Antonio Núñez

Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan.

A recent study has shown that losartan, an AT1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of the present study was to analyse the ability of different angiotensin II (Ang II) AT1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers and were stimulated with the thromboxane A2 analogue, U46619 (10-6 mol/L). U46619-stimulated platelet activation was significantly reduced by losartan in a dose-dependent manner. Only maximal doses of valsartan (5x10-6 mol/L), reduced U46619-induced platelet activation. The active form of candesartan cilexetil, candesartan (CV-11974), failed to modify platelet activation. Losartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed to a lesser extent with valsartan but not with CV-11974. These results suggest that, whilst some AT1-receptor antagonists reduce TxA2-dependent human platelet activation, it is not a feature common to all AT1 antagonists.

Inhibition of platelet activation in stroke-prone spontaneously hypertensive rats: comparison of losartan, candesartan, and valsartan.

In vitro studies have suggested that losartan interacts with the thromboxane (TxA2)/ prostaglandin H2 (PGH2) receptor in human platelets, reducing TxA2-dependent platelet activation. The aim of this study was to evaluate the effect of different angiotensin II type 1 receptor antagonists in stroke-prone spontaneously hypertensive rats (SHRSP). The level of platelet activation was assessed by determining P-selectin expression in platelets by flow cytometry. The ex vivo adhesion of platelets was also analyzed. The number of platelets that expressed P-selectin in SPSHR was significantly increased (% P-selectin expression: WKY 4 ± 0, 4%; SHRSP 15.5 ± 0, 8% [n = 8], p < 0.05). In SHRSP receiving losartan (20 mg/kg body weight per day) the percentage of platelets expressing P-selectin fell to levels close to that observed in WKY. The number of platelets from SHRSP treated with valsartan and candesartan (20 mg/kg body weight per day for 14 days) that expressed P-selectin was not significantly different from those from untreated SPRHR. Only losartan treatment reduced ex vivo platelet adhesion to a synthetic surface. The antiplatelet effect of losartan does not appear to be related to the level of blood pressure reduction. In ex vivo experiments, losartan significantly reduced the binding of the radiolabeled TxA2 agonist U46619 to platelets obtained from SHRSP in a dose-dependent manner. Treatment with losartan reduced the number of activated platelets in SHRSP independently of its blood pressure effects. TxA2-receptor blockade is proposed as a mechanism by which losartan can prevent platelet activation.

Vascular imaging before intravenous thrombolysis: consequences of in-hospital delay in applying two diagnostic procedures.

BACKGROUND Vascular imaging is increasingly used for diagnosis of arterial occlusions in acute ischemic stroke (AIS) patients. Our aim was to determine whether computed tomography angiography (CTA) and Doppler/duplex ultrasound (DUS) before intravenous thrombolysis (IVT) is associated with a delay in time-to-treatment. METHODS Observational analysis of a prospective cohort of AIS patients treated with IVT from January 2009 to December 2012. Patients were classified into three groups: the noncontrast computed tomography (NCCT) group (patients studied only with NCCT before IVT), CTA group (patients who underwent CTA in addition to NCCT), and the DUS group (patients studied with NCCT+DUS). RESULTS We treated 244 patients: 116 patients (47.5%) were studied with NCCT, 79 (32.4%) with CTA, and 49 (20.1%) with DUS. Door-to-needle time was significantly higher in the CTA group (median 60 [48-77] minutes) than in the NCCT group (51.5 [40-65]) and DUS group (48 [42-61]) (P = .008). No differences were observed for onset-to-door time and onset-to-needle time. In the multivariate linear regression analysis, onset-to-door time, prehospital stroke code activation, and performance of CTA influenced door-to-needle time. CONCLUSIONS Performing CTA before IVT seems to increase door-to-needle time. Vascular imaging based on DUS should be considered only if this does not lead to in-hospital delay.Vascular imaging is increasingly used for diagnosis of arterial occlusions in acute ischemic stroke (AIS) patients. Our aim was to determine whether computed tomography angiography (CTA) and Doppler/duplex ultrasound (DUS) before intravenous thrombolysis (IVT) is associated with a delay in time‐to‐treatment.

