular event after first-ever stroke, but also in other disease such as cerebral haemorrhage, migraine or syncope. In this review article, brachial artery FMD and its role in experimental and clinical practice is extensively discussed (AU)

The acute effect of various glycemic index dietary carbohydrates on endothelial function in nondiabetic overweight and obese subjects.

OBJECTIVES: This study sought to explore the effect of glycemic-index dietary carbohydrates on endothelium-dependent flow-mediated dilation (FMD) in overweight and obese nondiabetic volunteers. BACKGROUND: Post-prandial hyperglycemia has been recognized as a cardiovascular risk factor in both the diabetic and the general population. Endothelial dysfunction has been shown to occur in diabetic and hyperglycemic patients. METHODS: We prospectively assessed brachial artery FMD in 56 healthy overweight and obese nondiabetic volunteers (38 [67.9%] men, mean age 48 +/- 6 years) on 4 separate mornings, 1 to 2 weeks apart. After overnight fasting, the percent FMD (%FMD) improvement and endothelium-independent nitroglycerin-mediated dilation (%NTG) were assessed, after which subjects received 1 of 4 group meals at each visit (placebo [water] or a carbohydrate meal of glucose, cornflakes, or high-fiber cereal). Meals were distributed in a rotating randomized fashion, such that each subject received all 4 meals once throughout the study period. RESULTS: Fasting and 2-h post-prandial serum glucose levels were similar in all 3 meals, whereas at 30 to 90 min, serum glucose levels were significantly higher after glucose and cornflakes (high glycemic) compared with fiber (low glycemic). Baseline %FMD, not significantly different in the 3 carbohydrate-based meals, was reduced 2 h post-prandially in all groups, showing statistical significance in only high-glycemic index meals: glucose (15 +/- 9% vs. 10 +/- 8%, p < 0.01), cornflakes (13 +/- 7% vs. 9 +/- 7%, p < 0.01). No correlation was observed between the %FMD reduction rate and glucose levels throughout the study period. CONCLUSIONS: High- compared with low-glycemic carbohydrate consumption significantly suppresses FMD in nondiabetic overweight and obese volunteers, suggesting a mechanism whereby high-glycemic meals may enhance cardiovascular risk.

[Measurement of exhaled nitric oxide: methodology]. / Mesure du NO expiré: méthodologie.

INTRODUCTION: The singular relationship between the exhaled nitric oxide (NO) fraction and the expiratory flow rate has both technical (subject of international guidelines) and theoretical (modelling of pulmonary NO exchange) implications. STATE OF THE ART: Guidelines recommend the measurement of exhaled NO at a single, defined, expiratory flow rate (V') against a positive expiratory pressure to ensure velum closure, providing a fraction of exhaled NO, FE(NO,V'). With some oversimplifications concerning the relationship between FENO and V', NO exchange parameters independent of the expiratory flow rate can be calculated based on a two-compartment model: maximum conducting airway NO flux (J'awNO), alveolar NO concentration (CalvNO), and in some conditions, airway NO diffusing capacity (DawNO) and epithelial NO concentration of conducting airways (CawNO). PERSPECTIVES: Technical progress has provided the pulmonologist with simple equipment to allow the determination of the NO output from the respiratory tract. The two-compartment model provides the physiologist with a non-invasive technique for evaluating the contribution of alveolar space and conducting airways. CONCLUSION: The measurement of exhaled NO allows the non-invasive evaluation of a key mediator involved in the regulation of biological processes.

[The place of expired nitric oxide measurements in asthma]. / Place de la mesure du NO expiré dans l'asthme.

