title: Mechanism of action of Ca2+ sensitizers--update 2001.
abstract: Ca2+ sensitizers act on the central mechanism (Ca2+ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E-C coupling. Ca2+ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca2+ mobilization). Ca2+ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca2+ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca2+ sensitizing effect. No clinically available agents act primarily via Ca2+ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca2+ sensitivity. These agents are the hybrid of Ca2+ sensitizer and PDE III inhibitor. The extent of contribution of Ca2+ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca2+ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.
authors.affiliation: Department of Pharmacology, Yamagata University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Endoh
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002303:Cardiac Output, Low / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D000077464:Simendan
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; C041648:pimobendan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002118:Calcium