The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin c.
Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increases. Effective treatments are being sought and recently a new class of drugs, the calcium sensitisers, was developed. These drugs cause a positive inotropic effect on cardio-myocytes by interacting directly with the contractile apparatus. Their mechanism of action is not accompanied by an increase in intracellular calcium concentration at therapeutic doses, as seen for the older generation of positive inotropic drugs, and thus does not induce calcium-related deleterious effects such as arrhythmias or apoptosis. Levosimendan is a novel calcium sensitiser which has been discovered by using cardiac troponin C (cTnC) as target protein. This drug has been proved to be a well-tolerated and effective treatment for patients with severe decompensated heart failure. This review describes the basic principles of muscle contraction, the main components of the contractile apparatus and their roles in the heart contraction. The regulatory proteins troponin C (cTnC), troponin I (cTnI), troponin T (cTnT), and tropomyosin (Tm) and their interactions are discussed in details. The concept of calcium sensitisation is thereafter explained and a few examples of calcium sensitisers and their putative mechanisms are discussed. Finally, the binding of levosimendan to cTnC and its mechanism of action are described and the results discussed under the light of the action of this drug in vitro and in vivo.
Sorsa
Tia
T
Orion Pharma, Cardiovascular Research, Espoo, Finland.
Pollesello
Piero
P
Solaro
R John
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000378:metabolism* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D006835:Hydrazones / Q000378:metabolism* / Q000627:therapeutic use; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D011724:Pyridazines / Q000378:metabolism* / Q000627:therapeutic use; D000077464:Simendan; D014335:Tropomyosin / Q000737:chemistry / Q000378:metabolism; D019209:Troponin C / Q000737:chemistry / Q000378:metabolism*; D019210:Troponin I / Q000737:chemistry / Q000378:metabolism; D020107:Troponin T / Q000737:chemistry / Q000378:metabolism
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014335:Tropomyosin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D000077464:Simendan; D002118:Calcium