Ranolazine: an Antiischemic Drug with a Novel Mechanism of Action

It has been generally accepted that the primary mechanism of action of antianginal drugs is the improvement of the myocardial oxygen balance between supply and demand in the ischemic heart, by either an increase in coronary flow or a decrease in cardiac mechanical function, or both. Therefore, nitrates, b-adrenoceptor antagonists, and Ca channel blockers, which are thought to improve the myocardial oxygen balance through changes in hemodynamic parameters, have been widely used to treat patients with ischemic heart disease. Ranolazine (RS-43285) is a piperazine derivative developed by Syntex Laboratories (Edinburgh, UK). In 1987, Allely et al. (3) found that ranolazine attenuated metabolic derangements of the myocardium that were induced by the occlusion of the coronary artery in dogs. Subsequently, the antiischemic action of ranolazine has been demonstrated in both in vivo (2) and in vitro (14,23,24,45) animal studies. Clinical findings suggest that ranolazine is an orally active agent that is useful for therapy of angina pectoris (16,33, 54,59). Interestingly, the antiischemic (14,23,24,45) or antianginal action (16,33,53,59) of ranolazine can be produced without any detectable alterations in hemodynamics, and therefore the pharmacological property of ranolazine differes from that of nitrates, b-adrenoceptor antagonists, and Ca channel blockers. Recent studies have demonstrated that the cardioprotective action of ranolazine is associated with the modulation of the myocardial metabolism (15,45,46). Ranolazine may, therefore, belong to a new group of antiischemic drugs. In the present review, we outline the pharmacological profile of ranolazine and discuss the mechanism of the antiischemic (or antianginal) action of the drug. A preceding review has been published by McCormack et al. (46).