Effects of calcium sensitizer OR-1986 on a cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats.
Calcium-sensitizing agents have been shown to improve cardiac function in patients suffering from acute decompensated heart failure, however, their long-term effects on cardiac remodeling and cardiovascular mortality are still largely unknown. In the present study we tested the hypothesis whether OR-1896, an active and long-lasting metabolite of calcium sensitizer levosimendan, prevents cardiovascular mortality and hypertension-induced myocardial remodelling in salt-sensitive Dahl/Rapp rats. OR-1896 was given orally to Dahl/Rapp SS rats on high-salt diet (NaCl 7% w/w) for 7 weeks at two different doses (0.5 and 0.05 mg/kg). OR-1896 prevented salt-induced cardiovascular mortality (survival rate 75 % in OR-1896 treated groups vs 38 % in untreated controls, p<0.01), ameliorated cardiac hypertrophy and improved systolic functions of the heart without major influence on systemic blood pressure. OR-1896 also ameliorated salt-induced increase in cardiac ANP mRNA expression and plasma BNP level. Salt-induced cardiac remodelling was associated with 4-fold increase in cardiac p16(INK4a) mRNA expression, a marker of cellular senescence. OR-1896 dose-dependently ameliorated cardiomyocyte senescence. Our findings suggest a therapeutic role for OR-1896 in the prevention of cardiac remodelling in salt-sensitive forms of hypertension. The present study also underscores the importance of cellular senescence in the pathogenesis of salt-induced hypertensive heart disease.
Louhelainen
M
M
Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
Merasto
S
S
Finckenberg
P
P
Vahtola
E
E
Kaheinen
P
P
Leskinen
H
H
Levijoki
J
J
Pollesello
P
P
Haikala
H
H
Mervaala
E M A
EM
D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000419:Albuminuria / Q000652:urine; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011724:Pyridazines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D016019:Survival Analysis; D020257:Ventricular Remodeling / Q000187:drug effects*
D000081:Acetamides; D002316:Cardiotonic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D017673:Sodium Chloride, Dietary; D002118:Calcium