Effects of the calcium sensitizer OR-1896, a metabolite of levosimendan, on post-infarct heart failure and cardiac remodelling in diabetic Goto-Kakizaki rats.
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.
Louhelainen
Marjut
M
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
Merasto
Saara
S
Finckenberg
Piet
P
Vahtola
Erik
E
Kaheinen
Petri
P
Levijoki
Jouko
J
Mervaala
Eero
E
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
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
J Cardiovasc Pharmacol. 1995;26 Suppl 1:S57-62
8907132
Nat Cell Biol. 2008 Jul;10(7):825-36
18516091
Clin Pharmacokinet. 2007;46(7):535-52
17596101
Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H238-48
17982006
Br J Pharmacol. 2008 May;154(1):41-50
18297097
Cardiovasc Drugs Ther. 2006 Apr;20(2):123-7
16554965
J Hypertens. 2009 Oct;27(10):2094-107
19730126
J Pharmacol Exp Ther. 1999 Jan;288(1):316-25
9862786
Br J Pharmacol. 2006 Jul;148(5):696-702
16715115
J Biol Chem. 2001 Mar 23;276(12):9337-43
11113122
Rejuvenation Res. 2008 Apr;11(2):523-6
18341427
J Cardiovasc Pharmacol. 1995 May;25(5):794-801
7630157
Circ J. 2008 Dec;72(12):1915-25
18981594
Lung Cancer. 2009 Mar;63(3):348-53
18656278
Eur J Heart Fail. 2008 Dec;10(12):1246-54
18945637
Biochem Pharmacol. 2004 Sep 1;68(5):807-12
15294443
Eur J Pharmacol. 2001 May 11;419(2-3):243-8
11426847
Circ Res. 2006 Jul 7;99(1):42-52
16763167
Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H1775-84
12384454
Eur J Pharmacol. 2000 Jul 14;400(1):103-12
10913591
Mol Cell. 2000 Sep;6(3):729-35
11030352
Diabetes. 1999 Dec;48(12):2463-70
10580437
Drugs. 2003;63(23):2651-71
14636085
Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2002-7
14525795
Hypertension. 2008 Jul;52(1):123-9
18504326
Naunyn Schmiedebergs Arch Pharmacol. 2002 Nov;366(5):440-8
12382073
J Physiol. 2003 Sep 1;551(Pt 2):491-501
12824444
Circulation. 2003 Jan 7;107(1):81-6
12515747
Curr Opin Lipidol. 2007 Oct;18(5):515-20
17885421
Physiol Genomics. 2005 Feb 10;20(3):256-67
15623567
Circ Res. 1979 Apr;44(4):503-12
428047
J Pharmacol Exp Ther. 2008 Apr;325(1):331-40
18171907
Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2726-31
11356629
Eur J Pharmacol. 2004 Feb 13;486(1):67-74
14751410
Cardiovasc Res. 2005 Feb 15;65(3):609-18
15664387
Br J Pharmacol. 2007 Apr;150(7):851-61
17325658
J Cell Biol. 2003 Jul 21;162(2):173-83
12860972
Circ Res. 2008 Nov 21;103(11):1191-3
19028915
J Cardiovasc Pharmacol. 2009 Apr;53(4):302-10
19276987
Hypertension. 2001 Feb;37(2 Pt 2):433-9
11230314
Nat Rev Mol Cell Biol. 2007 Sep;8(9):703-13
17717515
J Hypertens. 2008 Feb;26(2):334-44
18192848