Advertisement

New Inotropic Agents for Treatment of Heart Failure

  • Keitaro Hashimoto

Summary

New positive inotropic agents have been synthesized and they are under intensive research to examine whether they are different from older drugs like digitalis and catecholamines in their mechanisms of action and in their clinical effectiveness. Among the positive inotropic agents, those developed by Japanese pharmaceutical laboratories were reviewed mainly in terms of their possible mechanism of action in the cardiac cells. OPC-8212 is orally active and has no chronotropic effect, which may prove beneficial in the treatment of heart failure. It increases intracellular cAMP by PDE inhibition, increases Ca current, and prolongs the duration of action potentials. OPC-8490, with a similar mechanism of action, has vasodilator and positive chronotropic action. MCI-154 is an orally active positive inotropic agent with vasodilator action. The mechanism of action also involves an increase in cAMP, but in addition, sensitization of the contractile elements to Ca has been demonstrated to play a partial role in the inotropic effect. RS-1893, ZSY-27, ZSY-39 and FK664 are orally active positive inotropic agents for which cAMP mechanisms are postulated, but their effectiveness was demonstrated only in experimentally produced heart failure.

Keywords

Inotropic Agent Positive Inotropic Effect Heart Failure Model Positive Inotropic Agent Positive Chronotropic Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Wetzel B, Hauel N (1988) New cardiotonic agents—a promising approach for treatment of heart failure. Trends Pharmacol Sci 9: 166–170PubMedCrossRefGoogle Scholar
  2. 2.
    Endoh M, Yanagisawa T, Taira N, Blinks JR (1986) Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 73 (Suppl III): 117–133Google Scholar
  3. 3.
    Kitada Y, Narimatsu A, Matsumura N, Endo M (1987) 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. J Pharmacol Exp Ther 243: 633–638PubMedGoogle Scholar
  4. 4.
    Taira N (1984) New positive inotropic agents: their modes and mechanisms of action. In: Abe H et al. (eds) Regulation of cardiac function. Japan Sci Soc Press, Tokyo, pp 293–303Google Scholar
  5. 5.
    Yamashita S, Hosokawa T, Kojima M, Mori T, Yabuuchi Y (1984) In vitro and in vivo studies of 3,4-dihydro-6-[4-(3, 4-dimethoxybenzoyl)-1-piperazinyl]-2 (1H)-quinolinone (OPC-8212), a novel positive inotropic drug, in various animals. Arzneimittel Forschung 34: 342–346PubMedGoogle Scholar
  6. 6.
    Hori M, Inoue M, Tamai J, Koretsune Y, Kitakaze M, Iwai K, Ito H, Kitabatake A, Kamada T (1986) Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3, 4-dimethoxybenzoyl)-1-piperazinyl]-2 (1H)-quinolinone (OPC-8212), in the dog with and without β-blocker and Ca2++-antagonist pretreatment. Jpn Circ J 50: 37–44PubMedCrossRefGoogle Scholar
  7. 7.
    Maruyama Y, Nishioka O, Watanabe J, Keitoku M, Satoh S, Isoyama S, Ashikawa K, Ino-Oka E, Takishima T (1986) Effects of OPC-8212, a new positive inotropic agent, and dobutamine on left ventricular global and ischemic regional functions and coronary hemodynamics under coronary artery stenosis. J Cardiovasc Pharmacol 8: 161–169PubMedCrossRefGoogle Scholar
  8. 8.
    Hashimoto K, Yabuuchi Y, Yamashita S, Mori T (1984) Positive inotropic effect of 3, 4-dihydro-6-[4-(3, 4- dimethoxybenoy1)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212) in the dog with experimentally-induced right-sided heart failure. Arzneimittel Forschung 34: 390–393PubMedGoogle Scholar
  9. 9.
    Hashimoto K, Mitsuhashi H (1986) Effects of OPC-8212, a new positive inotropic agent, on canine ventricular arrhythmias. Br J Pharmacol 88: 915–921PubMedGoogle Scholar
  10. 10.
    Yanagisawa T, Ishii K, Taira N (1987) Antitachycardic effect of OPC-8212, a novel cardiotonic agent, on tachycardiac responses of guinea pig isolated right atria to isoproterenol and histamine. J Cardiovasc Pharmacol 10: 47–54PubMedCrossRefGoogle Scholar
  11. 11.
    Mori T, Yamashita S, Hosokawa T, Yabuuchi Y (1988) Cardiovascular effects of OPC-8490, a new positive inotropic agent with vasodilator action, (abstract) Jpn J Pharmacol 46: 130PGoogle Scholar
  12. 12.
    Narimatsu A, Kitada Y, Satoh N, Suzuki R, Okushima (1987) Cardiovascular pharmacology of 6-[4-(4′-pyridy1) aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties. Arzneimittel Forschung 37: 398–406PubMedGoogle Scholar
  13. 13.
    Hosono M, Taira N (1987) Cardiac and coronary vasodilator effects of the novel cardiotonic agent, MCI-154, assessed in isolated, blood-perfused dog heart preparations. J Cardiovasc Pharmacol 10: 692–698PubMedCrossRefGoogle Scholar
  14. 14.
    Kitada Y, Narimatsu A, Suzuki R, Endoh M, Taira N (1987) Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP? J Pharmacol Exp Ther 243: 639–645PubMedGoogle Scholar
  15. 15.
    Miyake S, Shiga H, Koike H, Mizuno H, Yorikane R, Oda T, Iijima Y, Kumakura S, Morisawa Y (1988) Cardiovascular pharmacology of RS-1893, an orally active cardiotonic agent with arterial and venous vasodilator actions. Jpn J Pharmacol 47: 273–283PubMedCrossRefGoogle Scholar
  16. 16.
    Shiga H, Miyake S, Koike H (1988) Echocardiographic study of cardiotonic effects of RS-1893 in conscious beagles with congestive heart failure. (abstract) Jpn J Pharmacol 47: 215PGoogle Scholar
  17. 17.
    Chiba S, Furukawa Y, Saegusa K, Ogiwara Y (1986) Cardiovascular effects of ZSY-27 [5-methyl-6-(4-pyridiny1)-2H-1, 4-thiazine-3(4H)-one-hydrochloridel] in the dog cross-circulated atrial preparation. Jpn Heart J 27: 749–757PubMedCrossRefGoogle Scholar
  18. 18.
    Tanaka H, Tajimi K, Kasai T, Kobayashi K, Nakamura K, Okuaki A (1987) Cardiovascular effects of ZSY-27 in dogs with pentobarbital-induced heart failure. Circulation Control 8 (Supp1): 274–275Google Scholar
  19. 19.
    Tajimi K, Tanaka H, Kasai T, Kobayashi K, Okuaki A (1989) Selective pulmonary vasodilatory effect of ZSY-27 in dogs with pulmonary hypertension due to pulmonary embolism. Circ Care Med 17: 163–165CrossRefGoogle Scholar
  20. 20.
    Esumi K, Sudo Y, Ozaki T, Maeda K, Ono T (1988) Effect of FK664, a new cardioprotective agent, on acutely induced congestive heart failure in anesthetized dogs (abstract) FASEB J 2: A1817Google Scholar

Copyright information

© Springer-Verlag Tokyo 1989

Authors and Affiliations

  • Keitaro Hashimoto
    • 1
  1. 1.Department of PharmacologyYamanashi Medical CollegeYamanashiJapan

Personalised recommendations