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Chemical Compound Review

MCI-154     6-[4-(pyridin-4- ylamino)phenyl]-4,5...

Synonyms: CHEMBL543966, SureCN4519202, MCI 154, AC1L3XLD, AC1Q6NVI, ...
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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

 

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

 

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

  1. Effects of MCI-154, a calcium sensitizer, on left ventricular systolic and diastolic function in pacing-induced heart failure in the dog. Teramura, S., Yamakado, T., Maeda, M., Nakano, T. Circulation (1997) [Pubmed]
  2. MCI-154 increases Ca2+ sensitivity of reconstituted thin filament. A study using a novel in vitro motility assay technique. Sata, M., Sugiura, S., Yamashita, H., Fujita, H., Momomura, S., Serizawa, T. Circ. Res. (1995) [Pubmed]
  3. 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. Abe, Y., Kitada, Y., Narimatsu, A. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  4. Inotropic and lusitropic effects of MCI-154 (6-[4-(4- pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) on human myocardium. Warren, S.E., Kihara, Y., Pesaturo, J., Gwathmey, J.K., Phillips, P., Morgan, J.P. J. Mol. Cell. Cardiol. (1989) [Pubmed]
  5. Oxygen-saving effect of a new cardiotonic agent, MCI-154, in diseased human hearts. Mori, M., Takeuchi, M., Takaoka, H., Hata, K., Hayashi, Y., Yamakawa, H., Yokoyama, M. J. Am. Coll. Cardiol. (1997) [Pubmed]
  6. Beneficial effect of MCI-154, a cardiotonic agent, on ischemic contractile failure and myocardial acidosis of dog hearts: comparison with dobutamine, milrinone and pimobendan. Abe, Y., Kitada, Y., Narimatsu, A. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  7. 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. Takaoka, H., Takeuchi, M., Hata, K., Hayashi, Y., Mori, M., Yamakawa, H., Yamaguchi, K., Yokoyama, M. Am. Heart J. (1997) [Pubmed]
  8. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. Yang, G., Liu, L., Xu, J., Li, T. J. Cardiovasc. Pharmacol. (2006) [Pubmed]
  9. Effect of a calcium-sensitizing positive inotropic agent MCI-154 and its combined use with enalapril on postischemic contractile dysfunction of dog hearts. Abe, Y., Kitada, Y., Narimatsu, A. J. Cardiovasc. Pharmacol. (1995) [Pubmed]
  10. Preferential inhibition of Ikr by MCI-154, a putative cardiotonic Ca2+ sensitizer, in guinea pig atrial cells. Eto, K., Hashimoto, K., Nakaya, H. Cardiovasc. Res. (1998) [Pubmed]
  11. Lusitropic effects of a Ca2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts. Mori, M., Takeuchi, M., Takaoka, H., Yokoyama, M. Cardiovasc. Res. (1995) [Pubmed]
  12. Effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure in anesthetized dogs. Satoh, N., Abe, Y., Kitada, Y., Narimatsu, A., Tobe, A. Eur. J. Pharmacol. (1990) [Pubmed]
  13. 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. Kitada, Y., Narimatsu, A., Matsumura, N., Endo, M. J. Pharmacol. Exp. Ther. (1987) [Pubmed]
  14. 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. Kitada, Y., Kobayashi, M., Narimatsu, A., Ohizumi, Y. J. Pharmacol. Exp. Ther. (1989) [Pubmed]
  15. Calcium sensitization in perfused beating guinea pig heart by a positive inotropic agent MCI-154. Abe, Y., Ishisu, R., Onishi, K., Sekioka, K., Narimatsu, A., Nakano, T. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  16. The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs. Takahashi, S., Cho, S., Hara, T., Ureshino, H., Tomiyasu, S., Sumikawa, K. Anesth. Analg. (2004) [Pubmed]
  17. Inhibitory actions of MCI-154 on guinea-pig femoral artery and vein preparations. Suh, S.H., Chen, G., Xue, L., Zhang, G., Yamamoto, Y., Suzuki, H. Eur. J. Pharmacol. (1992) [Pubmed]
  18. 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. Okafor, C., Liao, R., Perreault-Micale, C., Li, X., Ito, T., Stepanek, A., Doye, A., de Tombe, P., Gwathmey, J.K. Mol. Cell. Biochem. (2003) [Pubmed]
  19. MCI-154, a cardiac Ca2+ sensitizer, reverses the depression in maximal Ca2+-activated force by inorganic phosphate and acidic pH in skinned fiber of guinea pig heart. Kitada, Y. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. (1997) [Pubmed]
  20. Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154. Abe, Y., Sekioka, K., Ishisu, R., Onishi, K., Ueda, Y., Nakano, T. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  21. Effects of MCI-154 and caffeine on Ca(++)-regulated interactions between troponin subunits from bovine heart. Liao, R., Gwathmey, J.K. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  22. Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent. Abe, Y., Kitada, Y., Narimatsu, A., Tobe, A. Eur. J. Pharmacol. (1991) [Pubmed]
  23. MCI-154, a Ca2+ sensitizer, increases survival in cardiomyopathic hamsters. Kawasumi, H., Abe, Y., Ishibashi, A., Kitada, Y. Eur. J. Pharmacol. (1999) [Pubmed]
 
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