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

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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 1 Pg. 142-52 (May 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20412071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Biomarkers
• N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide
• Pyridazines
• Tetrazoles
• Vasodilator Agents
• Valsartan
• Valine

Topics

• Acetamides (pharmacology, therapeutic use)
• Animals
• Biomarkers (metabolism)
• Cardiac Volume (drug effects)
• Cellular Senescence
• 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)
• Valsartan
• Vasodilator Agents (therapeutic use)
• Ventricular Pressure (drug effects)