Anti-ischemic Mechanism of Ranolazine

Anti-ischemic mechanism of ranolazine

Conventional antianginal agents like beta blockers act by reducing myocardial oxygen demand. This could be mediated by reduction of heart rate, blood pressure or myocardial contractility, either at rest or during exercise. But the antianginal action of ranolazine does not involve these hemodynamic mechanisms. Ranolazine has been shown to improve exercise duration, time to angina and time to ST segment depression, both as monotherapy and as part of combination therapy with conventional antianginal agents. Ranolazine is thought to have its antianginal action by preserving myocardial blood flow during ischemia by its effects on inhibition of late sodium current which in turn prevents cellular sodium overload and sequentially calcium overload.

Prevention of calcium overload reduces compression of intramyocardial blood vessels by reducing diastolic myocardial stiffness. Usually the late sodium channels remain open during myocardial ischemia leading to intracellular sodium overload. This extra sodium is extruded by the sodium-calcium exchange mechanism which leads to calcium overload. Calcium overload causes diastolic relaxation failure as the increased calcium ions cause increased tension in contractile elements of the myocyte. Thus the antianginal effect of ranolazine is mediated by a positive lusitropic effect in myocardial ischemia which resets the vicious cycle of ‘ischemia begets ischemia’.

A study by Stone PH and associates [1] showed that ranolazine decreases myocardial ischemia during submaximal and maximal exercise after the onset of ischemic ST depression. The magnitude of ischemia reduction was substantially more than the relatively minor reduction in heart rate or rate pressure product, the important determinants of myocardial oxygen demand. The authors concluded that the mechanism of action of ranolazine is most likely due to an improvement in regional coronary blood flow in areas of myocardial ischemia during submaximal and maximal exercise.

Reference

1. Stone PH, Chaitman BR, Stocke K, Sano J, DeVault A, Koch GG. The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. J Am Coll Cardiol, 2010; 56:934-942.