Document Detail


Effects of the calcium sensitizer OR-1896, a metabolite of levosimendan, on post-infarct heart failure and cardiac remodelling in diabetic Goto-Kakizaki rats.
MedLine Citation:
PMID:  20412071     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Levosimendan is a novel, short half-life calcium sensitizer used as pharmacological inotropic support in acute decompensated heart failure. After oral administration, levosimendan is metabolized to OR-1855, which, in rats, is further metabolized into OR-1896. OR-1896 is a long-lasting metabolite of levosimendan sharing the pharmacological properties of the parent compound.
EXPERIMENTAL APPROACH: Effects of oral OR-1896 treatment on post-infarct heart failure and cardiac remodelling were assessed in diabetic Goto-Kakizaki (GK) rats, an animal model of type II diabetes. Myocardial infarction (MI) was produced to GK rats by coronary ligation. Twenty-four hours after MI or sham operation, the rats were randomized into four groups: (i) MI; (ii) MI + OR-1896 treatment; (iii) sham; and (iv) sham + OR-1896. Cardiac function and markers of cardiac remodelling were assessed 1, 4 and 12 weeks after MI.
KEY RESULTS: OR-1896 increased ejection fraction and fractional shortening in GK rats with MI. OR-1896 ameliorated post-infarct cardiac hypertrophy, and prevented the MI-induced increase in cardiac mRNA for atrial natriuretic peptide, monocyte chemoattractant protein-1 and connective tissue growth factor, markers of pressure/volume overload, inflammation and fibrosis respectively. OR-1896 also suppressed mRNA for senescence-associated p16(INK4A) and p19(ARF). The beneficial effects of OR-1896 were more prominent at week 12 than at week 4. OR-1896 did not influence systolic blood pressure, blood glucose level, myocardial infarct size or cardiovascular mortality.
CONCLUSIONS AND IMPLICATIONS: Oral treatment with calcium sensitizer OR-1896 protects against post-infarct heart failure and cardiac remodelling in experimental model of type II diabetes.
Authors:
Marjut Louhelainen; Saara Merasto; Piet Finckenberg; Erik Vahtola; Petri Kaheinen; Jouko Levijoki; Eero Mervaala
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  160     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-23     Completed Date:  2010-07-26     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  142-52     Citation Subset:  IM    
Affiliation:
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
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MeSH Terms
Descriptor/Qualifier:
Acetamides / pharmacology*,  therapeutic use
Animals
Biological Markers / metabolism
Cardiac Volume / drug effects
Cell Aging
Diabetes Mellitus, Type 2 / complications,  drug therapy*,  physiopathology
Fibrosis
Heart Failure / drug therapy*,  etiology,  physiopathology
Inflammation / metabolism
Mitochondria, Heart / metabolism
Myocardial Infarction / etiology*,  pathology,  physiopathology
Myocytes, Cardiac / drug effects,  pathology
Pyridazines / pharmacology*,  therapeutic use
Random Allocation
Rats
Tetrazoles / therapeutic use
Time Factors
Valine / analogs & derivatives,  therapeutic use
Vasodilator Agents / therapeutic use
Ventricular Pressure / drug effects
Chemical
Reg. No./Substance:
0/Acetamides; 0/Biological Markers; 0/N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; 0/Pyridazines; 0/Tetrazoles; 0/Vasodilator Agents; 137862-53-4/valsartan; 7004-03-7/Valine
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