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Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action

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Summary

OPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1H) - quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10−6 to 10−4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by β-blockade. OPC-18790 (10−5 to 10−4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K+-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 × 10−6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.

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Authors and Affiliations

  1. Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi-cho, 771-01, Tokushima, Japan

    Tetsumi Hosokawa, Toyoki Mori, Hiroyuki Fujiki, Shizuo Kinoshita, Kazumi Takemoto, Takashi Imaizumi, Teruo Noda, Makoto Ohura, Michiaki Tominaga & Youichi Yabuuchi

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  1. Tetsumi Hosokawa
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  2. Toyoki Mori
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  3. Hiroyuki Fujiki
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  4. Shizuo Kinoshita
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  5. Kazumi Takemoto
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  7. Teruo Noda
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  10. Youichi Yabuuchi
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Hosokawa, T., Mori, T., Fujiki, H. et al. Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action. Heart Vessels 7, 66–75 (1992). https://doi.org/10.1007/BF01744451

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  • DOI: https://doi.org/10.1007/BF01744451

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