A Review on Role of the Calcium Sensitive Inotropic Agent, Levosimendan and Its Metabolites

Levosimendan is a pyridazinone-dinitrile derivative, emerged as a potent cardiotonic agent with dual inotropic and vasodilator activities in higher animals. This is a calcium (Ca2+) sensitizing cardiotonic agent, which has been shown to exert positive inotropic effects without increasing intracellular Ca2+ transient. This avoids Ca2+ overload that leads to arrhythmias and myocyte injuries, and do not increase the energy consumption for handling Ca2+ and has shown good activity against congestive heart failure (CHF), due to its increased myocardial contractility by stabilizing the calcium bound conformation of troponin C. Levosimendan also acts as a pulmonary and systemic vasodilator. The combination of positive inotropic and vasodilator activity has been beneficial in increasing cardiac output and decreasing left ventricular end-diastolic pressure, pulmonary wedge pressure, right atrial pressure, and systemic vascular resistance in CHF patients. The cardiac target protein of levosimendan and troponin C, is Ca2+-binding protein. This raises the possibility that levosimendan may interact with smooth muscle proteins, such as, calmodulin, and regulatory myosin light chains. Levosimendan relaxes coronary arteries and lowers Ca2+. The lowering of Ca2+ by levosimendan is consistent with opening of K+ channels and causes relaxation that is independent of Ca2+. However, most of the Ca2+ sensitizers may impair cardiac diastolic function as a result of increased Ca2+ sensitivity of the myofilaments. Levosimendan has not only improved the cardiac systolic function but also the diastolic relaxation in CHF.