Exenatide induces an increase in vasodilatory and a decrease in vasoconstrictive mediators.

In view of the known vasodilatory effects of glucagon-like peptide-1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor-ß and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin-angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.

Cyclical stretch induces structural changes in atrial myocytes.

Atrial fibrillation (AF) often occurs in the presence of an underlying disease. These underlying diseases cause atrial remodelling, which make the atria more susceptible to AF. Stretch is an important mediator in the remodelling process. The aim of this study was to develop an atrial cell culture model mimicking remodelling due to atrial pressure overload. Neonatal rat atrial cardiomyocytes (NRAM) were cultured and subjected to cyclical stretch on elastic membranes. Stretching with 1 Hz and 15% elongation for 30 min. resulted in increased expression of immediate early genes and phosphorylation of Erk and p38. A 24-hr stretch period resulted in hypertrophy-related changes including increased cell diameter, reinduction of the foetal gene program and cell death. No evidence of apoptosis was observed. Expression of atrial natriuretic peptide, brain natriuretic peptide and growth differentiation factor-15 was increased, and calcineurin signalling was activated. Expression of several potassium channels was decreased, suggesting electrical remodelling. Atrial stretch-induced change in skeletal α-actin expression was inhibited by pravastatin, but not by eplerenone or losartan. Stretch of NRAM results in elevation of stress markers, changes related to hypertrophy and dedifferentiation, electrical remodelling and cell death. This model can contribute to investigating the mechanisms involved in the remodelling process caused by stretch and to the testing of pharmaceutical agents.

Caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion.

Caveolae may act as mechanosensors and function as binding sites for calcium ions. The intracaveolar localization of atrial natriuretic peptide (ANP) derived from the direct interaction of atrial granules with caveolae has been demonstrated. The aim of this study was to define the effect of caveolae on ANP secretion induced by stretch and angiotensin II. The isolated perfused beating atria from Sprague-Dawley rats were used. To disrupt caveolae, 10mM methyl-ß-cyclodextrin (MbCD) was applied for 1h and the number of caveoli were markedly decreased. MbCD increased basal ANP secretion and atrial diastolic pressure. The molecular profile of ANP in perfusate from control atria showed mainly one major peak corresponded to synthetic ANP whereas that from MbCD-treated atria showed two major immunoreactive peaks corresponded to synthetic rat ANP and proANP. High atrial stretch induced by elevating the height of outflow catheter from 5 cm H2O to 7.5 cm H2O increased atrial contractility and ANP secretion. The response of ANP secretion to high stretch was attenuated in MbCD-pretreated atria. Pretreatment with MbCD abolished angiotensin II-induced suppression and losartan-induced stimulation of ANP secretion. However, the effect of angiotenisin (1-7) on ANP secretion was not altered by MbCD treatment. The expression of angiotensin II type 1 receptor protein was reduced by MbCD treatment. These data suggest that caveolae are essential for angiotensin II type 1 receptor-mediated ANP secretion and relate to the processing of proANP.

Differential effects of Pyk2 and FAK on the hypertrophic response of cardiac myocytes.

The related cytoplasmic non-receptor tyrosine kinases Pyk2 (proline-rich tyrosine kinase 2) and FAK (focal adhesion kinase) have been implicated in phenylephrine-induced G-protein-coupled receptor-mediated signaling mechanisms leading to cardiomyocyte hypertrophy. We report that, in phenylephrine-stimulated neonatal rat ventricular myocytes (NRVM), Pyk2 augments expression of the hypertrophic marker atrial natriuretic factor (ANF) but reduces cytoskeletal organization and cell spreading. In contrast, FAK attenuates ANF production but does not alter cytoskeletal organization and cell spreading. Pyk2 and FAK exhibit differential localization in both unstimulated and phenylephrine-stimulated myocytes. Pyk2 catalytic activity is required for Pyk2 to augment ANF secretion but is not necessary to reduce cell spreading. Pyk2 autophosphorylation is required but not sufficient for Pyk2 to augment ANF secretion. Expression of the Pyk2 FERM domain as an autonomous fragment inhibits phenylephrine-mediated ANF secretion and reduces cell spreading. In addition, expression of the Pyk2 FERM domain inhibits the ability of Pyk2 to augment ANF secretion; this is correlated with reduced Pyk2 autophosphorylation. These data indicate that Pyk2 and FAK have different roles and occupy different positions in signaling pathways leading to the development of cardiomyocyte hypertrophy.

