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


METHODS
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.


RESULTS
F 15845 reduced the persistent sodium current activated by veratridine (IC(50) 1.58 x 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 x 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
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.
Vacher
B
B
Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, Castres Cedex, France.
Pignier
C
C
Létienne
R
R
Verscheure
Y
Y
Le Grand
B
B
D000200:Action Potentials / Q000187:drug effects; D000787:Angina Pectoris / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001582:Benzothiepins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000502:physiology*; D014701:Veratridine
C541955:3-(3-(2-methoxyphenylthio)-2-methylpropyl)amino-3,4-dihydro-2H-1,5-benzoxathiepine; D001582:Benzothiepins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014701:Veratridine