Sodium late current blockers in ischemia reperfusion: is the bullet magic?
ABSTRACT We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.
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ABSTRACT: Inhibition of cardiac late Na(+) current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of this current are unselective and can be proarrhythmic. This study introduces GS967 (6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 micromolar, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations, torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium, and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally-induced arrhythmias in rabbit myocytes and hearts.Journal of Pharmacology and Experimental Therapeutics 09/2012; · 3.89 Impact Factor
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ABSTRACT: Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.ChemMedChem 09/2012; 7(10):1712-40. · 2.84 Impact Factor
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ABSTRACT: This review presents the roles of cardiac sodium channel NaV1.5 late current (late INa) in generation of arrhythmic activity. The assumption of the authors is that proper Na(+) channel function is necessary to maintenance of the transmembrane electrochemical gradient of Na(+) and regulation of cardiac electrical activity. Myocyte Na(+) channels openings during the brief action potential upstroke contribute to peak INa and initiate excitation-contraction coupling. Openings of Na(+) channels outside the upstroke contribute to late INa, a depolarizing current that persists throughout the action potential plateau. The small, physiological late INa does not appear to be critical for normal electrical or contractile function in the heart. Late INa does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na(+) loading. An increase of late INa, due to acquired conditions (e.g., heart failure) or inherited Na(+) channelopathies facilitates the formation of early and delayed afterpolarizations and triggered arrhythmias, spontaneous diastolic depolarization, and cellular Ca(2+) loading. These in turn increase the spatial and temporal dispersion of repolarization time and may lead to reentrant arrhythmias.Cardiovascular research 06/2013; · 5.81 Impact Factor