title: Effects of the calcium sensitizer OR-1896, a metabolite of levosimendan, on post-infarct heart failure and cardiac remodelling in diabetic Goto-Kakizaki rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  Oral treatment with calcium sensitizer OR-1896 protects against post-infarct heart failure and cardiac remodelling in experimental model of type II diabetes.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Marjut
authors.initials: M
authors.lastname: Louhelainen
authors.forename: Saara
authors.initials: S
authors.lastname: Merasto
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.forename: Erik
authors.initials: E
authors.lastname: Vahtola
authors.forename: Petri
authors.initials: P
authors.lastname: Kaheinen
authors.forename: Jouko
authors.initials: J
authors.lastname: Levijoki
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002306:Cardiac Volume / Q000187:drug effects; D016922:Cellular Senescence; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D013777:Tetrazoles / Q000627:therapeutic use; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068756:Valsartan; D014665:Vasodilator Agents / Q000627:therapeutic use; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000081:Acetamides; D015415:Biomarkers; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D013777:Tetrazoles; D014665:Vasodilator Agents; D000068756:Valsartan; D014633:Valine
references.citation: J Cardiovasc Pharmacol. 1995;26 Suppl 1:S57-62
references.pmid: 8907132
references.citation: Nat Cell Biol. 2008 Jul;10(7):825-36
references.pmid: 18516091
references.citation: Clin Pharmacokinet. 2007;46(7):535-52
references.pmid: 17596101
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H238-48
references.pmid: 17982006
references.citation: Br J Pharmacol. 2008 May;154(1):41-50
references.pmid: 18297097
references.citation: Cardiovasc Drugs Ther. 2006 Apr;20(2):123-7
references.pmid: 16554965
references.citation: J Hypertens. 2009 Oct;27(10):2094-107
references.pmid: 19730126
references.citation: J Pharmacol Exp Ther. 1999 Jan;288(1):316-25
references.pmid: 9862786
references.citation: Br J Pharmacol. 2006 Jul;148(5):696-702
references.pmid: 16715115
references.citation: J Biol Chem. 2001 Mar 23;276(12):9337-43
references.pmid: 11113122
references.citation: Rejuvenation Res. 2008 Apr;11(2):523-6
references.pmid: 18341427
references.citation: J Cardiovasc Pharmacol. 1995 May;25(5):794-801
references.pmid: 7630157
references.citation: Circ J. 2008 Dec;72(12):1915-25
references.pmid: 18981594
references.citation: Lung Cancer. 2009 Mar;63(3):348-53
references.pmid: 18656278
references.citation: Eur J Heart Fail. 2008 Dec;10(12):1246-54
references.pmid: 18945637
references.citation: Biochem Pharmacol. 2004 Sep 1;68(5):807-12
references.pmid: 15294443
references.citation: Eur J Pharmacol. 2001 May 11;419(2-3):243-8
references.pmid: 11426847
references.citation: Circ Res. 2006 Jul 7;99(1):42-52
references.pmid: 16763167
references.citation: Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H1775-84
references.pmid: 12384454
references.citation: Eur J Pharmacol. 2000 Jul 14;400(1):103-12
references.pmid: 10913591
references.citation: Mol Cell. 2000 Sep;6(3):729-35
references.pmid: 11030352
references.citation: Diabetes. 1999 Dec;48(12):2463-70
references.pmid: 10580437
references.citation: Drugs. 2003;63(23):2651-71
references.pmid: 14636085
references.citation: Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2002-7
references.pmid: 14525795
references.citation: Hypertension. 2008 Jul;52(1):123-9
references.pmid: 18504326
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2002 Nov;366(5):440-8
references.pmid: 12382073
references.citation: J Physiol. 2003 Sep 1;551(Pt 2):491-501
references.pmid: 12824444
references.citation: Circulation. 2003 Jan 7;107(1):81-6
references.pmid: 12515747
references.citation: Curr Opin Lipidol. 2007 Oct;18(5):515-20
references.pmid: 17885421
references.citation: Physiol Genomics. 2005 Feb 10;20(3):256-67
references.pmid: 15623567
references.citation: Circ Res. 1979 Apr;44(4):503-12
references.pmid: 428047
references.citation: J Pharmacol Exp Ther. 2008 Apr;325(1):331-40
references.pmid: 18171907
references.citation: Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2726-31
references.pmid: 11356629
references.citation: Eur J Pharmacol. 2004 Feb 13;486(1):67-74
references.pmid: 14751410
references.citation: Cardiovasc Res. 2005 Feb 15;65(3):609-18
references.pmid: 15664387
references.citation: Br J Pharmacol. 2007 Apr;150(7):851-61
references.pmid: 17325658
references.citation: J Cell Biol. 2003 Jul 21;162(2):173-83
references.pmid: 12860972
references.citation: Circ Res. 2008 Nov 21;103(11):1191-3
references.pmid: 19028915
references.citation: J Cardiovasc Pharmacol. 2009 Apr;53(4):302-10
references.pmid: 19276987
references.citation: Hypertension. 2001 Feb;37(2 Pt 2):433-9
references.pmid: 11230314
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):703-13
references.pmid: 17717515
references.citation: J Hypertens. 2008 Feb;26(2):334-44
references.pmid: 18192848