INTRODUCTION: The production of nitric oxide (NO) can be assessed by measuring the fraction of NO during a prolonged expiration (FENO) or by estimating other parameters of NO exchange including the alveolar NO concentration (CalvNO). STATE OF THE ART: Changes in the production of NO are seen in association with clinical events (allergen exposure, minor symptoms, acute crises, changes of treatment) and functional (bronchial hyper-reactivity) or pathological (eosinophilia, remodeling markers) features characterising asthmatic phenotypes. PERSPECTIVE: Measurement of NO is a non-invasive tool for the evaluation of atopy, particularly in the course of allergic asthma. The interpretation of a single measurement is limited by the variability of the values associated with a stable state in the allergic population: the use in practice (risk of exacerbation, follow up, adjustment of steroid treatment) depends on analysis of sequential variations in FENO. Calculation of CalvNO may provide information about small airway inflammation and assist the optimal control of the disease. CONCLUSION: Ambulatory measurement of expired NO and the estimation of parameters describing NO exchange, independently of expiratory flow, could become the key evaluations in the monitoring of allergic asthma.

Perivascular adipose tissue modulates vascular function in the human internal thoracic artery.

OBJECTIVE: Recent studies have shown that perivascular adipose tissue from the rat aorta secretes a substance that can dilate the aorta. The purpose of the present study was to examine whether this vasodilator is also present in human internal thoracic arteries. METHODS: Vascular function of human internal thoracic arteries with and without perivascular adipose tissue was assessed with wire myography, and morphology was examined with light microscopy. RESULTS: The presence of perivascular adipose tissue attenuated the maximal contraction to U 46619 and the contraction to phenylephrine (1 micromol/L) by 37% and 24%, respectively. Transfer of the solution incubated with a perivascular adipose tissue-intact vessel (donor) to a vessel without perivascular adipose tissue (recipient) induced a significant relaxation (36%) in the recipient artery precontracted with phenylephrine. Transfer of incubation solution with perivascular adipose tissue alone also induced a relaxation response in the recipient vessel (37%). The relaxation of the recipient artery induced by the transfer of incubation solution from the donor (artery with intact perivascular adipose tissue or perivascular adipose tissue alone) was absent in vessels precontracted by KCl (60 mmol/L) and was prevented by calcium-dependent potassium channel blockers (tetraethylammonium chloride, 1 mmol/L; iberiotoxin, 100 nmol/L), but not by the voltage-dependent potassium channel blocker 4-aminopyridine (1 mmol/L) and the adenosine triphosphate-dependent potassium channel blocker glibenclamide (10 micromol/L). CONCLUSIONS: Perivascular adipose tissue in human internal thoracic arteries releases a transferable relaxation factor that acts through the activation of calcium-dependent potassium channels. Because perivascular adipose tissue is often removed in coronary artery bypass grafting, retaining perivascular adipose tissue might be helpful in reducing the occurrence of vasospasm of the graft vessels.

Coronary blood flow responses are impaired independent of NO and endothelial function in conscious dogs with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by nitric oxide (NO) deficiency and endothelial dysfunction. Whether endothelium-independent vasodilation is preserved, particularly in the coronary circulation, remains controversial. METHODS AND RESULTS: We studied systemic and coronary flow responses to the endothelium-dependent agonist, acetylcholine, the cGMP-dependent NO-donor, nitroglycerin, the predominantly endothelium-independent agonist, adenosine, the beta-adrenergic cAMP-dependent agonist, isoproterenol, and the calcium channel antagonist, nicardipine, in conscious dogs with pacing-induced DCM. Systemic blood flow response was impaired to acetylcholine but preserved to other vasodilators in DCM. In contrast, coronary blood flow response was significantly ( P < .05) depressed to all agonists. (Peak coronary blood flow response, control versus DCM: acetylcholine: 221 +/- 14% versus 156 +/- 11%; nitroglycerin: 220 +/- 17% versus 138 +/- 9%; adenosine: 635 +/- 65% versus 376 +/- 56%; nicardipine: 338 +/- 59% versus 115 +/- 23%; isoproterenol: 219 +/- 18% versus 86 +/- 20%). The attenuation was independent of systemic hemodynamic differences. CONCLUSION: In contrast to systemic responses, coronary blood flow responses in DCM are impaired dependent or independent of NO or second messenger mechanisms, implying either distal signaling defects or structural abnormalities in the coronary vasculature.

