Disease relevance of 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one

• We studied the influence of acidosis on the positive inotropic effect of UD-CG 212 Cl (4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), an active metabolite of pimobendan, in canine ventricular trabeculae loaded with aequorin [1].

High impact information on 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one

• In contrast, the demethylated metabolite UD-CG 212 Cl failed to produce positive inotropic effects in failing myocardium alone, but in the presence of isoproterenol, it exerted an increase in force of contraction [2].
• Neither Pi nor UD-CG 212 Cl affected Ca2+ binding to myofilament troponin C (TnC) [3].
• Decrease in Ca(2+)-sensitizing effect of UD-CG 212 Cl, a metabolite of pimobendan, under acidotic condition in canine ventricular myocardium [1].
• UD-CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 mumol l-1) and in ventricular tissue (IC50 value 0.1 mumol l-1) [4].
• In guinea pig papillary muscles, UD-CG 212 Cl increased cAMP and stimulated Ca(++)-dependent slow action potentials (APs) in a dose-dependent manner [5].

Chemical compound and disease context of 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one

• The maximal inotropic effect of UD-CG 212 Cl was 18% of the maximal response to isoproterenol (ISO(max)) in association with an increase in Ca(2+) transients of 7% of ISO(max) in the control, while they are 8 and 6% of ISO(max) under acidosis, respectively [1].

Biological context of 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one

• After beta-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax were attenuated and almost abolished and amounted up to 15% and 20%, respectively [6].
• The effects of UD-CG 212 CL on the renal and skeletal muscle haemodynamics were different from those of pimobendan, which causes vasodilatation in the skeletal muscles but not in the kidneys [7].
• In conclusion, UD-CG 212 Cl has a positive inotropic effect partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted via cross talk with a signal transduction pathway that involves cAMP [8].

Anatomical context of 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one

• In voltage-clamped ventricular myocytes UD-CG 212 Cl (100 microM) could stimulate Ca++ current (+21 +/- 5%) when basal cAMP levels were enhanced with a submaximal dose of isoproterenol (10(-9)-10(-8) M) [5].
• The effect induced by UD-CG-212 CL, was completely abolished after the endocardial endothelium was damaged [9].
• Role of the endocardium in the inotropic action of UD-CG-212 CL [9].
• The vasodilator action of UD-CG 212 CL was noticed in several organs but the effects were relatively more marked (in decreasing order of magnitude) in the adrenals, kidneys, gastrointestinal tract, brain and LV epicardium [7].
• Both pimobendan and UD-CG 212 Cl induced relaxation of porcine coronary artery strips [10].

Associations of 5-methyl-6-[2-(4-oxo-1-cyclohexa-2,5-dienylidene)-1,3-dihydrobenzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one with other chemical compounds

• Reversal of phosphate induced decreases in force by the benzimidazole pyridazinone, UD-CG 212 CL, in myofilaments from human ventricle [11].

References