Utilidad diagnóstica del fragmento N-terminal del propéptido natriurético cerebral en los pacientes ingresados en un servicio de cardiología / Diagnostic usefulness of N-terminal brain natriuretic peptide in patients admitted to a cardiology service

FUNDAMENTO Y OBJETIVO: El fragmento N-terminaldel propéptido natriurético cerebral o tipo B (NTproBNP)se utiliza para el diagnóstico de pacientescon sospecha de insuficiencia cardíaca (IC). Los valoresde NT-proBNP inferiores a 300 pg/ml indicanun diagnóstico improbable de IC. Nuestro objetivoha sido determinar la validez de los puntos de cortedel NT-proBNP según la edad, propuestos en la bibliografíamédica (inclusión/exclusión), en los pacientesingresados en nuestro servicio.PACIENTES Y MÉTODO: Hemos recogido de formaprospectiva los datos de 90 pacientes que ingresaronen nuestro servicio con diagnóstico de IC (n= 37) y de otras enfermedades (n = 39), y en quienesse determinó la concentración de NT-proBNP.Se estudiaron la sensibilidad, la especificidad y losvalores predictivos de este análisis, así como la relaciónde los valores de dicho marcador con las variablesclínicas y ecocardiográficas.RESULTADOS: En los pacientes con IC el diámetroventricular era mayor y la fracción de eyección,menor. La sensibilidad para el diagnóstico de exclusiónfue del 97% y el valor predictivo negativo,del 94%.CONCLUSIONES: El punto de corte de exclusión propuesto(300 pg/ml) posee una alta sensibilidad yvalor predictivo negativo para el diagnóstico de ICen los pacientes ingresados en nuestro servicio

BACKGROUND AND OBJECTIVE: The N-terminal brainnatriuretic peptide (NT-proBNP) is a new tool forthe diagnosis of patients with evidence of heart failure(HF). The diagnosis of HF is improbable in patientswith a level of NT-proBNP < 300 pg/ml. Ourobjective is to determine the validity of the cut-offpoints proposed by literature (inclusion/exclusion)regarding the age for NT-proBNP in patients admittedto our service.PATIENTS AND METHOD: We gathered consecutivelythe data of 76 patients admitted to our service withthe diagnosis of HF (n = 37) and with other diseases(n = 39), taking a sample of plasma to determineNT-proBNP. We studied the sensitivity, specificityand predictive values of this test, as well as the relationbetween the levels of that marker and the clinicaland echocardiographic variables.RESULTS: The ventricular diameter was larger andthe ejection fraction was lower in patients with HF.Sensitivity for the diagnosis of exclusion reached avalue of 97% and the negative predictive value was94%.CONCLUSIONS: The cut-off point proposed for exclusion(300 pg/ml) shows high sensitivity and negativepredictive value in the diagnosis of HF in patientsadmitted to our service

Fragmento N-terminal del propéptido natriurético cerebral en el diagnóstico de la insuficiencia cardíaca aguda: ¿dónde nos encontramos ahora? / No disponible

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Effects of adrenomedullin on angiotensin II stimulated atrial natriuretic peptide and arginine vasopressin secretion in healthy humans.

AIMS: Adrenomedullin is a newly described peptide that has widespread tissue distribution. Its presence in cardiovascular (including vascular endothelial cells, smooth muscle cells, and cardiac atria and ventricles) and renal tissues, together with its vasodilatory and natriuretic properties, suggest a role in blood pressure regulation and fluid and electrolyte balance. METHODS: Nine normal volunteers were studied to determine whether or not adrenomedullin influenced plasma atrial natriuretic peptide and arginine vasopressin concentrations during systemic angiotensin II infusion. RESULTS: A significant (P = 0.02) augmentation of atrial natriuretic peptide concentrations, but no suppression of arginine vasopressin concentrations, was found with coinfusion of adrenomedullin and angiotensin II when compared with vehicle and angiotensin II. CONCLUSIONS: Despite its vasodilator and natriuretic action, adrenomedullin significantly augmented angiotensin II-stimulated plasma atrial natriuretic peptide concentrations in healthy humans. This provides further evidence of a synergistic interaction between adrenomedullin and atrial natriuretic peptide and suggests that adrenomedullin may have a role in fluid and electrolyte balance and blood pressure regulation.