Document Detail

Mechanisms of action of calcium-sensitizing drugs.
MedLine Citation:
PMID:  8907127     Owner:  NLM     Status:  MEDLINE    
This review compares the mechanisms of action of the calcium-sensitizing agents levosimendan, pimobendan, MCI-154, and EMD 53998. By using purified human recombinant troponin-C (cTnC), the role of cTnC as a target protein for these compounds was investigated. Accordingly, the calcium-dependent binding to cTnC in a cTnC-high-performance liquid affinity chromatography (HPLAC) column and the stabilizing effects of the compounds on the calcium-induced conformation of dansylated cTnC were studied. Only levosimendan showed calcium-dependent action on cTnC. Of the studied compounds, levosimendan was the most potent calcium sensitizer in skinned fiber experiments. Furthermore, EMD 53998 and MCI-154, but not levosimendan and pimobendan, increased myosin ATPase activity, indicating that they may enhance the cycling rate of myosin-actin crossbridges. By analyzing the velocity (dT/dt) of isometric tension development in paced papillary muscles, it was shown that levosimendan probably enhances the association rate but decreases the dissociation rate of myosin-actin crossbridges. These effects occurred before the peak twitch tension was achieved. Therefore, levosimendan does not seem to affect the actual relaxation phase. The other calcium sensitizers, however, appear to act mainly by decreasing the dissociation rate of crossbridges. The weak calcium-sensitizing effect of pimobendan may be based on indirectly mediated increase in affinity of cTnC for calcium. MCI-154 might act in a similar way but, like EMD 53998, MCI-154 also acts on myosin-actin crossbridges. We suggest that levosimendan binds in a calcium-dependent manner to the N-terminal domain of cTnC, which magnifies the extent of the contraction produced by cTnC when it is calcium-activated.
H Haikala; I B Linden
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Publication Detail:
Type:  Comparative Study; Journal Article; Review    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  26 Suppl 1     ISSN:  0160-2446     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  1995  
Date Detail:
Created Date:  1997-03-05     Completed Date:  1997-03-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  S10-9     Citation Subset:  IM    
Orion-Farmos, Orion Research, Espoo, Finland.
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MeSH Terms
Calcium / metabolism,  physiology*
Cardiotonic Agents / pharmacology*
Hydrazones / pharmacology
Myocardial Contraction / drug effects
Pyridazines / pharmacology
Quinolines / pharmacology
Sensitivity and Specificity
Thiadiazines / pharmacology
Troponin C / metabolism,  physiology
Reg. No./Substance:
0/Cardiotonic Agents; 0/Hydrazones; 0/Pyridazines; 0/Quinolines; 0/Thiadiazines; 0/Troponin C; 120223-04-3/EMD 53998; 131741-08-7/simendan; 74150-27-9/pimobendan; 7440-70-2/Calcium; 98326-33-1/MCI 154

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