Função endotelial em adultos jovens com infarto do miocárdio: influências ambientais e genéticas / Endothelium function in young adults with myocardial infarction: environomental and genetic influences

A disfunção endotelial atua tanto na aterogênese como na precipitação das síndromes coronárias agudas. A redução da biodisponibilidade do óxido nítrico é expressão de endotélio disfuncional. O mecanismo desta redução não está elucidado. A presença de disfunção endotelial foi correlacionada com fatores de risco (FR), nitrato sanguíneo e fatores genéticos (polimorfismo do óxido nítrico sintase endotelial / The endothelial dysfunction plays an important roll in the atherogenesis and precipitation of acute coronary syndromes. The reduction of bioavailability of the nitric oxide is the expression of endothelial dysfunction. The exact mechanism of this reduction is not yet well explained. In order to evaluate the presence of endothelial dysfunction and correlation with risk factors (FR), nitrate blood levels and genetic factors (endothelial nitric oxide syntethase polymorphism, fibrinogen and PAI-1) a 128 myocardial infarction patients group with age ≤ 40 year was studied, and underwent a brachial artery ultra-sound. The results were compared with a group of young health individuals...

Efecto de la ingesta de sal sobre la función endotelial y su relación con el fenómeno de la sensibilidad a la sal en la hipertensión arterial esencial / Effect of salt intake upon endothelial function and its relationship with the salt sensitivity phenomenon in essential hypertension

El objetivo del presente trabajo ha sido el de evaluar las alteraciones en la función de la célula endotelial inducidas por el consumo de sal en pacientes hipertensos esenciales caracterizados en funcion de la presencia de sensibilidad o resistencia a la sal. Para ello hemos incluido a 60 pacientes hipertensos esenciales de ambos sexos, con una media de 42 años, sometidos a ingesta de baja (50 mmol/día) y elevada (250 mmol/día) cantidad de sal, evaluando los cambios en los productos derivados del endotelio. La evaluación funcional de la función endotelial se ha realizado mediante pletismografía de oclusión venosa frente a infusiones intraarteriales de acetilcolina, nitroprusiato sódico y el inhibidor de la síntesis de óxido nítrico, L-NMMA. Los resultados muestran que en el conjunto de los pacientes estudiados, una elevada ingesta de sal induce un descenso estadísticamente significativo en la concentración plasmática de nitratos (p < 0,001) de endotelina (p = 0,005). Además los pacientes sensibles a la sal mostraron un descenso estadísticamente significativo de la excreción urinaria de nitratos (p = 0,045), inducidos por la ingesta de sal. Finalmente, el estudio mediante pletismografía mostró que los pacientes sensibles a la sal presentaban una menor vasodilatación dependiente del endotelio inducida por acetilcolina (p = 0,008) en comparación con los resistentes a la sal. Además, la infusión de L-NMMA indujo a un menor descenso en la respuesta vasodilatadora a acetilcolina en los pacientes sensibles a la sal (p = 0,013). En conclusión, la ingesta de una dieta rica en sal ejerce en los pacientes hipertensos un efecto inhibitorio sobre la secreción de la célula endotelial. Hay que añadir que los pacientes sensibles a la sal presentan mayores alteraciones en la función de la célula endotelial. Estos resultados apoyan la existencia de una relación entre la disfunción endotelial y el desarrollo de la hipertensión sensible a la sal (AU)

Effects of L-NAME and L-Arg on arterial blood pressure in normotensive and hypertensive streptozotocin diabetic rats

