| Abstract | 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. |
| Authors | M Louhelainen, S Merasto, P Finckenberg, E Vahtola, P Kaheinen, H Leskinen, J Levijoki, P Pollesello, H Haikala, E M A Mervaala
(Affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.)
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| Journal | Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
(J Physiol Pharmacol)
Vol. 60
Issue 3
Pg. 41-7
(Sep 2009)
ISSN: 1899-1505 [Electronic] Poland |
| PMID | 19826180
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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