Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/141098
- author
- Sorsa, T ; Pollesello, P ; Rosevear, PR ; Drakenberg, Torbjörn LU and Kilpelainen, L
- organization
- publishing date
- 2004
- 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
- 2016-04-01 12:31:00
- date last changed
- 2022-03-06 00:38:44
@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}},
keywords = {{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}},
doi = {{10.1016/j.ejphar.2003.12.006}},
volume = {{486}},
year = {{2004}},
}