Efecto del triflusal sobre la agregación y secreción de las plaquetas humanas: papel del óxido nítrico

INTRODUCTION AND AIMS: The thrombotic process is a multicellular phenomenon in which not only platelets are involved but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal reduced platelet aggregation by stimulating nitric oxide (NO) production by neutrophils. The aim of the present study was to evaluate whether the in vivo treatment with triflusal could also modify the ability of neutrophils to produce NO. Furthermore, the role of NO released by neutrophils on platelet aggregation and secretion was also tested. METHODS: The study was performed in 12 healthy volunteers of 32 +/- 6 years of age. The volunteers were treated with triflusal (600 mg/day) for 5 days and platelets and neutrophils were isolated before and after treatment. The ability of neutrophils to produce NO and the capacity of inhibiting platelet aggregation and secretion of transforming growth factor-beta (TGF-beta) were assessed. RESULTS: After the treatment with triflusal we obtained the following results: a) an increase in NO production by neutrophils; b) potentiation of the inhibition of platelet aggregation by neutrophils, an effect that was reverted by incubating neutrophils with an L-arginine antagonist, L-NAME, and c) the presence of neutrophils reduced the release of TGF-beta by platelets measured as index of platelet secretion by a NO-independent mechanism. CONCLUSIONS: Triflusal (600 mg/day/5 days) stimulated NO production by neutrophils. After the treatment with triflusal, neutrophils inhibited both platelet aggregation and secretion. The antiaggregating effect of neutrophils was an NO-dependent mechanism while the inhibition of platelet secretion mediated by neutrophils after the treatment with triflusal was an NO-independent mechanism.

Efecto del losartán sobre la activación de plaquetas humanas por tromboxano A2

Introduccion y objetivo Estudios previos han demostrado que el losartan, antagonista de los receptores de tipo AT-1 de la angiotensina II (Ang II) podria bloquear al receptor del tromboxano A2 (TXA2) en la pared vascular. El objetivo del trabajo fue estudiar el efecto del losartan sobre la activacion de plaquetas humanas. Materiales y metodos Las plaquetas fueron obtenidas de 15 voluntarios sanos con edades comprendidas entre los 26 y 40 anos. La activacion plaquetaria fue medida por cambios en la transmision de luz del plasma rico en plaquetas estimuladas por un analogo sintetico del TXA2, el U46619 (5 × 10 –6 mol/l). Resultados El U46619 estimulo la agregacion de las plaquetas, siendo significativamente inhibida por el losartan de manera dosis dependiente. Solo dosis altas del EXP 3174, el metabolito hepatico principal del losartan, consiguieron inhibir la activacion plaquetaria inducida por el U46619. Captopril, inhibidor de la enzima convertidora de angiotensina, no fue efectivo en modificar la agregacion plaquetaria inducida por el analogo del TXA2. A pesar de que las plaquetas expresan receptores de tipo AT-1 de la Ang II, la Ang II exogena no modifico la agregacion plaquetaria inducida por U46619. La union del U46619 a las plaquetas fue competitivamente inhibida por el losartan en forma dependiente de la dosis. Sin embargo, solo dosis altas de EXP 3174 redujeron la union del U46619. Captopril no modifico la union del U46619 a las plaquetas. Conclusiones Losartan disminuyo la agregacion plaquetaria por un mecanismo dependiente de TXA2. El EXP 3174 demostro una menor potencia que losartan en reducir la activacion plaquetaria por TXA2. El captopril y la Ang II exogena no tuvieron efecto sobre la activacion de plaquetas humanas. Estos resultados sugieren que el losartan redujo la activacion plaquetaria inducida por el TXA2 por un mecanismo independiente del bloqueo de los receptores de tipo AT-1.

