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: 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
- F1000Research. 01/2014; 3:245.
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ABSTRACT: The persistent sodium current is involved in myocardial ischaemia and is selectively inhibited by the newly described 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845). Here, we describe the pharmacological profile of F 15845 against the effects of hypoxia in femoral arteries in vitro. Isometric tension measurement of rat isolated femoral arteries was used to characterize the protective effect of F 15845 against contraction of the vessels induced by veratrine (100 microg.mL(-1)) or hypoxia. Rat femoral artery expressed the Na(v)1.5 channel isoform. When exposed to veratrine (100 microg.mL(-1)), vessels developed a rapid and strong contraction that was abolished by both absence of sodium and blockade of the Na(+)/Ca(++) exchanger by KB-R7943 (10 and 32 micromol.L(-1)) or treatment with F 15845. When used before veratrine exposure, the potency of F 15845 depended on the extracellular K(+) concentration (IC(50)= 11 and 0.77 micromol.L(-1) for 5 and 20 mmol.L(-1) KCl, respectively), whereas its potency was unaffected by extracellular K(+) concentration when given after veratrine. F 15845 did not affect either KCl (80 mmol.L(-1)) or phenylephrine-induced femoral artery contraction. Moreover, endothelium disruption did not affect the protective effect of F 15845 against veratrine-induced femoral artery contraction, suggesting a mechanism of action dependent on smooth muscle cells. Finally, F 15845 prevented in a concentration-dependent manner rat femoral artery contraction induced by hypoxia. F 15845, a selective blocker of the persistent sodium current prevented vascular contraction induced by hypoxic conditions.British Journal of Pharmacology 01/2010; · 5.07 Impact Factor