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Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization

Sorsa, T; Pollesello, P; Rosevear, PR; Drakenberg, Torbjörn LU and Kilpelainen, L (2004) In European Journal of Pharmacology 486(1). p.1-8
Abstract
The effects of the Ca2+ sensitizer levosimendan and that of its stereoisomer dextrosimendan on the cardiac contractile apparatus were studied using skinned fibers obtained from guinea pig hearts. Levosimendan was found to be more effective than dextrosimendan in this model. The respective concentrations of levosimendan and dextrosimendan at EC50 were 0.3 and 3 muM. In order to explain the difference in efficacy as Ca2+ sensitizers, the binding of the two stereoisomers on cardiac troponin C was studied by nuclear magnetic resonance in the absence and presence of two peptides of cardiac troponin I. The two stereoisomers interacted with both domains of cardiac troponin C in the absence of cardiac troponin I. In the presence of cardiac... (More)
The effects of the Ca2+ sensitizer levosimendan and that of its stereoisomer dextrosimendan on the cardiac contractile apparatus were studied using skinned fibers obtained from guinea pig hearts. Levosimendan was found to be more effective than dextrosimendan in this model. The respective concentrations of levosimendan and dextrosimendan at EC50 were 0.3 and 3 muM. In order to explain the difference in efficacy as Ca2+ sensitizers, the binding of the two stereoisomers on cardiac troponin C was studied by nuclear magnetic resonance in the absence and presence of two peptides of cardiac troponin I. The two stereoisomers interacted with both domains of cardiac troponin C in the absence of cardiac troponin I. In the presence of cardiac troponin I-(32-79) and cardiac troponin I-(128-180), the binding of both levosimendan and dextrosimendan to the C-terminal domain of cardiac troponin C was blocked and only the binding to the N-terminal domain was observable. Differences in the overall binding behavior of the two isomers to cardiac troponin C were highlighted in order to discuss their structure to activity relation. Our data are consistent with the notion that the action of levosimendan as a Ca2+ sensitizer and positive inotrope relates to its stereoselective binding to Ca2+-saturated cardiac troponin C. (C) 2003 Elsevier B.V. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cardiac troponin C, Levosimendan, NMR (nuclear magnetic resonance), Drug interaction
in
European Journal of Pharmacology
volume
486
issue
1
pages
1 - 8
publisher
Elsevier
external identifiers
  • pmid:14751401
  • wos:000188712700001
  • scopus:1642563971
ISSN
1879-0712
DOI
10.1016/j.ejphar.2003.12.006
language
English
LU publication?
yes
id
1947198d-143e-4030-99e0-b90acc3da115 (old id 141098)
date added to LUP
2007-06-29 14:25:49
date last changed
2017-02-26 03:40:35
@article{1947198d-143e-4030-99e0-b90acc3da115,
  abstract     = {The effects of the Ca2+ sensitizer levosimendan and that of its stereoisomer dextrosimendan on the cardiac contractile apparatus were studied using skinned fibers obtained from guinea pig hearts. Levosimendan was found to be more effective than dextrosimendan in this model. The respective concentrations of levosimendan and dextrosimendan at EC50 were 0.3 and 3 muM. In order to explain the difference in efficacy as Ca2+ sensitizers, the binding of the two stereoisomers on cardiac troponin C was studied by nuclear magnetic resonance in the absence and presence of two peptides of cardiac troponin I. The two stereoisomers interacted with both domains of cardiac troponin C in the absence of cardiac troponin I. In the presence of cardiac troponin I-(32-79) and cardiac troponin I-(128-180), the binding of both levosimendan and dextrosimendan to the C-terminal domain of cardiac troponin C was blocked and only the binding to the N-terminal domain was observable. Differences in the overall binding behavior of the two isomers to cardiac troponin C were highlighted in order to discuss their structure to activity relation. Our data are consistent with the notion that the action of levosimendan as a Ca2+ sensitizer and positive inotrope relates to its stereoselective binding to Ca2+-saturated cardiac troponin C. (C) 2003 Elsevier B.V. All rights reserved.},
  author       = {Sorsa, T and Pollesello, P and Rosevear, PR and Drakenberg, Torbjörn and Kilpelainen, L},
  issn         = {1879-0712},
  keyword      = {Cardiac troponin C,Levosimendan,NMR (nuclear magnetic resonance),Drug interaction},
  language     = {eng},
  number       = {1},
  pages        = {1--8},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmacology},
  title        = {Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization},
  url          = {http://dx.doi.org/10.1016/j.ejphar.2003.12.006},
  volume       = {486},
  year         = {2004},
}