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New Horizons for Failing Heart Syndrome pp 187–208Cite as

Mechanisms of Novel Cardiotonic Agents Developed to Treat the Failing Heart Syndrome

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Abstract

Several cardiotonic drugs have been developed as potential therapeutic agents for patients with the failing heart syndrome. These agents act through different but relatively limited subcellular signal-transduction pathways. Accumulation of 3′,5′ -cyclic adenosine monophosphate (cyclic AMP) plays a main role in mediating the cardiotonic effects of most of these agents. Cyclic AMP promotes mobilization of intracellular Ca2+ in association with a decrease in myofibrillar responsiveness to Ca2+, leading to the characteristic positive inotropic and lusitropic effects of these agents. The quantitative relation between the accumulation of cyclic AMP and a positive inotropic effect, however, differs among agents that act on cyclic AMP metabolism via different mechanisms: For a given increase in contractile force, accumulation of cyclic AMP induced by selective cyclic nucleotide phosphodiesterase (PDE) III inhibitors and 31-adrenoceptor partial agonists is much less than that produced by nonselective 3-adrenoceptor agonists or nonselective PDE inhibitors (or both). The relation between the amplitude of Ca2+ transients and the positive inotropic effect differs between selective PDE III inhibitors on the one hand and the β1-adrenoceptor partial agonist denopamine on the other, suggesting intracellular compartmentation of cyclic AMP in myocardial cells. Newly developed Ca2+ sensitizers are expected to be therapeutic agents because of their benefits in cardiac energetics and the absence of potential Ca2+ overload. It became evident from motility assays, in vitro binding of Ca2+ to troponin C, and Ca2+-dependent actomyosin ATPase activity that the processes responsible for the sensitization of myofibrils to Ca2+ involve multiple sites: (1) the binding of Ca2+ to troponin C; (2) thin filament interaction involving Ca2+ regulation sites; and (3) the actin-myosin interface leading to changes in crossbridge cycling in the absence of Ca2+ . In addition, (4) the environments where myofibrils are located may play a crucial role. The therapeutic relevance of these Ca2+ sensitizers and a novel Ca2+ channel promoter awaits the outcome of clinical application of these agents.

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  1. Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-23, Japan

    Masao Endoh

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  1. Masao Endoh
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  1. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606, Japan

    Shigetake Sasayama M.D.

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© 1996 Springer Japan

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Endoh, M. (1996). Mechanisms of Novel Cardiotonic Agents Developed to Treat the Failing Heart Syndrome. In: Sasayama, S. (eds) New Horizons for Failing Heart Syndrome. Springer, Tokyo. https://doi.org/10.1007/978-4-431-66945-6_11

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  • DOI: https://doi.org/10.1007/978-4-431-66945-6_11

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