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 (IC 50 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 (IC 50 0.64 × 10 −6 mol·L −1 ). In rabbits, F 15845 given i.v. (ED 50 0.05 mg·kg −1 ) or orally (ED 50 0.13 mg·kg −1 ) dose‐dependently and powerfully inhibited regional myocardial ischaemia‐induced ST segment elevation in the absence of haemodynamic effects, implying direct cardiac activity. In dogs, F 15845 dose‐dependently inhibited epicardial ST segment changes (70 ± 8% at 0.63 mg·kg −1 ) 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 Na v 1.5 channel isoforms, and prevents cardiac angina in animal models.