Activation of p38 in C2C12 myotubes following ATP depletion depends on extracellular glucose

Muscle cells adjust their glucose metabolism in response to myriad stimuli, and particular attention has been paid to glucose metabolism after contraction, ATP depletion, and insulin stimulation. Each of these requires translocation of GLUT4 to the cell membrane, and may require activation of glucose transporters by p38. In contrast, AICAR stimulates glucose transport without activation of p38, suggesting that p38 activation may be an indirect consequence of accelerated glucose transport or metabolism. This study was designed to investigate the contribution of AMPK and p38 to ATP homeostasis and glucose metabolism to test the hypothesis that p38 reflects glycolytic activity rather than controls glucose uptake. Treating mature myotubes with rotenone caused transient ATP depletion in 15 min with recovery by 120 min, associated with increased lactate production. Both ACC and p38 were rapidly phosphorylated, but ACC remained phosphorylated while p38 phosphorylation declined as ATP recovered. AMPK inhibition blocked ATP recovery, lactate production, and phosphorylation of p38 and ACC. Inhibition of p38 had little effect. AICAR induced ACC phosphorylation, but not lactate production or p38 phosphorylation. Finally, removing extracellular glucose potentiated rotenone-induced AMPK activation, but reduced lactate generation, ATP recovery and p38 activation. Thus, glucose metabolism is highly sensitive to ATP homeostasis via AMPK activity, but p38 activity is dispensable. Although p38 is strongly phosphorylated during ATP depletion, this appears to be an indirect consequence of accelerated glycolysis

Antiagregación oral e intervencionismo coronario percutáneo / Oral antiplatelet therapy and percutaneous coronary intervention

La lesión que la propia intervención coronaria percutánea (ICP) provoca en la pared arterial pone en marcha la activación y agregación plaquetarias. Por este motivo, todos los pacientes deben estar eficazmente antiagregados durante y después de la intervención. La combinación de aspirina más clopidogrel es hoy día el tratamiento antiplaquetario oral estándar para los pacientes tratados con ICP. En los pacientes que no estén tomando aspirina, se deben administrar 500 mg por vía oral al menos 3 h antes de la intervención, o 300 mg por vía intravenosa en el momento de ésta; y después de la ICP se administrarán 100 mg diarios de aspirina de forma indefinida. El clopidogrel debe administrarse también antes de la ICP, idealmente en dosis de carga de 300 mg al menos 6 h antes del procedimiento. Cuando esto no sea posible, y especialmente en pacientes de alto riesgo o en aquellos con una demostrada menor respuesta al clopidogrel, como por ejemplo los pacientes diabéticos, se debe considerar la administración de dosis más altas de carga de clopidogrel, aunque el beneficio clínico de esta medida es todavía discutido. Tras la implantación de un stent convencional se mantendrá el clopidogrel durante un mes, y tras un stent recubierto de fármacos antiproliferativos, durante 3-12 meses. Mientras tanto, y con el objetivo de superar algunas de las limitaciones del clopidogrel, continúa la búsqueda del antagonista «ideal» de los receptores plaquetarios del adenosindifosfato (ADP), es decir, un fármaco que, administrado por vía oral, sea reversible, con un rápido efecto de acción, un alto grado de inhibición y sin resistencias. Fármacos antiplaquetarios potentes como el prasugrel y el AZD6140 han demostrado ya tener un perfil de seguridad similar al clopidogrel, y su eficacia clínica está siendo valorada en grandes ensayos multicéntricos que persiguen facilitar y optimizar el tratamiento de los pacientes tratados con ICP (AU)

The arterial wall lesion caused by percutaneous coronary intervention (PCI) induces platelet activation and aggregation. Consequently, all patients should receive effective antiplatelet drugs during and after the intervention. Currently, standard oral antiplatelet therapy for patients undergoing PCI comprises the combination of aspirin and clopidogrel. In those who are not taking aspirin, 500 mg should be given orally at least 3 hours prior to the intervention or 300 mg should be given intravenously immediately before the procedure. In addition, after the procedure, 100 mg of aspirin should be given daily for an indefinite period. Clopidogrel should also be administered before PCI, ideally as a 300 mg loading dose given at least 6 hour before the procedure. When this is not possible, and especially in high-risk patients and those who have a demonstrably poor response to clopidogrel, such as diabetics, the administration of a higher loading dose should be considered, even though the clinical benefits of this approach are still debated. After implantation of a baremetal stent, clopidogrel should be continued for 1 month; after implantation of a drug-eluting stent, it should be continued for 3-12 months. Meanwhile, with the aim of overcoming some of clopidogrel’s limitations, the search for the «ideal» adenosine diphosphate platelet receptor antagonist continues: that is, an agent that can be administered orally, whose effects are reversible, that has a rapid onset of action and a substantial inhibitory effect, and to which there is no resistance. Potent antiplatelet drugs, such as prasugrel and AZD6140, have been shown to have a safety profile similar to clopidogrel. In addition, their clinical efficacy is currently being evaluated in large multicenter trials whose aims are to simplify and optimize the management of patients undergoing PCI (AU)