F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models

Abstract

Background and purpose: Activation of the persistent sodium current in ischaemic myocardium results in calcium overload which is toxic for the cardiomyocyte. Thus, the activity of 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate (F 15845), a new selective persistent sodium current blocker, in protecting against the effects of cardiac ischaemia was examined, in both in vitro and in vivo models. Experimental approach: Electrophysiological studies using patch-clamp and conventional microlelectrode techniques, isolated perfused hearts and models of angina in anaesthetized animals were used to assess the protection afforded by F 15845 against ischaemia-induced changes. Key results: F 15845 reduced the persistent sodium current activated by veratridine (IC50 1.58 ¥ 10 -6 mol·L -1). F 15845 blocked voltage-gated human cardiac sodium channels in a novel, voltage-dependent manner, selectively affecting steady-state inactivation. F 15845 did not affect action potential shape and basal function of guinea pig isolated perfused hearts but did reduce ischaemia-induced diastolic contracture in this model (IC50 0.64 ¥ 10 -6 mol·L ) in an experimental angina model of demand ischaemia, again without haemodynamic effects, confirming a direct anti-anginal activity. Conclusions and implications: F 15845 is a selective, potent blocker of the persistent sodium current, generated by the human Nav1.5 channel isoforms, and prevents cardiac angina in animal models.

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

“…The inhibition of I Na,L and prevention of Na + overload may therefore be cardioprotective [3,[33][34][35][36] . 18β-GA preferentially blocks the I Na,L induced by ATX-II (mimicking I Na,L activation evoked by ischemia [36] ) in isolated human atrial myocytes.…”

3-(R)-[3-(2-Methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine Bromhydrate (F 15845) Prevents Ischemia-Induced Heart Remodeling by Reduction of the Intracellular Na+ Overload

“…Thus, LPC-modified Na ϩ channel function causes Ca 2ϩ loading and contractile dysfunction against which the protective effects of F 15845 were tested (Tamareille et al, 2002). Our results show that F 15845, a new, persistent sodium channel blocker Vacher et al, 2009), counteracted LPC-induced hypercontracture, suggesting that reduction of Na ϩ channel dysfunction induced Ca 2ϩ loading in isolated cardiomyocytes exerts cardioprotective activities. Because LPC accumulates quickly during ischemia and reperfusion and is proarrhythmic, it is conceivable that it contributes to the pathogenesis of ischemic cell death (Sedlis et al, 1997).…”

“…Under these conditions, F 15845 (5 mg/kg) reduced infarct size and plasma troponin I levels. Furthermore, F 15845 at this dose was devoid of significant effects on blood pressure, heart rate, and myocardial oxygen consumption (Vacher et al, 2009), revealing a direct cardioprotective action. The importance of troponin I for the diagnosis of myocardial infarction originates from its cardiac specificity.…”

“…Thus, it remains unknown whether the cardioprotective activity of ranolazine is attributable to blockade of the persistent sodium current or whether it is due to a combination of effects. We recently described a new, selective, and potent persistent sodium current blocker, F 15845 (Le Vacher et al, 2009), which is currently entering in phase II clinical trials for the treatment of refractory angina. It is unknown, however, whether blockade of persistent sodium current by F 15845 can influence the ischemic Na ϩ accumulation of the heart.…”

Pharmacological treatment of chronic stable angina pectoris

“…F 15845 (3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate) is a newly described selective inhibitor of the persistent Na + current, which has shown anti-ischaemic properties and an ability to prevent ischaemia-induced arrhythmias in animal models; it currently is being assessed in phase II clinical trials. [39][40][41] …”