The present study was designed to examine blood pressure response to nitric oxide synthase-pathway inhibition and stimulation in normotensive and hypertensive diabetic rats. Rats treated with streptozotocin (60 mg/Kg ip) developed high blood glucose, polyuria and slow weight gain compared with control. One group of diabetic rats developed hypertension, consequently we studied three experimental groups: control rats (C), normotensive diabetic rats (ND) and hypertensive diabetic rats (HD). Mean arterial pressure (MAP), systolic blood pressure, diastolic blood pressure and heart rate were recorded: baseline time, 30after L-nitro arginine methyl ester (L-NAME: 1 mg/Kg iv) and post L-arginine (L-arg: 250 mg/Kg iv) injection. L-NAME induced a significantly increase in MAP in all groups. This enhancement was smaller in diabetic than in control rats. The increase in MAP in HD was significantly lower than that in NDL-arg induced a significantly decrease in MAP in all groups. This decrease was significantly attenuated in diabetic compared with control rats. The degree of hypotension in response to L-arg in diabetic groups was lower in hypertensive than that in normotensive diabetic rats. These data suggest that an impairment of nitric oxide formation could be involved in the development of hypertension in this model. (AU)

Effects of L-NAME and L-Arg on arterial blood pressure in normotensive and hypertensive streptozotocin diabetic rats

The present study was designed to examine blood pressure response to nitric oxide synthase-pathway inhibition and stimulation in normotensive and hypertensive diabetic rats. Rats treated with streptozotocin (60 mg/Kg ip) developed high blood glucose, polyuria and slow weight gain compared with control. One group of diabetic rats developed hypertension, consequently we studied three experimental groups: control rats (C), normotensive diabetic rats (ND) and hypertensive diabetic rats (HD). Mean arterial pressure (MAP), systolic blood pressure, diastolic blood pressure and heart rate were recorded: baseline time, 30'after L-nitro arginine methyl ester (L-NAME: 1 mg/Kg iv) and post L-arginine (L-arg: 250 mg/Kg iv) injection. L-NAME induced a significantly increase in MAP in all groups. This enhancement was smaller in diabetic than in control rats. The increase in MAP in HD was significantly lower than that in NDL-arg induced a significantly decrease in MAP in all groups. This decrease was significantly attenuated in diabetic compared with control rats. The degree of hypotension in response to L-arg in diabetic groups was lower in hypertensive than that in normotensive diabetic rats. These data suggest that an impairment of nitric oxide formation could be involved in the development of hypertension in this model.

Estimation of EDRF and nitric oxide release using [3H]GTP-labeled human platelets.

We have developed a new bioassay for endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) using human [3H]guanosine triphosphate (GTP)-labeled platelets. The labeled platelets were preincubated with isobutyl-methylxanthine and co-cultured with endothelial cells and the [3H]cyclic guanosine monophosphate (cGMP) formed was isolated by ion-exchange chromatography. Endothelial cells, either in monolayer cells or in suspension, increased platelet cGMP accumulation dose-dependently, a significant increase being detected with 5000 endothelial cells or more/assay when suspended cells were used. Co-culturing with the same number of skin fibroblasts failed to elevate platelet cGMP. Preincubation of endothelial cells with bradykinin and superoxide dismutase (SOD) synergistically potentiated the increase in platelet cGMP, but was attenuated by Nomega-nitro-L-arginine, with partial restoration by L-arginine but not by D-arginine. These compounds, however, did not affect cGMP accumulation by sodium nitroprusside. Moreover, preincubation of the labeled platelets with the NO synthase inhibitor prior to EDRF assay had no effect. We conclude that [3H]GTP-labeled platelets could provide a simple, sensitive and specific bioassay for estimating EDRF or NO release.

Historia del Descubrimiento de la Vía L-arginina: Oxido Nítrico

En la última década se ha podido establecer que el Oxido Nítrico (ON) corresponde al llamado Factor Relajante Derivado del Endotelio, dado que mediante el uso de inhibidores competitivos del ON se inducía contracción vascular, efecto revertido por el tratamiento con L-arginina, precursor de la biosíntesis del ON, mediada ésta por la acción de la ON Sintetasa. El ON ha sido implicado entre muchos aspectos, en la generación de daño tisular y patogénesis de algunas condiciones vasculares como vasoespasmo, ateroesclerosis, diabetes mellitus, hipertensión esencial y preeclampsia; de igual forma han sido planteadas novedosas aplicaciones de la inhibición de la ON Sintetasa en el enfoque terapéutico de la inflamación y el shock