F15845

Persistent sodium current

In the cardiac myocyte, the persistent sodium current corresponds to the delayed inactivation of the major sodium channel Nav1.5. Under these conditions the heart is more susceptible to damage and malfunctions. Inhibition of the persistent sodium current is a novel therapeutic target to prevent long term changes in the heart resulting from ischemia. Hypoxia, heart failure and oxygen derived free radicals are all factors believed to activate the persistent sodium current. In ischemia, the major damage to the cardiac myocyte, due to hypoxia, is seen following the reperfusion of blood. High intracellular sodium levels from the persistent current results in high influx of calcium during reperfusion; leading to calcium overload, hypercontraction and cardiac myocyte death. The main contributor to this calcium overload is the sodium/calcium exchanger working in reverse, driven by the high intracellular concentration of sodium exchanging out of the cell with the extracellular calcium moving in.

Pharmacology

F15845 has been shown to selectively inhibit the persistent sodium current of Nav1.5 exerting cardioprotective effects following ischemia. In vitro testing showed minimal effects of F15845 on other important ion channels of the heart, including major Ca2+ and K+ channels. This characteristic is thought to account for the limited effect of F15845 to change other heart parameters such as basal cardiac function, hemodynamic functions and ventricular fibrillation. F15845 was also shown to exert improved effects when the membrane potential was depolarized, by acting on the extracellular side of the channel. This effect of the F15845 on the depolarised state of the persistent sodium current renders the drug particularly useful in ischemic conditions when the cardiac cell is depolarised.

F15845 and angina

The F15845 drug has been developed as a potential drug for therapy of angina pectoris.

References

References

1. (January 2009). "F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models". British Journal of Pharmacology.
2. (September 2010). "Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias". British Journal of Pharmacology.
3. (December 2009). "Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig". European Journal of Pharmacology.
4. (September 2009). "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". The Journal of Pharmacology and Experimental Therapeutics.
5. (March 1999). "Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current". Cellular and Molecular Life Sciences.
6. (June 1999). "Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury". Circulation Research.