Molecular actions of drugs that sensitize cardiac myofilaments to Ca²⁺

Ca²⁺-sensitizers are inotropic agents that modify the response of myofilaments to Ca²⁺, and are potentially valuable drugs in the treatment of heart failure. These agents have diverse chemical structures, and in some cases also have effects as inhibitors of phosphodiesterase activity. Advantages of their actions include vasodilation combined with inotropic effects. Reduction in the amounts of Ca²⁺ required to activate the myofilaments also lowers the oxygen consumption required for Ca²⁺ transport, lowers the threat of arrhythmias, and may blunt Ca²⁺-dependent transcriptional and translational mechanisms leading to hypertrophy and failure. Although diastolic abnormalities and impaired relaxation were thought to be potential undesirable effects of Ca²⁺-sensitizers, studies of hearts beating in situ indicate that this may not be a major problem. We focus here on Ca²⁺-sensitizers that act on cardiac troponin C, the Ca²⁺ receptor that triggers activation of the actin-myosin interaction. Structural studies have identified a unique mode of Ca²⁺ signaling in cardiac troponin C that should aid in targeting drugs to the heart. Moreover, identification of docking sites of Ca²⁺-sensitizers on troponin C suggest new directions for rational drug design.