Disease relevance of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• Whether MCI-154 has beneficial effects on left ventricular dysfunction in chronic heart failure is not known [1].
• And 10(-4) mol/L of MCI-154 reversed the desensitization effect induced by either acidosis (pH 6.8), low temperature (15 degrees C), or the addition of inorganic phosphate (10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)[2]
• The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow [3].
• We studied the inotropic and lusitropic responses to MCI-154 in 12 right or left ventricular trabeculae carneae isolated from 7 organ donors (non-cardiac) without known cardiovascular disease who met accepted criteria for brain death [4].
• Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs [3].

High impact information on 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• BACKGROUND: MCI-154 is a positive inotropic agent that increases the myofilament response to Ca2+ [1].
• In heart failure, left ventricular contractility as assessed by shifts of the end-systolic pressure-volume ratio, evaluated by inferior vena cava occlusion, was improved by MCI-154 (+ 1.94 mm Hg/mL, P < .05) to an extent similar to that in the control state (+2.47 mm Hg/mL, P < .05) [1].
• Left cineventriculograms with simultaneous left ventricular pressures (tip manometer) were obtained before and during intravenous administration of MCI-154 (I.O. microgram.kg-1.min-1 for 15 minutes) in the control and heart-failure states [1].
• MCI-154 (6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)pyridazinone hydrochloride trihydrate) is a potent novel cardiotonic agent whose positive inotropism is shown to be mainly based on an increase in Ca2+ sensitivity of the contractile apparatus [2].
• Consequently, the oxygen cost of contractility (delta PVA-independent Vo2/delta Emax) was less with MCI-154 than with dobutamine (0.14 +/- 0.18 vs. 1.10 +/- 0.80 J/mm Hg per ml per m2, p < 0.05) [5].

Chemical compound and disease context of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• Beneficial effect of MCI-154, a cardiotonic agent, on ischemic contractile failure and myocardial acidosis of dog hearts: comparison with dobutamine, milrinone and pimobendan [6].
• Beneficial effects of a Ca2+ sensitizer, MCI-154, on the myocardial oxygen consumption-cardiac output relation in patients with left ventricular dysfunction after myocardial infarction: comparison with dobutamine and phosphodiesterase inhibitor [7].
• The objectives of this study were to investigate the effects of 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate (MCI-154), a newly developed cardiotonic agent, on vascular reactivity and contractile responses to extracellular Ca2+ ([Ca2+]o) after hemorrhagic shock and primarily explore its mechanism [8].
• The results showed that the NE-induced pressor response after hemorrhagic shock was significantly decreased (P<0.01), and MCI-154 made it decrease further [8].
• The alleviation of the postischemic contractile dysfunction by MCI-154 was augmented when the animals were treated with a bous injection of enalapril (0.3 mg/kg) 15 min before ischemia followed by an infusion of the drug (0.003 mg/kg/min) [9].

Biological context of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• MCI-154 at concentrations of 10 and 100 microM increased the action potential duration (APD) in left atria stimulated at 0.5 Hz [10].
• The present results suggest that MCI-154 would be an ideal Ca2+ sensitizing agent that enhances force during systole without impairing diastolic function [11].
• MCI-154 decreased LV end-diastolic pressure and systemic blood pressure [3].
• The effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure (an index of total body venous tone), total peripheral resistance and the heart were examined in anesthetized dogs [12].
• MCI-154 increased cardiac output and decreased myocardial oxygen consumption [7].

Anatomical context of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• In single right atrial myocytes, MCI-154 at concentrations of 10 and 100 microM failed to increase the inward L-type Ca2+ current, but decreased the delayed rectifier K+ current (IK) in a concentration-dependent manner [10].
• In sinoatrial node preparations MCI-154 at a concentration of 100 microM produced a negative chronotropic response and prolonged APD [10].
• Inotropic and lusitropic effects of MCI-154 (6-[4-(4- pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) on human myocardium [4].
• Increase in Ca++ sensitivity of the contractile system by MCI-154, a novel cardiotonic agent, in chemically skinned fibers from the guinea pig papillary muscles [13].
• In myofibrils and reconstituted actomyosin, MCI-154 (10(-7) to 10(-4) M) caused a parallel shift of the pCa-ATPase activity relation curve to the left without affecting the maximum activity, suggesting an increase in Ca++ sensitivity [14].

Associations of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one with other chemical compounds

• We investigated the effects of MCI-154, a positive inotropic agent that increases the myofilament response to Ca++, on Ca++ transients, left ventricular (LV) function and phosphodiesterase (PDE) III activity of guinea pig heart, and compared them with the effects of pimobendan and milrinone [15].
• Potent stimulation of myofilament force and adenosine triphosphatase activity of canine cardiac muscle through a direct enhancement of troponin C Ca++ binding by MCI-154, a novel cardiotonic agent [14].
• However, unlike MCI-154, nitroglycerin did not alter cardiac output and right atrial pressure [12].
• In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone [16].
• ACh-induced relaxations of guinea-pig femoral artery preparations precontracted with high-K were not affected by MCI-154 [17].

Gene context of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• Mg-ATPase and Ca+ activated myosin AtPase activity in ventricular myofibrils from non-failing and diseased human hearts--effects of calcium sensitizing agents MCI-154, DPI 201-106, and caffeine [18].
• Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2 were assessed before and after infusion of MCI-154 or dobut-amine [5].
• MCI-154 increased myofibrillar ATPase Ca2+ sensitivity in myofibrils from non-failing and failing human hearts [18].
• These results indicate that the Ca2+ sensitizer MCI-154 could reverse the contractile failure induced by Pi and/or acidic pH in a skinned fiber preparation via modulation of the strong crossbridge reaction with myosin [19].
• We wished to elucidate the effects of the calcium-sensitizing positive inotropic agent MCI-154 and its combined use with an angiotensin-converting enzyme (ACE) inhibitor enalapril on postischemic contractile dysfunction [9].

Analytical, diagnostic and therapeutic context of 6-[4-(pyridin-4-ylamino)phenyl]-4,5-dihydro-2H-pyridazin-3-one

• We investigated the effect of a new Ca++ sensitizer, MCI-154, which is known to increase myofibrillar Ca++ sensitivity and maximal Ca(++)-activated force, on Ca++ transients and left ventricular (LV) function in indo-1-loaded Langendorff guinea plg hearts subjected to a reduction in coronary perfusion pressure from 80 to 40 mm Hg [20].
• The titration of MCI-154 to bovine cardiac troponin C (TnC) resulted in a concentration-dependent change in intrinsic fluorescence, indicating that MCI-154 may induce conformational changes and perturb the microenvironments of the intrinsic fluorophores [21].
• MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion [22].
• The cumulative survival times in the two MCI-154 treated groups were significantly prolonged in comparison with that in the control group (P < 0.0001) [23].
• The intravenous infusion of MCI-154 (0.1 or 0.3 micrograms/kg/min) initiated 10 min after occlusion and throughout reperfusion significantly improved the recovery of segment shortening [9].

References