Efficacy of New Measures Saving Time in Acute Stroke Management: A Quantified Analysis

BACKGROUND Time to treatment remains the most important factor in acute ischemic stroke prognosis. We quantified the effect of new interventions reducing in-hospital delays in acute stroke management and assessed its repercussion on door-to-imaging (DTI), imaging-to-needle (ITN), and door-to-needle (DTN) times. METHODS Prospective registry of consecutive stroke patients who were candidates for reperfusion therapy attended in a tertiary care hospital from February 1 to December 31, 2014. A series of measures aimed at reducing in-hospital delays were implemented. We compared DTI, ITN, and DTN times between patients who underwent the interventions and those who did not. RESULTS 231 patients. DTI time was lower when personal history was reviewed and tests were ordered before patient arrival (2.5 minutes saved, P = .016) and when electrocardiogram was not made (5.4 minutes saved, P < .001). Not performing a computed tomography angiography and not waiting for coagulation results from laboratory before intravenous thrombolysis (25.5%) reduced ITN time significantly (14 and 12 minutes saved, respectively, P < .001). These interventions remained as independent predictors of a shorter ITN and DTN time. Completing all steps resulted in the lowest DTI and ITN times (13 and 19 minutes, respectively). CONCLUSIONS Every measure is an important part of a chain focused on saving time in acute stroke: the lowest DTI and ITN times were obtained when all steps were completed. Measures shortening ITN time produced a greater impact on DTN time reduction; therefore, ITN interventions should be considered a critical part of new protocols and guidelines.

Doxazosina y guanilato ciclasa soluble en un modelo de ratas hipertensas

Introduccion Aunque existen diferentes estudios sobre la capacidad del endotelio de generar oxido nitrico en la disfuncion endotelial asociada a la hipertension, el sistema de la guanilato ciclasa soluble (GCs) ha sido menos estudiado. Objetivo Analizar en ratas espontaneamente hipertensas que desarrollan accidentes cerebrovasculares (SHRSP) el nivel de expresion de la GCs en la pared vascular. Tambien se estudio el efecto del tratamiento con doxazosina, antagonista a1-adrenergico, sobre la expresion de la GCs en la pared vascular de estos animales. Metodos Se utilizaron ratas SHRSP (edad, 20 semanas; n = 24). Un grupo de estas ratas fue tratado con doxazosina (10 mg/kg peso/dia; n = 12) durante 2 semanas, y se comparo con ratas Wistar-Kyoto (WKY) normotensas (n = 12). Resultados Segmentos aorticos aislados de ratas SHRSP presentaron una disminucion de la respuesta vasodilatadora al nitroprusiato sodico. La respuesta al nitroprusiato sodico mejoro en las ratas SHRSP tratadas con doxazosina respecto de las SHRSP sin tratamiento. La expresion de la b1-GCs determinada por Western blot e inmunohistoquimica estaba disminuida en las ratas SHRSP respecto a las WKY. La administracion de doxazosina aumento la expresion de GCs, particularmente en la capa media cuando se comparara con ratas SHRSP no tratadas. Conclusiones En las ratas SHRSP existe una disminucion de la expresion de b1-GCs en la pared vascular y una reduccion en la respuesta a nitroprusiato sodico que mejora tras la administracion de doxazosina cuando se compara con SHRSP no tratadas. Estos resultados sugieren la importancia que tambien puede tener el sistema de la GCs en el tratamiento global de la disfuncion endotelial.

Computed Tomography Angiography before Intravenous Thrombolysis Does Not Increase the Risk of Renal Dysfunction

Our aim is to determine whether computed tomography angiography (CTA) before intravenous thrombolysis (IVT) affects renal function in acute ischemic stroke (AIS) patients. We performed an observational analysis of AIS patients treated with IVT for three years. Patients were classified into 2 groups: those who underwent CTA (CTA-group) and those who did not (control-group). Differences in creatinine levels between baseline and 24–72 hours after IVT were calculated. Acute renal dysfunction (ARD) was defined as an increase in serum creatinine level of ≥0.5 mg/dL and/or ≥25% above baseline within 24–72 hours after IVT. 190 patients were treated with IVT. Renal function (before and after IVT) was assessed in 162 (115 in control-group; 47 in CTA-group). Nine patients (5.5%) developed ARD (2 (4.2%) in CTA-group and 7 (6.1%) in control-group; ). CTA was not associated with a higher risk of ARD and did not affect the efficacy or safety of IVT. Previous chronic renal insufficiency, baseline creatinine levels, and previous use of nonsteroidal anti-inflammatory drugs were associated with a significant increase in creatinine levels, independently of contrast use. In conclusion, CTA does not seem to increase the risk of renal dysfunction. This technique may be used safely without knowledge of baseline creatinine levels.