n-(4-(4-methyl-6-oxo-1-4-5-6-tetrahydropyridazin-3-yl)phenyl)acetamide and Hypertension

Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone are reported. An effect of substitution at 2-position of pyridazinone ring on vasodilatory potential has also been explored. The most active compound 6-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-2-(4-fluorophenyl)-4,5-dihydropyridazin-3(2H)-one (11) exhibited vasodilating activity in nanomolar range (IC(50)=0.051 microM).

Topics: Animals; Aorta; Female; Hydrazines; Hypertension; Male; Pyridazines; Rats; Rats, Wistar; Structure-Activity Relationship; Vasodilation; Vasodilator Agents

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.

Topics: Acetamides; Albuminuria; Animals; Blood Pressure; Calcium; Cardiomegaly; Cardiotonic Agents; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Dose-Response Relationship, Drug; Echocardiography; Heart Rate; Hypertension; Kidney; Male; Myocardium; Pyridazines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Survival Analysis; Ventricular Remodeling