Hypertension is the key risk factor for myocardial infarction, stroke and development of heart failure (1). Although the molecular mechanisms underlying the transition of cardiac hypertrophy to heart failure in hypertension remain partly unclear recent evidence suggests an important role for mechanical overload, neurohormonal factors and cytokine pathways leading to structural remodeling in the pathogenesis of hypertensive heart disease (2). In patients with decompensated heart failure classic inotropic agents such as beta-adrenergic agonists and phosphodiesterase III inhibitors provide usually short-term hemodynamic benefits, however, their long-term use has been correlated with poor survival rates (3). Calcium sensitizers comprise a new drug class that may offer hemodynamic and symptomatic improvements without increasing cAMP and intracellular calcium concentrations (4, 5). It has been suggested that calcium sensitizers could enhance contractility without a concurrent increase in the risk of cardiac events and thus may represent a significant improvement over classic positive inotropic agents. However, the clinical data so far are still controversial. We have shown recently using a widely used animal model for hypertensive heart disease, namely Dahl salt-sensitive rat on a high salt diet (6, 7) that chronic oral treatment with levosimendan is associated with improved outcome and amelioration of hypertensive myocardial remodeling (8). As compared with other calcium sensitizers levosimendan has a dual action; it is an inodilator acting both via calcium sensitization and opening of ATP-dependent potassium channels in the vasculature. OR-1896 (the (-) enantiomer of N[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl] acetamide) is a biologically active metabolite of levosimendan. OR-1896 has been studied to a lesser extent than the parent compound; however, preliminary data suggest that OR-1896 exerts similar hemodynamical and pharmacological properties as levosimendan (9, 10). The aim of the present study was to investigate whether OR-1896 could prevent cardiovascular mortality and hypertension-induced myocardial remodelling in salt-sensitive Dahl/Rapp rats. Furthermore, as Westhoff et al. showed very recently that hypertension may induce cardiomyocyte senescence (11), the effects of levosimendan on markers of cardiomyocyte aging were also evaluated.
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