| Diclofenaco prolonga la repolarización del músculo ventricular con daño en la repolarización de reserva |
Diclofenac prolongs repolarization in ventricular muscle with impaired repolarization reserve.
Kristóf A, Husti Z, Koncz I, Kohajda Z, Szél T, Juhász V, Biliczki P, Jost N, Baczkó I, Papp JG, Varró A, Virág L.
Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
PLoS One. 2012;7(12):e53255. doi: 10.1371/journal.pone.0053255. Epub 2012 Dec 31.
Abstract
BACKGROUND: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. METHODS: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. RESULTS: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2) application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QT(c) interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c). Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (I(Kr)) and slow (I(Ks)) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca)) was slightly diminished, but the transient outward (I(to)) and inward rectifier (I(K1)) potassium currents were not influenced. CONCLUSIONS: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534043/pdf/pone.0053255.pdf
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| Nuevas acciones de los AINES sobre los canales iónicos vasculares: La contabilización de los efectos secundarios cardiovasculares e identificación de nuevas aplicaciones terapéuticas. |
Novel Actions of Nonsteroidal Anti-Inflammatory Drugs on Vascular Ion Channels: Accounting for Cardiovascular Side Effects and Identifying New Therapeutic Applications.
Brueggemann LI, Mani BK, Mackie AR, Cribbs LL, Byron KL.
Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois.
Mol Cell Pharmacol. 2010;2(1):15-19.
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications for the treatment of both acute and chronic pain. Selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex(®)), rofecoxib (Vioxx(®)), and diclofenac, have been among the most widely prescribed NSAIDs because they prevent the generation of prostaglandins involved in inflammation and pain, but avoid some of the gastrointestinal complications associated with less selective COX-1/COX-2 inhibitors. In 2004, rofecoxib (Vioxx(®)) was voluntarily withdrawn from the market because of adverse cardiovascular side effects. This led to an explosion of research into the cardiovascular effects of the 'coxibs', which revealed differential cardiovascular risk profiles among the members of this drug class. The differential risk profiles may relate to the tendency of some of the drugs to elevate blood pressure (BP). An important component of BP regulation is dependent on the contractile state of vascular smooth muscle cells (VSMCs), which is controlled to a large extent by the activities of KCNQ (Kv7 family) potassium channels and L-type calcium channels. Our recently published data indicate that celecoxib, but not rofecoxib or diclofenac, at therapeutically relevant concentrations, acts as a Kv7 potassium channel activator and a calcium channel blocker, causing relaxation of VSMCs and decreasing vascular tone. These vasorelaxant ion channel effects may account for the differential cardiovascular risk profiles among the different COX-2 inhibitors. We further speculate that these properties may be exploited for therapeutic benefit in the treatment of cardiovascular diseases or other medical conditions.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915785/pdf/nihms-184534.pdf
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Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
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